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1
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Oppizzi L, Hosszu K, Prockop S, Bidgoli A, Bonfim C, Ciccocioppo R, Ruggeri A, Maiers M, Bertaina A, Boelens JJ. Immune Monitoring after Cell Therapy and Hematopoietic Cell Transplantation: Guidelines by the ISCT Stem Cell Engineering Committee. Cytotherapy 2025:S1465-3249(25)00690-5. [PMID: 40493000 DOI: 10.1016/j.jcyt.2025.04.069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 06/12/2025]
Abstract
Allogeneic hematopoietic cell transplantation and cell therapy (TCT) are potentially lifesaving treatments for patients with high-risk hematologic malignancies and life-threatening acquired and genetic hematologic disorders. However, these treatments face significant challenges, particularly in the risks of relapse and severe toxicity, leading to both relapse-related and non-relapse mortality (NRM). The immune system plays a critical role in controlling these risks, but predictive immune biomarkers for relapse and toxicity have yet to be fully established. To better understand factors driving outcomes in TCT recipients, researchers are increasingly relying on minimally invasive specimens for analysis, such as peripheral blood. These liquid biopsies provide a cost-effective and rapid means to evaluate parameters such as minimal residual disease and genomic mutation profiles. The evolution of these techniques opens new possibilities for monitoring immune reconstitution, including tracking immune cell development and the diversity of surface and secreted biomarkers. This review presents a practical guideline for establishing an immune monitoring program tailored to the TCT environment. By adopting a proactive, harmonized approach, such programs can enhance prognosis prediction and enable early relapse detection, potentially surpassing traditional diagnostic methods. While recent advancements are promising, considerable progress is still needed to make liquid biopsies a routine component of clinical practice. © 2025 International Society for Cell & Gene Therapy. Published by Elsevier Inc.
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Affiliation(s)
- Linda Oppizzi
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Kinga Hosszu
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
| | - Susan Prockop
- Dana Farber/Boston Children's Hospital Cancer and Blood Disorders Center, and Department of Pediatrics, Harvard Medical School, Boston Massachusetts, USA
| | - Alan Bidgoli
- Division of Blood and Marrow Transplantation, Children's Healthcare of Atlanta, Aflac Blood and Cancer Disorders Center, Emory University, Atlanta, Georgia, USA
| | - Carmen Bonfim
- Pediatric Blood and Marrow Transplantation Division and Pele Pequeno Principe Research Institute, Hospital Pequeno Principe, Curitiba, Brazil
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Annalisa Ruggeri
- Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Martin Maiers
- Center for International Blood & Marrow Transplant Research (CIBMTR), NMDP, Minneapolis, Minnesota, USA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Jaap Jan Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Bordoni V, Guarracino F, Galaverna F, Bertaina V, Li Pira G, Rosichini M, Pitisci A, Matusali G, Maggi F, Velardi E, Merli P, Locatelli F, Agrati C. Antiviral potential of Vδ2 T cells in children given TCR αβ/CD19 cell-depleted HLA-haploidentical HSCT. Blood Adv 2025; 9:990-1002. [PMID: 39626282 PMCID: PMC11907438 DOI: 10.1182/bloodadvances.2024013902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/06/2024] [Indexed: 02/28/2025] Open
Abstract
ABSTRACT γδ T cells represent key players in immune surveillance after T-cell receptor α/β (αβ)/CD19-depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Although encouraging data are available on the impact of Vδ2-targeting therapy in improving HSCT clinical outcomes, their role in providing antimicrobial immunity is largely unexplored. This study aimed to investigate the antiviral protective profile of Vδ2 T cells in pediatric patients given haplo-HSCT. The characterization of γδ T cells was performed in pediatric recipients (n = 26) in the donor graft and at 30, 60, and 120 days after haplo-HSCT. The antiviral activity of Vδ2 T cells and the cytomegalovirus (CMV)-specific αβ T-cell immunity was analyzed. Early after HSCT, Vδ2 T cells was significantly higher in patients who did not experience viral reactivation (No-VR) than in patients with CMV reactivation. Interestingly, this difference was already present in the grafts. Clustering analysis identified a protective subset of Vδ2 T cells in patients with No-VR, expressing CD16, NKG2D, and CD107a, and producing Th1 cytokines. This subset directly correlated with interleukin-15 and inversely with the CMV DNA level. Stimulated Vδ2 T cells inhibit CMV replication, acquired CD86/HLA-DR molecules, induced HLA-DR on monocytes, and improved the αβ CMV-specific T-cell response. Altogether, these results identify an antiviral protective profile displayed by Vδ2 T cells early after HSCT, and define their ability to inhibit CMV replication, to induce antigen-presenting cell maturation and to improve αβ virus-specific T-cell response, opening a new application of Vδ2-targeting immunotherapy after HSCT, adding the antiviral to the antitumor potential.
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MESH Headings
- Humans
- Hematopoietic Stem Cell Transplantation/methods
- Hematopoietic Stem Cell Transplantation/adverse effects
- Child
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Male
- Female
- Adolescent
- Child, Preschool
- Antigens, CD19/immunology
- Antigens, CD19/metabolism
- Cytomegalovirus Infections/immunology
- Cytomegalovirus Infections/prevention & control
- Cytomegalovirus/immunology
- Transplantation, Haploidentical
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- HLA Antigens
- Lymphocyte Depletion
- Infant
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Affiliation(s)
- Veronica Bordoni
- Research Area of Hematology and Oncology, Unit of Pathogen Specific Immunity, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Federica Guarracino
- Research Area of Hematology and Oncology, Unit of Pathogen Specific Immunity, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Federica Galaverna
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Valentina Bertaina
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giuseppina Li Pira
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Marco Rosichini
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Angela Pitisci
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giulia Matusali
- Lazzaro Spallanzani National Institute for Infectious Diseases, Laboratory of Virology–IRCCS, Rome, Italy
| | - Fabrizio Maggi
- Lazzaro Spallanzani National Institute for Infectious Diseases, Laboratory of Virology–IRCCS, Rome, Italy
| | - Enrico Velardi
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Pietro Merli
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Franco Locatelli
- Research Area of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Maternal and Child Health, Catholic University of the Sacred Heart, Rome, Italy
| | - Chiara Agrati
- Research Area of Hematology and Oncology, Unit of Pathogen Specific Immunity, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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3
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Han G, Stern A, Lee YJ, Li Y, Dahi PB, Tamari R, Gyurkocza B, Jakubowski AA, Papadopoulos EB, Shaffer B, Perales MA, Obeid KM, Young JAH, Papanicolaou GA. Letermovir for Prevention of Recurrent Cytomegalovirus in High-Risk Allogeneic Hematopoietic Cell Transplantation Recipients. Transplant Cell Ther 2025; 31:105.e1-105.e9. [PMID: 39701288 PMCID: PMC11936460 DOI: 10.1016/j.jtct.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 12/21/2024]
Abstract
We evaluated letermovir (LTV) for secondary prophylaxis for cytomegalovirus (CMV) in allogeneic hematopoietic cell transplant recipients (HCT) at high-risk for CMV recurrence. This open-label study was conducted at Memorial Sloan Kettering Cancer Center and the University of Minnesota. Patients with clinically significant CMV infection (cs-CMVi) and ≥1 high-risk criteria for CMV who achieved viral suppression with standard CMV antivirals received LTV secondary prophylaxis for up to 14 weeks. The primary endpoint was cs-CMVi at week 14; secondary endpoints included LTV resistance, CMV end-organ disease (EOD), CMV-related death, and LTV-related adverse events at week 14. Thirty-six patients were analyzed (CMV seropositive, n = 33; T cell-depleted HCT, n = 25; cord blood allograft, n = 5). By week 14 post-transplantation, 5 patients met the primary endpoint of cs-CMVi, for a cumulative incidence of 14.9% (95% confidence interval, 2.6% to 27.1%). Four patients developed LTV breakthrough cs-CMVi (including 2 patients with confirmed LTV resistance). The remaining patient developed rebound cs-CMVi after premature discontinuation of LTV due to enrollment in a clinical trial. There were no cases of CMV EOD, CMV-related death, or LTV-related adverse events by week 14 or by week 24. Our data support that LTV secondary prophylaxis is safe and effective in high-risk HCT recipients.
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Affiliation(s)
- Gyuri Han
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anat Stern
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yeon Joo Lee
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yuxuan Li
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Parastoo B Dahi
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Roni Tamari
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Boglarka Gyurkocza
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Ann A Jakubowski
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Esperanza B Papadopoulos
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Brian Shaffer
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Miguel-Angel Perales
- Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine Weill Cornell Medicine, New York, New York
| | - Karam M Obeid
- Department of Medicine, Division of Infectious Disease, University of Minnesota, Minneapolis, Minnesota
| | - Jo-Anne H Young
- Department of Medicine, Division of Infectious Disease, University of Minnesota, Minneapolis, Minnesota
| | - Genovefa A Papanicolaou
- Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York.
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4
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Yoon E, Shin S, Choi S, Jang JH, Kim K, Kim SJ, Kim WS, Jung CW, Kang ES. QuantiFERON monitor predicts early cytomegalovirus infection and viral burden in allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2024; 26:e14328. [PMID: 38980949 DOI: 10.1111/tid.14328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 05/23/2024] [Accepted: 06/20/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Cytomegalovirus (CMV) infection is a major cause of transplantation-related morbidity and mortality. This study assessed the utility of the QuantiFERON monitor (QFM; Qiagen) for the prediction of early CMV infection and viral burden. METHODS QuantiFERON-CMV (QF-CMV; Qiagen) and QFM were measured at the post-allogeneic hematopoietic stem cell transplantation (HSCT) week 4. CMV DNA was measured at every visit until post-HSCT week 24. The QFM cutoff specific to CMV infection was established. RESULT At the post-HSCT week 4, the QFM cutoff predicting CMV infection was 86.95 IU/mL. While QF-CMV results at the post-HSCT week 4 were associated with high-level CMV infection (CMV DNA ≥ 5,000 IU/mL) but not with CMV infection (CMV DNA ≥ 500 IU/mL), QFM was associated with both CMV infection and high-level CMV infection. Both indeterminate QF-CMV and nonreactive QFM were associated with increased peak CMV DNA. CONCLUSION Low QFM is a risk factor for CMV infection and increased CMV viral loads. QFM at post-HSCT week 4 can be utilized as an assay to predict the risk and burden of early CMV infection in HSCT recipients, in conjunction with other risk factors.
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Affiliation(s)
- Eungjun Yoon
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sunghwan Shin
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Laboratory Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea
| | - Sooin Choi
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Jun Ho Jang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kihyun Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seok Jin Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Won Seog Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chul Won Jung
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eun-Suk Kang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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5
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AlQahtani HY, AlSuhebany N, Alowais SA, AlShehri B, Althemery A, Alghanim A, Alqahtani H, Alkhathran L, Alyaqub M, Alsulimani M, AlHarbi A, Alhatmi H, Almansour S, Almohaya A, Bosaeed M. Characterization of recurrent cytomegalovirus reactivations post allogenic stem cell transplantation in a population with high seropositivity. Virol J 2024; 21:149. [PMID: 38956615 PMCID: PMC11218190 DOI: 10.1186/s12985-024-02421-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 06/21/2024] [Indexed: 07/04/2024] Open
Abstract
OBJECTIVES This study aimed to characterize incidences of CMV reactivations within one year post-allo-SCT and identify risk factors for CMV second reactivation episode in population with high seropositivity where first CMV reactivation episode deemed to be high. METHODS This retrospective cohort study analyzed data from 359 allo-SCT patients aged 14 and older admitted to a tertiary academic hospital. Data on demographic and clinical factors, CMV serostatus, conditioning regimens, graft-versus-host disease prophylaxis, engraftment time, and CMV reactivations were collected. RESULTS First and second CMV reactivations occurred in 88.9% and 18.4% of post-allo-SCT patients respectively. Patients were stratified into two groups based on primary disease necessitating allo-SCT, patients with malignant (Group 1) and non-malignant (Group 2) hematological disease. Factors associated with the second reactivation included cord blood as a stem cell source, human leukocyte antigen mismatch, acute graft-versus-host disease, and hematological malignancies. Patients with non-malignant hematological disease displayed better outcomes, including a higher rate of spontaneous clearance of first CMV reactivation (70% versus 49.4%) and lower rates of second CMV reactivation (9.6% versus 31%) than those with malignant hematological disease. The one-year overall survival rate was 87.7% (95.5% in non-malignant hematological disease and 78.13% in malignant hematological disease). CONCLUSION Our findings are concordant with previous local study in regard to high rate of first CMV reactivation post-allo-SCT. It appears that patients with nonmalignant hematological disease had better outcomes, such as lower second CMV reactivation and higher survival rates compared to patients with malignant hematological disease. Further investigation is needed to identify other factors affecting recurrent CMV reactivations in allo-SCT in patients with malignant hematological disease.
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Affiliation(s)
- Hajar Y AlQahtani
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| | - Nada AlSuhebany
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Shuroug A Alowais
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Bashayer AlShehri
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Abdullah Althemery
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Al Riyadh Province, Saudi Arabia
| | - Amirah Alghanim
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hessa Alqahtani
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Lama Alkhathran
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Majd Alyaqub
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mariam Alsulimani
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Ahmad AlHarbi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hind Alhatmi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Sarah Almansour
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Abdulellah Almohaya
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Mohammed Bosaeed
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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Krueger MB, Bonifacius A, Dragon AC, Santamorena MM, Nashan B, Taubert R, Kalinke U, Maecker-Kolhoff B, Blasczyk R, Eiz-Vesper B. In Vitro Profiling of Commonly Used Post-transplant Immunosuppressants Reveals Distinct Impact on Antiviral T-cell Immunity Towards CMV. Transpl Int 2024; 37:12720. [PMID: 38655204 PMCID: PMC11035762 DOI: 10.3389/ti.2024.12720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/27/2024] [Indexed: 04/26/2024]
Abstract
Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.
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Affiliation(s)
- Markus Benedikt Krueger
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Agnes Bonifacius
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
| | - Anna Christina Dragon
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Maria Michela Santamorena
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Björn Nashan
- Clinic for Hepatopancreaticobiliary Surgery and Transplantation, First Affiliated Hospital, University of Science and Technology of China, Hefei, China
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ulrich Kalinke
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Britta Maecker-Kolhoff
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
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7
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Zhang P, Fleming P, Andoniou CE, Waltner OG, Bhise SS, Martins JP, McEnroe BA, Voigt V, Daly S, Kuns RD, Ekwe AP, Henden AS, Saldan A, Olver S, Varelias A, Smith C, Schmidt CR, Ensbey KS, Legg SR, Sekiguchi T, Minnie SA, Gradwell M, Wagenaar I, Clouston AD, Koyama M, Furlan SN, Kennedy GA, Ward ES, Degli-Esposti MA, Hill GR, Tey SK. IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation. J Clin Invest 2024; 134:e174184. [PMID: 38557487 PMCID: PMC10977988 DOI: 10.1172/jci174184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 02/09/2024] [Indexed: 04/04/2024] Open
Abstract
Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.
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Affiliation(s)
- Ping Zhang
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Peter Fleming
- Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
| | - Christopher E. Andoniou
- Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
| | - Olivia G. Waltner
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Shruti S. Bhise
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Jose Paulo Martins
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | | | - Valentina Voigt
- Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
| | - Sheridan Daly
- Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
| | - Rachel D. Kuns
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Adaeze P. Ekwe
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Andrea S. Henden
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- University of Queensland, St Lucia, Queensland, Australia
- Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
| | - Alda Saldan
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- University of Queensland, St Lucia, Queensland, Australia
| | - Stuart Olver
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Antiopi Varelias
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- University of Queensland, St Lucia, Queensland, Australia
| | - Corey Smith
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Christine R. Schmidt
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Kathleen S. Ensbey
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Samuel R.W. Legg
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Tomoko Sekiguchi
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Simone A. Minnie
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Mark Gradwell
- Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom
| | - Irma Wagenaar
- Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom
| | | | - Motoko Koyama
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Scott N. Furlan
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Pediatrics and
| | - Glen A. Kennedy
- University of Queensland, St Lucia, Queensland, Australia
- Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
| | - E Sally Ward
- Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom
| | - Mariapia A. Degli-Esposti
- Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia
| | - Geoffrey R. Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Medical Oncology, University of Washington, Seattle, Washington, USA
| | - Siok-Keen Tey
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- University of Queensland, St Lucia, Queensland, Australia
- Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
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8
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van der Ploeg K, Sottile R, Kontopoulos T, Shaffer BC, Papanicolaou GA, Maloy MA, Cho C, Robinson KS, Perales MA, Le Luduec JB, Hsu KC. Emergence of human CMV-induced NKG2C+ NK cells is associated with CD8+ T-cell recovery after allogeneic HCT. Blood Adv 2023; 7:5784-5798. [PMID: 37196646 PMCID: PMC10561005 DOI: 10.1182/bloodadvances.2022008952] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 04/19/2023] [Accepted: 04/23/2023] [Indexed: 05/19/2023] Open
Abstract
Cytomegalovirus (CMV) infection is associated with the expansion of a mature NKG2C+FcεR1γ- natural killer (NK) cell population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T-cell-depleted (TCD) allografts. We analyzed peripheral blood lymphocytes from 119 patients at serial time points after infusion of their TCD allograft and compared immune recovery with that in samples obtained from recipients of T-cell-replete (T-replete) (n = 96) or double umbilical cord blood (DUCB) (n = 52) allografts. NKG2C+ NK cells were detected in 92% (45 of 49) of recipients of TCD HCT who experienced CMV reactivation. Although NKG2A+ cells were routinely identifiable early after HCT, NKG2C+ NK cells were identified only after T cells could be detected. T-cell reconstitution occurred at variable times after HCT among patients and predominantly comprised CD8+ T cells. In patients with CMV reactivation, recipients of TCD HCT expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared with patients who received T-replete HCT or DUCB transplantation. NKG2C+ NK cells after TCD HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared with the adaptive the NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of a CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.
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Affiliation(s)
- Kattria van der Ploeg
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rosa Sottile
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Theodota Kontopoulos
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Brian C. Shaffer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Genovefa A. Papanicolaou
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Molly A. Maloy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Christina Cho
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Kevin S. Robinson
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Adult BMT Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Miguel-Angel Perales
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Jean-Benoît Le Luduec
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Katharine C. Hsu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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9
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Panesso M, Uría ML, Renedo B, Esperalba J, Benítez-Carabante MI, Mendoza-Palomar N, Alonso L, Oliveras M, Diaz-de-Heredia C. CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation. Front Pediatr 2023; 11:1197828. [PMID: 37554153 PMCID: PMC10405925 DOI: 10.3389/fped.2023.1197828] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/06/2023] [Indexed: 08/10/2023] Open
Abstract
Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.
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Affiliation(s)
- Melissa Panesso
- Division of Pediatric Oncology and Haematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
| | - María Luz Uría
- Division of Pediatric Oncology and Haematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
| | - Berta Renedo
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
- Pharmacy Division, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Juliana Esperalba
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
- Microbiology Division, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - María Isabel Benítez-Carabante
- Division of Pediatric Oncology and Haematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
| | - Natalia Mendoza-Palomar
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Laura Alonso
- Division of Pediatric Oncology and Haematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
| | - Maria Oliveras
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
- Pharmacy Division, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Cristina Diaz-de-Heredia
- Division of Pediatric Oncology and Haematology, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Institut de Recerca Vall d’Hebron, Barcelona, Spain
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10
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Li X, Liang H, Fan J. Prospects of Cytomegalovirus-Specific T-Cell Receptors in Clinical Diagnosis and Therapy. Viruses 2023; 15:1334. [PMID: 37376633 DOI: 10.3390/v15061334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 06/03/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Human cytomegalovirus (HCMV) is responsible for widespread infections worldwide. In immunocompetent individuals it is typically latent, while infection or reactivation in immunocompromised individuals can result in severe clinical symptoms or even death. Although there has been significant progress in the treatment and diagnosis of HCMV infection in recent years, numerous shortcomings and developmental limitations persist. There is an urgent need to develop innovative, safe, and effective treatments, as well as to explore early and timely diagnostic strategies for HCMV infection. Cell-mediated immune responses are the primary factor controlling HCMV infection and replication, but the protective role of humoral immune responses remains controversial. T-cells, key effector cells of the cellular immune system, are critical for clearing and preventing HCMV infection. The T-cell receptor (TCR) lies at the heart of T-cell immune responses, and its diversity enables the immune system to differentiate between self and non-self. Given the significant influence of cellular immunity on human health and the indispensable role of the TCR in T-cell immune responses, we posit that the impact of TCR on the development of novel diagnostic and prognostic methods, as well as on patient monitoring and management of clinical HCMV infection, will be far-reaching and profound. High-throughput and single-cell sequencing technologies have facilitated unprecedented quantitative detection of TCR diversity. With these current sequencing technologies, researchers have already obtained a vast number of TCR sequences. It is plausible that in the near future studies on TCR repertoires will be instrumental in assessing vaccine efficacy, immunotherapeutic strategies, and the early diagnosis of HCMV infection.
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Affiliation(s)
- Xuejie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Hanying Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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11
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Xia J, Li X, Gui G, Wu J, Gong S, Shang Y, Fan J. Early immune surveillance to predict cytomegalovirus outcomes after allogeneic hematopoietic stem cell transplantation. Front Cell Infect Microbiol 2022; 12:954420. [PMID: 35992173 PMCID: PMC9382130 DOI: 10.3389/fcimb.2022.954420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundThere is no method of predicting human cytomegalovirus (HCMV) outcomes in allogeneic hematopoietic stem cell transplant recipients clinically, leading in some cases to excessive or insufficient antiviral therapy. We evaluated the early immune response of recipients with disparate HCMV outcomes.MethodsThe HCMV outcomes of recipients were determined by long-term monitoring of HCMV DNA levels posttransplant. HCMV IgG and IgM concentrations at 1 week before and 1 week after transplantation, absolute lymphocyte counts, and HCMV-specific IFN-γ secreting cells at 1 month posttransplant were evaluated based on HCMV outcome.ResultsAll recipients were negative for HCMV IgM. Significant differences between recipients with and without HCMV reactivation were observed in pre- and post-transplant HCMV IgG antibody levels, absolute lymphocyte counts, and HCMV-specific IFN-γ secreting cells (P < 0.05). HCMV IgG antibody levels significantly increased after transplantation in recipients with HCMV reactivation (P = 0.032), but not in those without reactivation. Multivariate analysis revealed that except for the absolute lymphocyte count these biomarkers were related to HCMV reactivation, independent of other clinical factors. In time-to-event analyses, lower levels of these biomarkers were associated with an increased 150-day cumulative incidence of HCMV reactivation (log-rank P < 0.05). In recipients with HCMV reactivation, the duration of HCMV DNAemia had negative correlation with HCMV-specific IFN-γ-secreting cells (P = 0.015, r = -0.372). The relationships between the peak HCMV DNA load and absolute lymphocyte count and HCMV-specific IFN-γ-secreting cells followed the same trends (P = 0.026, r = -0.181 and P = 0.010, r = -0.317).ConclusionsHCMV IgG, absolute lymphocyte count, and HCMV-specific IFN-γ secreting cells represent the humoral and cellular immune response. Early monitoring of these immune markers could enable prediction of HCMV outcomes posttransplant and assessment of the severity of HCMV DNAemia.
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Affiliation(s)
- Jintao Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xuejie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Genyong Gui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shengnan Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuxin Shang
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London South Kensington Campus, London, United Kingdom
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Jun Fan,
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12
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Lange J, Rivera-Ballesteros O, Buggert M. Human mucosal tissue-resident memory T cells in health and disease. Mucosal Immunol 2022; 15:389-397. [PMID: 34743182 PMCID: PMC8571012 DOI: 10.1038/s41385-021-00467-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/11/2021] [Accepted: 10/18/2021] [Indexed: 02/04/2023]
Abstract
Memory T cells are fundamental to maintain immune surveillance of the human body. During the past decade, it has become apparent that non-recirculating resident memory T cells (TRMs) form a first line memory response in tissues to tackle re-infections. The fact that TRMs are essential for local immunity highlights the therapeutic potential of targeting this population against tumors and infections. However, similar to other immune subsets, TRMs are heterogenous and may form distinct effector populations with unique functions at diverse tissue sites. Further insight into the mechanisms of how TRM function and respond to pathogens and malignancies at different mucosal sites will help to shape future vaccine and immunotherapeutic approaches. Here, we review the current understanding of TRM function and biology at four major mucosal sites: gastrointestinal tract, lung, head and neck, as well as female reproductive tract. We also summarize our current knowledge of how TRM targets invading pathogens and developing tumor cells at these mucosal sites and contemplate how TRMs may be exploited to protect from infections and cancer.
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Affiliation(s)
- Joshua Lange
- grid.4714.60000 0004 1937 0626Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Olga Rivera-Ballesteros
- grid.4714.60000 0004 1937 0626Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Marcus Buggert
- grid.4714.60000 0004 1937 0626Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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13
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Alonso-Álvarez S, Colado E, Moro-García MA, Alonso-Arias R. Cytomegalovirus in Haematological Tumours. Front Immunol 2021; 12:703256. [PMID: 34733270 PMCID: PMC8558552 DOI: 10.3389/fimmu.2021.703256] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 09/14/2021] [Indexed: 12/11/2022] Open
Abstract
The exquisite coupling between herpesvirus and human beings is the result of millions of years of relationship, coexistence, adaptation, and divergence. It is probably based on the ability to generate a latency that keeps viral activity at a very low level, thereby apparently minimising harm to its host. However, this evolutionary success disappears in immunosuppressed patients, especially in haematological patients. The relevance of infection and reactivation in haematological patients has been a matter of interest, although one fundamentally focused on reactivation in the post-allogeneic stem cell transplant (SCT) patient cohort. Newer transplant modalities have been progressively introduced in clinical settings, with successively more drugs being used to manipulate graft composition and functionality. In addition, new antiviral drugs are available to treat CMV infection. We review the immunological architecture that is key to a favourable outcome in this subset of patients. Less is known about the effects of herpesvirus in terms of mortality or disease progression in patients with other malignant haematological diseases who are treated with immuno-chemotherapy or new molecules, or in patients who receive autologous SCT. The absence of serious consequences in these groups has probably limited the motivation to deepen our knowledge of this aspect. However, the introduction of new therapeutic agents for haematological malignancies has led to a better understanding of how natural killer (NK) cells, CD4+ and CD8+ T lymphocytes, and B lymphocytes interact, and of the role of CMV infection in the context of recently introduced drugs such as Bruton tyrosine kinase (BTK) inhibitors, phosphoinosytol-3-kinase inhibitors, anti-BCL2 drugs, and even CAR-T cells. We analyse the immunological basis and recommendations regarding these scenarios.
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Affiliation(s)
- Sara Alonso-Álvarez
- Haematology and Haemotherapy Department, Hospital Universitario Central de Asturias, Oviedo, Spain.,Laboratory Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain.,Department of Hematologic Malignancies, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
| | - Enrique Colado
- Haematology and Haemotherapy Department, Hospital Universitario Central de Asturias, Oviedo, Spain.,Laboratory Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain.,Department of Hematologic Malignancies, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
| | - Marco A Moro-García
- Laboratory Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain.,Department of Cardiac Pathology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
| | - Rebeca Alonso-Arias
- Department of Cardiac Pathology, Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain.,Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
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14
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Camargo JF, Ebisu Y, Jimenez-Jimenez A, Natori Y, Moroz I, Morris MI, Alencar M, Anderson AD, Lekakis L, Beitinjaneh A, Goodman M, Wang T, Pereira D, Komanduri KV. Lower Incidence of Cytomegalovirus Reactivation Following Post-Transplantation Cyclophosphamide HLA-Mismatched Unrelated Donor Transplantation. Transplant Cell Ther 2021; 27:1017.e1-1017.e7. [PMID: 34543769 DOI: 10.1016/j.jtct.2021.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022]
Abstract
The use of haploidentical or HLA-mismatched unrelated donors (MMUD) allows allogeneic hematopoietic cell transplantation in individuals without suitable matched donors. Post-transplantation cyclophosphamide (PTCy) is used routinely for prevention of graft-versus-host disease in recipients of haploidentical transplants, and its use has been recently explored in MMUD transplantation. We compared the incidence of cytomegalovirus (CMV) reactivation and rate of lymphocyte recovery between PTCy MMUD and alternative transplantation modalities. Single-center retrospective study of 22 consecutive PTCy MMUD recipients transplanted between April 2017 and January 2019. Patients undergoing anti-thymocyte globulin (ATG) MMUD (n = 37) and PTCy haploidentical transplantation (n = 19) between January 2015 and July 2018 served as historical controls. We assessed the incidence of CMV (any viremia) and clinically significant CMV reactivation (cs-CMVi; defined as CMV disease or CMV viremia leading to preemptive treatment) in these 3 groups. Immune reconstitution was assessed by absolute lymphocyte count (ALC) at days 30, 90, 180, and 360 after transplantation. Statistical analyses included Kaplan-Meier plots with a log-rank test, Kruskal-Wallis test, and Fisher's exact test where appropriate, and logistic regression analyses. For PTCy MMUD, PTCy haploidentical and ATG MMUD groups, the 100-day and 200-day incidence of CMV (any viremia) were 41%, 63%, and 77% (P = .02), and 64%, 68%, and 86% (P = .049), respectively. The rate of cs-CMVi was also lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (14% versus 53% and 54% at day 100 [P = .01] and 25% versus 53% and 58% at day 200 [P = .03]). There was a trend toward lower 200-day incidence of cs-CMVi in PTCy MMUD compared to ATG MMUD, even after excluding letermovir-treated patients from the analysis (25% versus 58% [P = .06]). The association between PTCy MMUD and lower risk of cs-CMVi remained significant even after adjusting for letermovir prophylaxis (odds ratio = 0.23, 95% confidence interval, 0.07-0.81 [P = .02]). Day 30 ALC was lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (0.14, 0.33, 0.44 × 109/L, respectively [P = .005) but similar across groups at other time points. PTCy MMUD transplantation was associated with lower incidence of CMV events, independent of the use of CMV prophylaxis. Larger studies are needed.
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Affiliation(s)
- Jose F Camargo
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida.
| | - Yosuke Ebisu
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Antonio Jimenez-Jimenez
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Yoichiro Natori
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Ilona Moroz
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Michele I Morris
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Maritza Alencar
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Anthony D Anderson
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Lazaros Lekakis
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Amer Beitinjaneh
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Mark Goodman
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Trent Wang
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Denise Pereira
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Krishna V Komanduri
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
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15
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Papadopoulou A, Koukoulias K, Alvanou M, Papadopoulos VK, Bousiou Z, Kalaitzidou V, Kika FS, Papalexandri A, Mallouri D, Batsis I, Sakellari I, Anagnostopoulos A, Yannaki E. Patient risk stratification and tailored clinical management of post-transplant CMV-, EBV-, and BKV-infections by monitoring virus-specific T-cell immunity. EJHAEM 2021; 2:428-439. [PMID: 35844677 PMCID: PMC9175754 DOI: 10.1002/jha2.175] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022]
Abstract
Background Despite routine post-transplant viral monitoring and pre-emptive therapy, viral infections remain a major cause of allogeneic hematopoietic cell transplantation-related morbidity and mortality. Objective We here aimed to prospectively assess the kinetics and the magnitude of cytomegalovirus-(CMV), Epstein Barr virus-(EBV), and BK virus-(BKV)-specific T cell responses post-transplant and evaluate their role in guiding therapeutic decisions by patient risk-stratification. Study design The tri-virus-specific immune recovery was assessed by Elispot, in 50 consecutively transplanted patients, on days +20, +30, +60, +100, +150, +200 post-transplant and in case of reactivation, weekly for 1 month. Results The great majority of the patients experienced at least one reactivation, while over 40% of them developed multiple reactivations from more than one of the tested viruses, especially those transplanted from matched or mismatched unrelated donors. The early reconstitution of virus-specific immunity (day +20), favorably correlated with transplant outcomes. Εxpanding levels of CMV-, EBV-, and BKV-specific T cells (VSTs) post-reactivation coincided with decreasing viral load and control of infection. Certain cut-offs of absolute VST numbers or net VST cell expansion post-reactivation were determined, above which, patients with CMV or BKV reactivation had >90% probability of complete response (CR). Conclusion Immune monitoring of virus-specific T-cell reconstitution post-transplant may allow risk-stratification of virus reactivating patients and enable patient-tailored treatment. The identification of individuals with high probability of CR will minimize unnecessary overtreatment and drug-associated toxicity while allowing candidates for pre-emptive intervention with adoptive transfer of VSTs to be appropriately selected.
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Affiliation(s)
- Anastasia Papadopoulou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Kiriakos Koukoulias
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
- Department of Genetics, Development and Molecular Biology, School of BiologyAristotle University of ThessalonikiThessalonikiGreece
| | - Maria Alvanou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | | | - Zoe Bousiou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Vasiliki Kalaitzidou
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Fotini S. Kika
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Apostolia Papalexandri
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Despina Mallouri
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Ioannis Batsis
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Ioanna Sakellari
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Achilles Anagnostopoulos
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
| | - Evangelia Yannaki
- Hematology Department‐Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center“George Papanikolaou” HospitalThessalonikiGreece
- Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
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16
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Jakharia N, Howard D, Riedel DJ. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2021; 13:123-140. [PMID: 34305463 PMCID: PMC8294301 DOI: 10.1007/s40506-021-00253-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2021] [Indexed: 12/15/2022]
Abstract
Purpose of Review Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients. Recent Findings The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial. Summary CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.
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Affiliation(s)
- Niyati Jakharia
- Department of Internal Medicine, Section of Infectious Diseases, Stanford University Hospital, 300 Pasteur Dr., Lane L 134, Stanford, CA 94305 USA
| | - Dianna Howard
- Department of Internal Medicine, Section of Hematology-Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC USA
| | - David J Riedel
- Department of Internal Medicine, Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD USA
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17
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Fuji S, Byrne M, Nagler A, Mohty M, Savani BN. How we can mitigate the side effects associated with systemic glucocorticoid after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2021; 56:1248-1256. [PMID: 33514922 DOI: 10.1038/s41409-020-01205-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 01/30/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with a hematologic disease. Although the clinical outcomes after allo-HCT have significantly improved during the last few decades, graft-versus-host disease (GVHD) is still a major cause of post-HCT morbidity and mortality. Systemic glucocorticoids (GC) remain an integral part of treatment in patients with GVHD including both acute and chronic GVHD. Although it is well-known that usage of systemic GC is associated with various side effects, the short- and long-term effects of GCs in the HCT setting are not well-characterized due to limited published data. In order to clarify this issue, we summarize the information on side effects associated with GCs, focusing specifically on the sequelae of these agents in the early post-HCT period. In instances where limited data are available, we included data from other fields such as autoimmune diseases, given the potential parallels between autoimmune conditions and GVHD.
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Affiliation(s)
- Shigeo Fuji
- Department of Hematology, Osaka International Cancer Institute, Osaka, Japan.
| | - Michael Byrne
- Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN, USA
| | - Arnon Nagler
- Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mohamad Mohty
- Service d'Hématologie Clinique, Hopital Saint-Antoine, Sorbonne University, INSERM UMRs 938, Paris, France
| | - Bipin N Savani
- Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN, USA
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18
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Wagner-Drouet E, Teschner D, Wolschke C, Schäfer-Eckart K, Gärtner J, Mielke S, Schreder M, Kobbe G, Hilgendorf I, Klein S, Verbeek M, Ditschkowski M, Koch M, Lindemann M, Schmidt T, Rascle A, Barabas S, Deml L, Wagner R, Wolff D. Comparison of Cytomegalovirus-Specific Immune Cell Response to Proteins versus Peptides Using an IFN-γ ELISpot Assay after Hematopoietic Stem Cell Transplantation. Diagnostics (Basel) 2021; 11:diagnostics11020312. [PMID: 33671952 PMCID: PMC7919014 DOI: 10.3390/diagnostics11020312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8+ counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.
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Affiliation(s)
- Eva Wagner-Drouet
- Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (E.W.-D.); (D.T.)
| | - Daniel Teschner
- Department of Hematology, Medical Oncology, and Pneumology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (E.W.-D.); (D.T.)
| | - Christine Wolschke
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Eppendorf, Hamburg, Germany;
| | - Kerstin Schäfer-Eckart
- Medizinische Klinik 5, Klinikum Nürnberg Nord, Paracelsus Medizinische Privatuniversität, 90419 Nürnberg, Germany; (K.S.-E.); (J.G.)
| | - Johannes Gärtner
- Medizinische Klinik 5, Klinikum Nürnberg Nord, Paracelsus Medizinische Privatuniversität, 90419 Nürnberg, Germany; (K.S.-E.); (J.G.)
| | - Stephan Mielke
- Department of Medicine II, University Medical Center Würzburg, 97080 Würzburg, Germany; (S.M.); (M.S.)
- Department of Laboratory Medicine, CAST, Karolinska Institutet and University Hospital, 17177 Stockholm, Sweden
| | - Martin Schreder
- Department of Medicine II, University Medical Center Würzburg, 97080 Würzburg, Germany; (S.M.); (M.S.)
| | - Guido Kobbe
- Department of Hematology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany;
| | - Inken Hilgendorf
- Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, 07747 Jena, Germany;
| | - Stefan Klein
- Department of Hematology and Oncology, UMM University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany;
| | - Mareike Verbeek
- Medical Department, Hematology and Oncology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany;
| | - Markus Ditschkowski
- Innere Klinik, Tumorforschung, University Hospital Essen, 45147 Essen, Germany;
| | - Martina Koch
- Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Eppendorf, Hamburg, Germany;
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, 45147 Essen, Germany;
| | - Traudel Schmidt
- Lophius Biosciences, 93053 Regensburg, Germany; (T.S.); (A.R.); (S.B.); (L.D.)
| | - Anne Rascle
- Lophius Biosciences, 93053 Regensburg, Germany; (T.S.); (A.R.); (S.B.); (L.D.)
| | - Sascha Barabas
- Lophius Biosciences, 93053 Regensburg, Germany; (T.S.); (A.R.); (S.B.); (L.D.)
| | - Ludwig Deml
- Lophius Biosciences, 93053 Regensburg, Germany; (T.S.); (A.R.); (S.B.); (L.D.)
| | - Ralf Wagner
- Lophius Biosciences, 93053 Regensburg, Germany; (T.S.); (A.R.); (S.B.); (L.D.)
- Institute of Clinical Microbiology and Hygiene, University Medical Center Regensburg, 93053 Regensburg, Germany
- Correspondence: (R.W.); (D.W.); Tel.: +49-941-944-6452 (R.W.); +49-941-944-5542 (D.W.)
| | - Daniel Wolff
- Department of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, 93053 Regensburg, Germany
- Correspondence: (R.W.); (D.W.); Tel.: +49-941-944-6452 (R.W.); +49-941-944-5542 (D.W.)
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19
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Wagner-Drouet E, Teschner D, Wolschke C, Janson D, Schäfer-Eckart K, Gärtner J, Mielke S, Schreder M, Kobbe G, Kondakci M, Hilgendorf I, von Lilienfeld-Toal M, Klein S, Heidenreich D, Kreil S, Verbeek M, Grass S, Ditschkowski M, Gromke T, Koch M, Lindemann M, Hünig T, Schmidt T, Rascle A, Guldan H, Barabas S, Deml L, Wagner R, Wolff D. Standardized monitoring of cytomegalovirus-specific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. Haematologica 2021; 106:363-374. [PMID: 31879324 PMCID: PMC7849569 DOI: 10.3324/haematol.2019.229252] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 12/18/2019] [Indexed: 12/22/2022] Open
Abstract
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
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Affiliation(s)
- Eva Wagner-Drouet
- Dpt of Hematology, Medical Oncology, and Pneumology, University Medical Center, Mainz, Germany
| | - Daniel Teschner
- Dpt of Hematology, Medical Oncology, and Pneumology, University Medical Center, Mainz, Germany
| | - Christine Wolschke
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Dietlinde Janson
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany
| | - Kerstin Schäfer-Eckart
- Oncology, Hematology and Bone Marrow Transplantation Unit, Klinikum Nord, Nürnberg, Germany
| | - Johannes Gärtner
- Oncology, Hematology and Bone Marrow Transplantation Unit, Klinikum Nord, Nürnberg, Germany
| | - Stephan Mielke
- Department of Laboratory Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Martin Schreder
- First Department of Medicine, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria
| | - Guido Kobbe
- Department of Hematology, University Hospital, Heinrich Heine University Düsseldorf, Germany
| | - Mustafa Kondakci
- Department of Hematology, University Hospital, Heinrich Heine University Düsseldorf, Germany
| | - Inken Hilgendorf
- Klinik f. Innere Medizin II, Abt. Haematol. und Internist. Onkologie, Univ.-Klinikum Jena, Germany
| | | | - Stefan Klein
- Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany
| | - Daniela Heidenreich
- Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany
| | - Sebastian Kreil
- Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany
| | - Mareike Verbeek
- III. Medical Department, Hematology and Oncology, Klinikum rechts der Isar, TUM, Munich, Germany
| | - Sandra Grass
- III. Medical Department, Hematology and Oncology, Klinikum rechts der Isar, TUM, Munich, Germany
| | | | - Tanja Gromke
- Innere Klinik, Tumorforschung, University Hospital Essen, Germany
| | - Martina Koch
- Dpt of Transplantation Surgery, University Medical Center of the JGU, Mainz, Germany
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, Germany
| | - Thomas Hünig
- Institute of Virology and Immunobiology, University Medical Center Würzburg, Germany
| | | | | | | | | | | | - Ralf Wagner
- Institute of Clinical Microbiology and Hygiene, University Medical Center Regensburg, Germany
| | - Daniel Wolff
- Dpt of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, Germany
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20
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Hepatic interferon γ and tumor necrosis factor a expression in infants with neonatal cholestasis and cytomegalovirus infection. Clin Exp Hepatol 2021; 6:367-373. [PMID: 33511286 PMCID: PMC7816637 DOI: 10.5114/ceh.2020.102172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/26/2020] [Indexed: 11/17/2022] Open
Abstract
Aim of the study To determine the hepatic interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) levels in infants with neonatal cholestasis (NC) and associated cytomegalovirus (CMV) infection. Material and methods This study was conducted in 21 infants with NC over a period of 6 months from June 2017 to December 2017 to determine the hepatic IFN-γ and TNF-α levels in infants with NC and associated CMV infection. Results IFN-γ levels were positive in 16 (80%), low positive in 3 (16%) and negative in 1 (5%) patients. High positive and positive TNF-α levels were seen in 9 (56.3%) patients with positive liver CMV PCR and low positive levels were seen in 7 (43.7%) patients with positive liver CMV PCR (odds ratio [OR] = 2.6). Positive IFN-γ was present in 13 (81.3%) patients with positive liver CMV PCR and low positive or negative IFN-γ was seen in 3 (18.7%) patients with positive liver CMV PCR (OR = 2.2). Six (60%) patients with positive or high positive TNF-α levels in liver tissue had biliary atresia (BA) whereas 7 (77.7%) with low positive TNF-α levels had non-BA neonatal hepatitis (OR = 5.25). Six (37.5%) patients with positive IFN-γ had BA whereas 2 (50%) patients with low positive or negative IFN-γ had BA (OR = 0.6). Conclusions There is high prevalence of CMV in liver tissues in patients with NC and elevated TNF-α and IFN-γ levels are seen in these patients. Elevated TNF-α is also seen in patients with BA. The association of elevated TNF-α, BA and CMV infection needs to be evaluated further.
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21
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Zinter MS, Hume JR. Effects of Hematopoietic Cell Transplantation on the Pulmonary Immune Response to Infection. Front Pediatr 2021; 9:634566. [PMID: 33575235 PMCID: PMC7871005 DOI: 10.3389/fped.2021.634566] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/04/2021] [Indexed: 12/20/2022] Open
Abstract
Pulmonary infections are common in hematopoietic cell transplant (HCT) patients of all ages and are associated with high levels of morbidity and mortality. Bacterial, viral, fungal, and parasitic pathogens are all represented as causes of infection. The lung mounts a complex immune response to infection and this response is significantly affected by the pre-HCT conditioning regimen, graft characteristics, and ongoing immunomodulatory therapy. We review the published literature, including animal models as well as human data, to describe what is known about the pulmonary immune response to infection in HCT recipients. Studies have focused on the pulmonary immune response to Aspergillus fumigatus, gram-positive and gram-negative bacteria, and viruses, and show a range of defects associated with both the innate and adaptive immune responses after HCT. There are still many open areas for research, to delineate novel therapeutic targets for pulmonary infections as well as to explore linkages to non-infectious inflammatory lung conditions.
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Affiliation(s)
- Matt S. Zinter
- Department of Pediatrics, Divisions of Critical Care and Bone Marrow Transplantation, University of California, San Francisco, San Francisco, CA, United States
| | - Janet R. Hume
- Department of Pediatrics, Division of Critical Care Medicine, University of Minnesota Medical School, Minnesota, MN, United States
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22
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Annaloro C, Serpenti F, Saporiti G, Galassi G, Cavallaro F, Grifoni F, Goldaniga M, Baldini L, Onida F. Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications. Front Immunol 2021; 11:569381. [PMID: 33552044 PMCID: PMC7854690 DOI: 10.3389/fimmu.2020.569381] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.
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Affiliation(s)
- Claudio Annaloro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Fabio Serpenti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giorgia Saporiti
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Giulia Galassi
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesca Cavallaro
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Federica Grifoni
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Maria Goldaniga
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Luca Baldini
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
| | - Francesco Onida
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano, Italy
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23
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Chemaly RF, El Haddad L, Winston DJ, Rowley SD, Mulane KM, Chandrasekar P, Avery RK, Hari P, Peggs KS, Kumar D, Nath R, Ljungman P, Mossad SB, Dadwal SS, Blanchard T, Shah DP, Jiang Y, Ariza-Heredia E. Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study. Clin Infect Dis 2020; 71:2365-2374. [PMID: 32076709 PMCID: PMC7713694 DOI: 10.1093/cid/ciz1210] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 01/02/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients. CMV cell-mediated immunity (CMV-CMI) as determined by a peptide-based enzyme-linked immunospot (ELISPOT) CMV assay may identify patients at risk for clinically significant CMV infection (CS-CMVi). METHODS The CS-CMVi was defined as CMV viremia and/or disease necessitating antiviral therapy. CMV-CMI was characterized as high when the intermediate-early 1 (IE-1) antigen spot counts (SPCs) were >100 (cutoff 1) or when the IE-1 and phosphoprotein 65 antigen SPCs were both >100 SPCs per 250 000 cells (cutoff 2), and a low CMV-CMI when SPCs were below these thresholds. In this prospective multicenter study, we evaluated CMV-CMI every 2 weeks from the pretransplant period until 6 months posttransplantation in 241 allo-HCT recipients with positive CMV serostatus. The primary endpoint was CS-CMVi occurring within 2 weeks of the last measurement of CMV-CMI. RESULTS CS-CMVi occurred in 70 allo-HCT recipients (29%). CMV-CMI was low in patients who experienced CS-CMVi (94%), whereas those who had a high CMV-CMI were less likely to have CS-CMVi (P < .0001). Patients with CS-CMVi had higher all-cause mortality (P = .007), especially those with low CMV-CMI (P = .035). On multivariable analysis, CMV-CMI, sex, race, antithymocyte globulin, and steroid use were independent predictors of CS-CMVi, and the time from transplant to engraftment was the only predictor of mortality. CONCLUSIONS Measurement of CMV-CMI using a novel ELISPOT assay would be useful clinically to monitor allo-HCT recipients and distinguish between those at risk of developing CS-CMVi and requiring antiviral prophylaxis or therapy and those who are protected.
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Affiliation(s)
- Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lynn El Haddad
- Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Drew J Winston
- Ronald Reagan UCLA Medical Center, Los Angeles, California, USA
| | | | - Kathleen M Mulane
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Pranatharthi Chandrasekar
- Division of Infectious Diseases, Department of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Robin K Avery
- Division of Infectious Diseases (Transplant Oncology), Johns Hopkins University, Baltimore, Maryland, USA
| | - Parameswaran Hari
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Karl S Peggs
- Department of Haematology, University College London Cancer Institute and University College London Hospitals National Health Service Foundation Trust, London, United Kingdom
| | - Deepali Kumar
- Transplant Infectious Diseases, University Health Network, Toronto, Ontario, Canada
| | - Rajneesh Nath
- Bone Marrow Transplant, Banner MD Anderson Cancer Center, Gilbert, Arizona, USA
| | - Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Sherif B Mossad
- Department of Infectious Diseases, Respiratory Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Sanjeet S Dadwal
- Division of Infectious Diseases, City of Hope, Duarte, California, USA
| | - Ted Blanchard
- Oxford Immunotec USA, Inc, Charlotte, North Carolina, USA
| | - Dimpy P Shah
- Department of Epidemiology and Biostatistics, University of Texas Health, San Antonio, Texas, USA
| | - Ying Jiang
- Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ella Ariza-Heredia
- Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Sugawara E, Matsui K, Amasaki Y. Cytomegalovirus Enteritis in a Patient with Rheumatoid Arthritis Receiving Baricitinib. J Rheumatol 2020; 47:1835-1836. [PMID: 33262287 DOI: 10.3899/jrheum.191395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Eri Sugawara
- Department of Rheumatology, Tonan Hospital, Sapporo, Japan.
| | - Kazuo Matsui
- Department of Rheumatology, Tonan Hospital, Sapporo, Japan
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25
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The association of CMV with NK-cell reconstitution depends on graft source: results from BMT CTN-0201 samples. Blood Adv 2020; 3:2465-2469. [PMID: 31427278 DOI: 10.1182/bloodadvances.2019000298] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/21/2019] [Indexed: 11/20/2022] Open
Abstract
Key Points
CMV reactivation was associated with the maturation of reconstituting NK cells from BM, but not PB, unrelated donor grafts. CMV reactivation was associated with CD8+, but not CD4+, T-cell recovery, more so after BM than PB unrelated donor grafts.
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26
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Sekine T, Perez-Potti A, Nguyen S, Gorin JB, Wu VH, Gostick E, Llewellyn-Lacey S, Hammer Q, Falck-Jones S, Vangeti S, Yu M, Smed-Sörensen A, Gaballa A, Uhlin M, Sandberg JK, Brander C, Nowak P, Goepfert PA, Price DA, Betts MR, Buggert M. TOX is expressed by exhausted and polyfunctional human effector memory CD8 + T cells. Sci Immunol 2020; 5:5/49/eaba7918. [PMID: 32620560 DOI: 10.1126/sciimmunol.aba7918] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/22/2020] [Indexed: 12/30/2022]
Abstract
CD8+ T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8+ T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8+ T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8+ T cell landscape. Here, we demonstrate that circulating TOX+ CD8+ T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8+ T cells generally expressed TOX, whereas naive and early-differentiated memory CD8+ T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8+ T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8+ T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8+ T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8+ T cell subsets and not exclusively linked to exhaustion.
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Affiliation(s)
- Takuya Sekine
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - André Perez-Potti
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Son Nguyen
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jean-Baptiste Gorin
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Vincent H Wu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Emma Gostick
- Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
| | - Sian Llewellyn-Lacey
- Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
| | - Quirin Hammer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Sara Falck-Jones
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Sindhu Vangeti
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Meng Yu
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Anna Smed-Sörensen
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed Gaballa
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Michael Uhlin
- Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.,Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Johan K Sandberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Christian Brander
- IrsiCaixa AIDS Research Institute, Badalona, Spain.,Universitat de Vic-Universitat Central de Catalunya, Vic, Spain.,Institució Catalana de Recerca i Estudis Avançats, ICREA, Barcelona, Spain
| | - Piotr Nowak
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paul A Goepfert
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK.,Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK
| | - Michael R Betts
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marcus Buggert
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
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27
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El Haddad L, Ariza-Heredia E, Shah DP, Jiang Y, Blanchard T, Ghantoji SS, El Chaer F, El-Haddad D, Prayag A, Nesher L, Rezvani K, Shpall E, Chemaly RF. The Ability of a Cytomegalovirus ELISPOT Assay to Predict Outcome of Low-Level CMV Reactivation in Hematopoietic Cell Transplant Recipients. J Infect Dis 2020; 219:898-907. [PMID: 30295846 DOI: 10.1093/infdis/jiy592] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/04/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infections in hematopoietic cell transplant (HCT) recipients cause substantial morbidity and mortality. CMV cell-mediated immunity (CMV-CMI) can be determined by levels of interferon gamma (IFN-γ) production using an enzyme-linked immunospot (ELISPOT) CMV assay (T-SPOT.CMV assay). In this study, we evaluated the ability of this assay to predict the outcome of low-level CMV reactivation in HCT recipients. METHODS We followed 55 HCT recipients with low-level CMV reactivation up to 8 weeks from enrollment. Progression to clinically significant CMV infection (CS-CMVi) was defined as a CMV load >1000 IU/mL or > 500 IU/mL in patients receiving matched related/autologous or matched unrelated transplants, respectively, and initiation of antiviral treatment. RESULTS Progression to CS-CMVi occurred in 31 (56%) of the HCT recipients. Spot counts of CMV-specific pp65 and IE1 antigens were significantly lower in patients who had CS-CMVi than in patients who did not. On multivariate analysis, the ELISPOT CMV responses and steroids use were the only predictors of progression to CS-CMVi. CONCLUSIONS A strong association between low CMV-CMI and progression to CS-CMVi was observed in HCT recipients. The implementation of serial monitoring of CMV-CMI may identify patients at risk of progression to CS-CMVi that require antiviral therapy.
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Affiliation(s)
- Lynn El Haddad
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Ella Ariza-Heredia
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Dimpy P Shah
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Ying Jiang
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Ted Blanchard
- Oxford Immunotec Incorporation, Marlborough, Massachusetts
| | - Shashank S Ghantoji
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Firas El Chaer
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Danielle El-Haddad
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Amrita Prayag
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Lior Nesher
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
| | - Katy Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston
| | - Elizabeth Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston
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28
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Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, Hubacek P, Navarro D, Cordonnier C, Ward KN. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). THE LANCET. INFECTIOUS DISEASES 2019; 19:e260-e272. [PMID: 31153807 DOI: 10.1016/s1473-3099(19)30107-0] [Citation(s) in RCA: 312] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 01/05/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022]
Abstract
Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.
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Affiliation(s)
- Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, and Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | | | - Christine Robin
- Assistance Publique-Hopitaux de Paris, Department of Hematology, Henri Mondor Hospital and Université Paris-Est Créteil, Créteil, France
| | - Roberto Crocchiolo
- Servizio Immunoematologia e Medicina Trasfusionale, Azienda Socio Sanitaria Territoriale di Bergamo Ovest, Treviglio, Italy
| | - Hermann Einsele
- Medizinische Klinik und Poliklinik II, Julius Maximilians Universitaet, Würzburg, Germany
| | - Joshua A Hill
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Petr Hubacek
- Department of Medical Microbiology and Department of Paediatric Haematology and Oncology, Second Faculty of Medicine of Motol University Hospital and Charles University, Prague, Czech Republic
| | - David Navarro
- Microbiology Service, Hospital Clínico Universitario, Instituto de Investigación INCLIVA, Valencia, Spain; Department of Microbiology, School of Medicine, University of Valencia, Valencia, Spain
| | - Catherine Cordonnier
- Assistance Publique-Hopitaux de Paris, Department of Hematology, Henri Mondor Hospital and Université Paris-Est Créteil, Créteil, France
| | - Katherine N Ward
- Division of Infection and Immunity, University College London, London, UK
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29
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Stern L, Withers B, Avdic S, Gottlieb D, Abendroth A, Blyth E, Slobedman B. Human Cytomegalovirus Latency and Reactivation in Allogeneic Hematopoietic Stem Cell Transplant Recipients. Front Microbiol 2019; 10:1186. [PMID: 31191499 PMCID: PMC6546901 DOI: 10.3389/fmicb.2019.01186] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 05/09/2019] [Indexed: 12/14/2022] Open
Abstract
Human cytomegalovirus (HCMV) reactivation is a major infectious cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). HCMV is a ubiquitous beta-herpesvirus which asymptomatically infects immunocompetent individuals but establishes lifelong latency, with the potential to reactivate to a life-threatening productive infection when the host immune system is suppressed or compromised. Opportunistic HCMV reactivation is the most common viral complication following engraftment after HSCT and is associated with a marked increase in non-relapse mortality, which appears to be linked to complex effects on post-transplant immune recovery. This minireview explores the cellular sites of HCMV latency and reactivation in HSCT recipients and provides an overview of the risk factors for HCMV reactivation post-HSCT. The impact of HCMV in shaping post-transplant immune reconstitution and its relationship with patient outcomes such as relapse and graft-versus-host disease will be discussed. Finally, we survey current and emerging strategies to prevent and control HCMV reactivation in HSCT recipients, with recent developments including adoptive T cell therapies to accelerate HCMV-specific T cell reconstitution and new anti-HCMV drug therapy for HCMV reactivation after HSCT.
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Affiliation(s)
- Lauren Stern
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Barbara Withers
- Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Selmir Avdic
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia
| | - David Gottlieb
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia.,Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, NSW, Australia
| | - Allison Abendroth
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Emily Blyth
- Westmead Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.,Sydney Cellular Therapies Laboratory, Westmead, NSW, Australia.,Blood and Marrow Transplant Unit, Westmead Hospital, Sydney, NSW, Australia
| | - Barry Slobedman
- Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
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30
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Zöllner SK, Herbrüggen H, Kolve H, Mihailovic N, Schubert F, Reicherts C, Rössig C, Groll AH. Cytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2019; 21:e13089. [PMID: 30972869 DOI: 10.1111/tid.13089] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/19/2019] [Accepted: 03/23/2019] [Indexed: 11/28/2022]
Abstract
Cytomegalovirus retinitis (CMVR) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). However, little is known about its incidence, strategies for ophthalmic surveillance, and timely implementation of adequate antiviral treatment in pediatric allogeneic HSCT recipients. We provide a retrospective analysis of the epidemiology and clinical features of CMVR in pediatric allogeneic HSCT patients transplanted at our center over a 16-year period. Two patients of this cohort with leukemia are presented. Our analysis is supplemented by a systematic review on pediatric patients with leukemia and CMVR in the setting of allogeneic HSCT. The overall incidence of CMVR in our cohort was 1% (4/338) and 14.2% (3/21) in leukemic patients. In published cases, CMVR occurred at a median of 143 days after transplantation, and, in the majority of patients, was preceded by CMV detection in blood by a median of 93 days. Continued immune suppression following engraftment likely triggers CMVR. Preemptive treatment with ganciclovir as standard is usually successful. Foscarnet is used in case of resistance to ganciclovir or drug-induced granulocytopenia. Overall, CMVR after HSCT in pediatric leukemic patients is rare, but a potentially higher vulnerability of this population for involvement of the eye warrants a standardized ophthalmological examination plan.
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Affiliation(s)
- Stefan K Zöllner
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Heidrun Herbrüggen
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Hedwig Kolve
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.,Pharmacy Department, University Hospital Muenster, Muenster, Germany
| | - Natasa Mihailovic
- Department of Ophthalmology, University Hospital Muenster, Muenster, Germany
| | - Friederike Schubert
- Department of Ophthalmology, University Hospital Muenster, Muenster, Germany
| | | | - Claudia Rössig
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
| | - Andreas H Groll
- Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
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31
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Camargo JF, Anderson AD, Rosa R, Kimble E, Komanduri KV, Morris MI. Use of maintenance therapy and incidence of recurrent Cytomegalovirus DNAemia among allogeneic hematopoietic cell transplant recipients. Transpl Infect Dis 2019; 21:e13054. [PMID: 30689300 DOI: 10.1111/tid.13054] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 11/28/2018] [Accepted: 01/15/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is the most common infection following hematopoietic cell transplantation (HCT). Preemptive antiviral therapy is highly effective at halting viral replication and preventing CMV disease; however, recurrence rates after clearance of CMV DNAemia are high (50-70%). Current treatment guidelines recommend maintenance therapy after initial clearance. Yet, the effectiveness of this intervention to prevent recurrence is not well defined. OBJECTIVES We aimed to assess the impact of maintenance therapy on the probability of recurrent CMV in allogeneic HCT recipients with early CMV reactivation. STUDY DESIGN Sixty-six patients with an initial episode of early CMV reactivation who achieved viral clearance in response to preemptive therapy were included. We compared the incidence of recurrent CMV DNAemia in patients who received maintenance therapy vs those who underwent early discontinuation of antiviral therapy. RESULTS Recurrence occurred in 47/64 (73%) patients, including 11/14 (79%) patients without maintenance therapy and 36/50 (72%) of patients who received maintenance therapy (P = 0.74). The propensity score adjusted risk ratio for the effect of maintenance therapy on recurrence was 0.89 (95% CI 0.64-1.25; P = 0.41). In a time to event analysis using the unweighted cohort, the 90-day probability of CMV recurrence was similar between patient groups independent of maintenance therapy administration (54% vs 64% for maintenance vs non-maintenance groups, respectively; log-rank P = 0.37). CONCLUSION These data suggest that maintenance antiviral therapy does not reduce the incidence of CMV recurrence while off therapy and is of limited value in HCT recipients who have successfully eradicated CMV DNAemia in response to preemptive therapy. Larger studies in this area are needed.
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Affiliation(s)
- Jose F Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Anthony D Anderson
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Rossana Rosa
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Erik Kimble
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Krishna V Komanduri
- Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Michele I Morris
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
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32
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Cheng YW, Phelps E, Ganapini V, Khan N, Ouyang F, Xu H, Khanna S, Tariq R, Friedman-Moraco RJ, Woodworth MH, Dhere T, Kraft CS, Kao D, Smith J, Le L, El-Nachef N, Kaur N, Kowsika S, Ehrlich A, Smith M, Safdar N, Misch EA, Allegretti JR, Flynn A, Kassam Z, Sharfuddin A, Vuppalanchi R, Fischer M. Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience. Am J Transplant 2019; 19:501-511. [PMID: 30085388 PMCID: PMC6349556 DOI: 10.1111/ajt.15058] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/30/2018] [Accepted: 07/31/2018] [Indexed: 02/06/2023]
Abstract
Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.
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Affiliation(s)
- Yao-Wen Cheng
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Emmalee Phelps
- Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Vincent Ganapini
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Noor Khan
- Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Fangqian Ouyang
- Department of Biostatistics, The Richard M. Fairbanks School of Public Health and School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Huiping Xu
- Department of Biostatistics, The Richard M. Fairbanks School of Public Health and School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Sahil Khanna
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Raseen Tariq
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Michael H. Woodworth
- Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA
| | - Tanvi Dhere
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA
| | - Colleen S. Kraft
- Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Justin Smith
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Lien Le
- Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Najwa El-Nachef
- Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Nirmal Kaur
- Division of Gastroenterology, Department of Medicine, Henry Ford Medical Center, Detroit, MI, USA
| | - Sree Kowsika
- Division of Gastroenterology, Department of Medicine, Henry Ford Medical Center, Detroit, MI, USA
| | - Adam Ehrlich
- Division of Gastroenterology, Department of Medicine, Temple University, Philadelphia, PA, USA
| | - Michael Smith
- Division of Gastroenterology, Department of Medicine, Temple University, Philadelphia, PA, USA
| | - Nasia Safdar
- Division of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- William S. Middleton Memorial Veterans Hospital, Madison WI, USA
| | - Elizabeth Ann Misch
- Division of Infectious Diseases, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jessica R. Allegretti
- Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Ann Flynn
- Division of Gastroenterology, Department of Medicine, University of Utah, Salt Lake City, UT, USA
| | | | - Asif Sharfuddin
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Monika Fischer
- Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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33
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Zhang R, Zhang Y, Hu J, Wu W, Chen X, Lu Z, Yang R, Huang Y, Fan J. Specific T-cell receptor gene transfer enhances immune response: A potential therapeutic strategy for the control of human cytomegalovirus infection in immunocompromised patients. Cell Immunol 2019; 336:58-65. [PMID: 30626494 DOI: 10.1016/j.cellimm.2018.12.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/20/2018] [Accepted: 12/31/2018] [Indexed: 12/24/2022]
Abstract
Human cytomegalovirus (HCMV) infection is a leading cause of morbidity and mortality in immunocompromised patients, but no specific therapeutic strategy is effective clinically, despite recent achievements. HCMV-specific T-cell therapy was thought to be helpful for the management of HCMV infection. To conduct a deep exploration, we investigated the possibility of engineering peripheral blood mononuclear cells (PBMCs) from immunocompetent and immunocompromised subjects with specific T-cell receptor (TCR) genes. CD8-positive T cells that specifically bind to NLV pentamers could be generated by transferring TCR genes to PBMCs from immunocompetent and immunocompromised subjects. The generation of functional T cells varied among transduction of different PBMCs. The numbers of IFN-γ-secreting T cells increased significantly in immunocompetent and immunodeficient PBMCs, but were unchanged in immune-reconstituted PBMCs. TCR gene transfer is a potential therapeutic strategy for controlling HCMV infection in immunocompromised patients. The transfer of TCR genes into immunocompetent and immunodeficient PBMCs would be more meaningful in response to HCMV infection than would the transfer into immune-reconstituted PBMCs.
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Affiliation(s)
- Runan Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Yanyue Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Jianhua Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Xiaoming Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Zhongjie Lu
- Department of Radiotherapy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Rong Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Yaping Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China.
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Deep functional immunophenotyping predicts risk of cytomegalovirus reactivation after hematopoietic cell transplantation. Blood 2018; 133:867-877. [PMID: 30573634 DOI: 10.1182/blood-2018-10-878918] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 12/16/2018] [Indexed: 12/12/2022] Open
Abstract
Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8+ T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n = 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n = 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n = 21): experienced clinically significant CMV. Two CMV-specific CD8+ T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-2-IFN-γ+TNF-α-MIP-1β+), found at increased levels among NC; and (ii) the protective signature (PS; IL-2+IFN-γ+TNF-α+MIP-1β+) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P = .02; and 40% vs 12%; P = .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8+ T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.
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Jin A, Feng J, Wang Z, Jiang L, Hu Y, Zhao K, Huang H. Severe dyspnea caused by rapid enlargement of cervical lymph node in a relapsed/refractory B-cell lymphoma patient following chimeric antigen receptor T-cell therapy. Bone Marrow Transplant 2018; 54:969-972. [PMID: 30563981 DOI: 10.1038/s41409-018-0412-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/19/2018] [Indexed: 11/10/2022]
Abstract
Adoptive transfer of T cells modified to express chimeric antigen receptors (CARs) targeting CD19 (CART19s) has demonstrated impressive results in treating B-cell malignancies. Although CART19-induced complications have been gradually recognized, local cytokine-release syndrome (CRS) at particular parts of the body has not been extensively studied. In this paper, we firstly present a successfully treated case of severe dyspnea caused by the rapid enlargement of cervical lymph node following CART19 therapy in a relapsed/refractory DLBCL patient, with emphasis on the recognition, workup, and treatment. This report reminds for a careful evaluation and observation of the pre-existing mass, which could enlarge rapidly again as a result of CRS and be life threatening, in the CART therapy.
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Affiliation(s)
- Aiyun Jin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Jingjing Feng
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Zhudan Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Li Jiang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Yongxian Hu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Kui Zhao
- PET/CT Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Institute of Hematology, Zhejiang University, Hangzhou, China. .,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
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36
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Divining T-cell targets for cancer immunotherapy. Blood 2018; 132:1861-1863. [PMID: 30385487 DOI: 10.1182/blood-2018-09-873588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Widmann T, Sester U, Schmidt T, Gärtner BC, Schubert J, Pfreundschuh M, Sester M. Rapid reconstitution of CMV-specific T-cells after stem-cell transplantation. Eur J Haematol 2018; 101:38-47. [PMID: 29652096 DOI: 10.1111/ejh.13077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2018] [Indexed: 01/08/2023]
Abstract
OBJECTIVE As reconstitution of virus-specific T-cells is critical to control cytomegalovirus (CMV)-viremia following stem-cell transplantation (SCT), we characterized the dynamics in CMV-specific T-cell reconstitution after SCT. METHODS Cytomegalovirus-specific T-cells from 51 SCT-recipients were prospectively quantified and phenotypically characterised by intracellular cytokine-staining after specific stimulation and HLA class-I-specific pentamers using flow cytometry. RESULTS Cytomegalovirus-specific CD4 T-cells reconstituted after a median of 2.3 (IQR, 2.0-3.0) weeks following autografting, and 4.0 (IQR, 3.0-5.6) weeks after allografting, with CMV-specific T-cells originating from donors and/or recipients. The time for reconstitution of CMV-specific CD4 and CD8 T-cells did not differ (P = .58). Factors delaying the time to initial reconstitution of CMV-specific CD4 T-cells included a negative recipient serostatus (P = .016) and CMV-viremia (P = .026). Percentages of CMV-specific CD4 T-cells significantly increased over time and reached a plateau after 90 days (P = .043). Relative CMV-specific CD4 T-cell levels remained higher in long-term transplant recipients compared with those in controls (P < .0001). However, due to persisting lymphopenia, absolute numbers of CMV-specific T-cells were similar as in controls. CONCLUSION Cytomegalovirus-specific T-cells rapidly reconstitute after SCT and their percentages remain high in the long term. In the face of persistent lymphopenia, this results in similar absolute numbers of CMV-specific T-cells as in controls to ensure sufficient pathogen control.
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Affiliation(s)
- Thomas Widmann
- Department of Internal Medicine I, Saarland University, Homburg, Germany
| | - Urban Sester
- Department of Internal Medicine IV, Saarland University, Homburg, Germany
| | - Tina Schmidt
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Barbara C Gärtner
- Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany
| | - Jörg Schubert
- Department of Internal Medicine I, Saarland University, Homburg, Germany
| | | | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
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Davies JK, Brennan LL, Wingard JR, Cogle CR, Kapoor N, Shah AJ, Dey BR, Spitzer TR, de Lima M, Cooper LJ, Thall PF, Champlin RE, Nadler LM, Guinan EC. Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation. Clin Cancer Res 2018; 24:4098-4109. [PMID: 29769208 DOI: 10.1158/1078-0432.ccr-18-0449] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/06/2018] [Accepted: 05/09/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098-109. ©2018 AACR.
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Affiliation(s)
- Jeff K Davies
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - John R Wingard
- University of Florida College of Medicine, Gainesville, Florida
| | | | - Neena Kapoor
- Children's Hospital Los Angeles, Los Angeles, California
| | - Ami J Shah
- Division of Stem Cell Transplantation and Regenerative Medicine, Lucille Packard Children's Hospital, Stanford University School of Medicine, Stanford, California
| | - Bimalangshu R Dey
- Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts
| | - Thomas R Spitzer
- Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts
| | - Marcos de Lima
- Bone Marrow Transplant, University Hospital Cleveland Medical Center, Cleveland, Ohio
| | - Laurence J Cooper
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peter F Thall
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Richard E Champlin
- Department of Stem Cell Transplant and Cellular Therapies, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lee M Nadler
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Eva C Guinan
- Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. .,Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts
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Shams El-Din AA, El-Desoukey NA, Amin Tawadrous DG, Fouad NMBED, Abdel-Mooti M, Hotar SF. The potential association of CMV-specific CD8+ T lymphocyte reconstitution with the risk of CMV reactivation and persistency in post allogeneic stem cell transplant patients. ACTA ACUST UNITED AC 2018; 23:463-469. [PMID: 29313439 DOI: 10.1080/10245332.2017.1422686] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES development of cytomegalovirus (CMV)-specific CD8+ T cell response is crucial in preventing symptomatic CMV infection specially, in stem cell transplant (SCT) patients. The aim of this study was to evaluate CMV-specific CD8+ T cell reconstitution in allogeneic SCT recipients and to study the possible association between CMV-specific CD8+ T cell recovery with protection from CMV reactivation and persistency. METHODS Human leuKocyte antigen (HLA)-tetramers were used for CMV-specific CD8+ cell quantitation by Flow cytometry in twenty post-allogeneic SCT patients. RESULTS Nine patients (45%) developed rapid recovery of CMV-specific CD8+ cells, among them; 7 patients (78%) had no CMV reactivation in the first 95 days post-transplant. Five patients had developed persistent CMV viremia; all of them had not developed CMV-specific CD8+ recovery till day 95 post-transplant. Patients with persistent CMV viremia had a statistically significant lower means of CMV-specific CD8+ percent and absolute count compared to those without persistent viremia (p = .001, .015), respectively. DISCUSSION The incidence of CMV reactivation and persistency was higher among patients with delayed CMV-specific CD8+ reconstitution in the first 95 days post-transplant. CONCLUSION CMV-specific CD8+ cells can help in categorizing patients into risk groups: (early recovery/low risk) and (delayed recovery/increased risk), this tool may guide clinicians in the selection of patients who may profit from prophylactic antiviral therapy and frequent viral monitoring.
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Affiliation(s)
- Ahmed Ali Shams El-Din
- a Clinical and Chemical Pathology, Faculty of Medicine , Cairo University , Giza , Egypt
| | - Nermeen Ahmed El-Desoukey
- b Clinical and Chemical Pathology, The BMT Unit, Faculty of Medicine , Cairo University , Giza , Egypt
| | | | | | | | - Said Fathy Hotar
- d Clinical and Chemical Pathology, Egyptian Anti Doping Lab , International Medical Center , Cairo , Egypt
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40
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Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol 2018; 15:47-62. [PMID: 28925994 PMCID: PMC6733403 DOI: 10.1038/nrclinonc.2017.148] [Citation(s) in RCA: 1727] [Impact Index Per Article: 246.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.
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Affiliation(s)
- Sattva S Neelapu
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Sudhakar Tummala
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - William Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Cristina Gutierrez
- Department of Critical Care, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Frederick L Locke
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, Florida 33613, USA
| | - Krishna V Komanduri
- Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, University of Miami, 1475 Northwest 12 th Avenue, Miami, Florida 33136, USA
| | - Yi Lin
- Division of Hematology, Mayo Clinic, 200 First Street South West, Rochester, Minnesota 55905, USA
| | - Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Jason Westin
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Alison M Gulbis
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Monica E Loghin
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - John F de Groot
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Sherry Adkins
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Suzanne E Davis
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Patrick Hwu
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
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Camargo JF, Kimble E, Rosa R, Shimose LA, Bueno MX, Jeyakumar N, Morris MI, Abbo LM, Simkins J, Alencar MC, Benjamin C, Wieder E, Jimenez A, Beitinjaneh A, Goodman M, Byrnes JJ, Lekakis LJ, Pereira D, Komanduri KV. Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients. Biol Blood Marrow Transplant 2017; 24:806-814. [PMID: 29217388 DOI: 10.1016/j.bbmt.2017.11.038] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/28/2017] [Indexed: 12/25/2022]
Abstract
The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.
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Affiliation(s)
- Jose F Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida.
| | - Erik Kimble
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Rossana Rosa
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Luis A Shimose
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Maria X Bueno
- Department of Medicine, Jackson Memorial Hospital, Miami, Florida
| | - Nikeshan Jeyakumar
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Michele I Morris
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Lilian M Abbo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Jacques Simkins
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Maritza C Alencar
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Cara Benjamin
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Eric Wieder
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Antonio Jimenez
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Amer Beitinjaneh
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Mark Goodman
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - John J Byrnes
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Lazaros J Lekakis
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Denise Pereira
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Krishna V Komanduri
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, Miami, Florida
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Yanagisawa K, Ogawa Y, Hosogai M, Todokoro D, Mitsui T, Yokohama A, Kishi S, Handa H. Cytomegalovirus retinitis followed by immune recovery uveitis in an elderly patient with rheumatoid arthritis undergoing administration of methotrexate and tofacitinib combination therapy. J Infect Chemother 2017; 23:572-575. [DOI: 10.1016/j.jiac.2017.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 02/21/2017] [Accepted: 03/07/2017] [Indexed: 11/28/2022]
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Lilleri D, Gerna G. Strategies to control human cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. Immunotherapy 2017; 8:1135-49. [PMID: 27485084 DOI: 10.2217/imt-2015-0028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Human cytomegalovirus (HCMV) represents the major viral complication after hematopoietic stem cell transplantation. HCMV infection may be controlled by the reconstituting immune system and remain subclinical or can lead to severe systemic and/or organ disease (mainly pneumonia and gastroenteritis) when immune reconstitution is delayed or impaired. In order to prevent the occurrence of HCMV disease, a prompt diagnosis of HCMV infection is mandatory. The adoption of pre-emptive therapy strategies guided by virological monitoring dramatically reduced the occurrence of HCMV disease. However, late-onset end-organ disease may occur in some patients with apparent immune reconstitution. In the near future, introduction of immunological monitoring and immunotherapies could markedly improve management of HCMV infection.
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Affiliation(s)
- Daniele Lilleri
- Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.,Università della Svizzera Italiana, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
| | - Giuseppe Gerna
- Laboratori Sperimentali di Ricerca-Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Marchesi F, Pimpinelli F, Ensoli F, Mengarelli A. Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant. Hematol Oncol 2017; 36:381-391. [DOI: 10.1002/hon.2453] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 05/28/2017] [Accepted: 06/05/2017] [Indexed: 12/13/2022]
Affiliation(s)
- F. Marchesi
- Hematology and Stem Cell Transplant Unit; Regina Elena National Cancer Institute; Rome Italy
| | - F. Pimpinelli
- Molecular Virology, Pathology and Microbiology Laboratory; San Gallicano Dermatological Institute; Rome Italy
| | - F. Ensoli
- Molecular Virology, Pathology and Microbiology Laboratory; San Gallicano Dermatological Institute; Rome Italy
| | - A. Mengarelli
- Hematology and Stem Cell Transplant Unit; Regina Elena National Cancer Institute; Rome Italy
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45
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Ogonek J, Verma K, Schultze-Florey C, Varanasi P, Luther S, Schweier P, Kühnau W, Göhring G, Dammann E, Stadler M, Ganser A, Koehl U, Koenecke C, Weissinger EM, Hambach L. Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation. THE JOURNAL OF IMMUNOLOGY 2017. [DOI: 10.4049/jimmunol.1601992] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther 2017. [PMID: 28641094 DOI: 10.1016/j.hemonc.2017.05.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite the refinements in molecular methods for the detection of cytomegalovirus (CMV) and the advent of highly effective preemptive strategies, CMV remains a leading cause of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. CMV can cause tissue-invasive disease including pneumonia, hepatitis, colitis, retinitis, and encephalitis. Mortality in HCT recipients with CMV disease can be as high as 60%. CMV infection has been associated with increased risk of secondary bacterial and fungal infections, increased risk of graft-versus-host disease, and high rates of non-relapse mortality following HCT. The risk of CMV is highly dependent on the donor (D) and the recipient (R) serostatus (D-/R+>D+/R+>D+/R->D-/R-). Among allogeneic HCT recipients, high-dose corticosteroids, T-cell depletion, graft-versus-host disease, and mismatched or unrelated donors constitute the main predisposing factors. However, not all seropositive individuals with these risk factors develop CMV, which strongly suggests that host factors, such as those regulating CMV-specific T-cell responses, play a major role in predisposition to CMV in HCT recipients. Here, we discuss emerging concepts in CMV infection in HCT with emphasis on immunological factors that govern CMV reactivation and the applicability of immune monitoring to understand correlates of pathogenesis and its potential to guide clinical decision making.
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Affiliation(s)
- Jose F Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Krishna V Komanduri
- Departments of Medicine, Microbiology and Immunology and Adult Stem Cell Transplant Program, Sylvester Cancer Center, University of Miami, Miami, FL, USA.
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Gea-Banacloche J, Komanduri KV, Carpenter P, Paczesny S, Sarantopoulos S, Young JA, El Kassar N, Le RQ, Schultz KR, Griffith LM, Savani BN, Wingard JR. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report. Biol Blood Marrow Transplant 2017; 23:870-881. [PMID: 27751936 PMCID: PMC5392182 DOI: 10.1016/j.bbmt.2016.10.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 10/05/2016] [Indexed: 12/11/2022]
Abstract
Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged.
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Affiliation(s)
- Juan Gea-Banacloche
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland.
| | - Krishna V Komanduri
- Sylvester Adult Stem Cell Transplant Program, University of Miami, Coral Gables, Florida
| | - Paul Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine Pediatrics, Seattle, Washington
| | - Sophie Paczesny
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Stefanie Sarantopoulos
- Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine and Duke Cancer Institute, Durham, North Carolina
| | - Jo-Anne Young
- Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Nahed El Kassar
- National Heart, Lung and Blood Institute, Bethesda, Maryland
| | - Robert Q Le
- Medical Officer, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
| | - Kirk R Schultz
- Professor of Pediatrics, UBC, Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital and Research Institute, Vancouver, Canada
| | - Linda M Griffith
- Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Bipin N Savani
- Long Term Transplant Clinic, Vanderbilt University Medical Center, Nashville, Tennessee
| | - John R Wingard
- University of Florida Health Cancer Center, Gainesville, Florida; Bone Marrow Transplant Program, Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida
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Wu Z, Zhang H, Jin M, Liang H, Huang Y, Yang R, Gui G, Wang H, Gong S, Wang J, Fan J. Relationship between T-cell receptor beta chain sequences and human cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients. Mol Med Rep 2017; 15:3898-3904. [PMID: 28440401 DOI: 10.3892/mmr.2017.6453] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 02/10/2017] [Indexed: 11/05/2022] Open
Abstract
In the present study, clonal amplifications of T-cell receptor β variable (TCR BV) linked to human cytomegalovirus (HCMV) infection were detected in recipients of allogeneic hematopoietic stem cell transplants (HSCT), and certain relationships between them were identified. Furthermore, the relationship between TCR BV sequences and HCMV infections was investigated. The results indicated that the 3 recipients of HSCT had monoclonal expansion of specific TCR BV clones following HSCT. Among these recipients, 2 suffered from pp65 and immediate early (IE) antigenemia. These patients demonstrated preferential expansion of TCR BV9 (QVRGGTDTQ) and TCR BV11 (VATDFQ). The remaining recipient did not express TCR BV9 and TCR BV11, nor did this individual have pp65 and IE antigenemia. These results suggest that expression of TCR BV9 and TCR BV11 may be associated with HCMV antigenemia, and may be involved in the immune response. The amino acid sequences 'QVRGGTDTQ' and 'VATDFQ' may be involved in HCMV reactivation in patients who have undergone HSCT. Assessment of the TCR BV families may provide valuable insight into HCMV pathogenesis and may aid in the diagnosis and therapy for HSCT recipients infected with HCMV.
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Affiliation(s)
- Zhihua Wu
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Huiping Zhang
- Department of Clinical Laboratory, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Min Jin
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Hanying Liang
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Yaping Huang
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Rong Yang
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Genyong Gui
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Huiqi Wang
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Shengnan Gong
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jindong Wang
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Jun Fan
- Virology Department, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, Weissinger E. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2016; 7:507. [PMID: 27909435 PMCID: PMC5112259 DOI: 10.3389/fimmu.2016.00507] [Citation(s) in RCA: 301] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/02/2016] [Indexed: 12/17/2022] Open
Abstract
The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT.
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Affiliation(s)
- Justyna Ogonek
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Mateja Kralj Juric
- BMT, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Sakhila Ghimire
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | - Pavankumar Reddy Varanasi
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Ernst Holler
- Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
| | | | - Eva Weissinger
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
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50
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Kim T, Lee YM, Lee SO, Choi SH, Kim YS, Woo JH, Sung H, Jung JH, Shin S, Kim YH, Kang YA, Lee YS, Lee JH, Lee JH, Lee KH, Park SK, Han DJ, Kim SH. Differences of cytomegalovirus diseases between kidney and hematopoietic stem cell transplant recipients during preemptive therapy. Korean J Intern Med 2016; 31:961-70. [PMID: 27055664 PMCID: PMC5016278 DOI: 10.3904/kjim.2015.079] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 05/22/2015] [Accepted: 06/30/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/AIMS Cytomegalovirus (CMV) surveillance and preemptive therapy is a widely-used strategy for preventing CMV disease in transplant recipients. However, there are limited data on the incidence and patterns of CMV disease during the preemptive period. Thus, we investigated the incidence and pattern of tissue-invasive CMV disease in CMV seropositive kidney transplantation (KT) and hematopoietic stem cell transplantation (HCT) recipients during preemptive therapy. METHODS We prospectively identified patients with tissue-invasive CMV disease among 664 KT (90%) and 496 HCT (96%) recipients who were D+/R+ (both donor and recipient seropositive) during a 4-year period. RESULTS The incidence rates of CMV disease were 4.1/100 person-years (4%, 27/664) in KT recipients and 5.0/100 person-years (4%, 21/496) in HCT recipients. Twenty-six (96%) of the KT recipients with CMV disease had gastrointestinal CMV, whereas 17 (81%) of the HCT recipients had gastrointestinal CMV and 4 (19%) had CMV retinitis. Thus, CMV retinitis was more common among HCT recipients (p = 0.03). All 27 KT recipients with CMV disease suffered abrupt onset of CMV disease before or during preemptive therapy; 10 (48%) of the 21 HCT recipients with CMV disease were also classified in this way but the other 11 (52%) were classified as CMV disease following successful ganciclovir preemptive therapy (p < 0.001). CONCLUSIONS The incidence of CMV disease was about 4% in both KT and HCT recipients during preemptive therapy. However, CMV retinitis and CMV disease as a relapsed infection were more frequently found among HCT recipients.
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Affiliation(s)
- Tark Kim
- Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yu-Mi Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Department of Infectious Diseases, Inje University Busan Paik Hospital, Busan, Korea
| | - Sang-Oh Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang-Ho Choi
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yang Soo Kim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun Hee Woo
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Heungsup Sung
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joo Hee Jung
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Shin
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Hoon Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-Ah Kang
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-Shin Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jung-Hee Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Je-Hwan Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoo-Hyung Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Su-Kil Park
- Department of Nephrology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Duck Jong Han
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Han Kim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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