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Leonhard J, Schaier M, Kälble F, Zeier M, Steinborn A. Exhaustion of CD8 + central memory responder T cell differentiation provokes non-melanoma skin cancer in elderly kidney transplant recipients. Front Immunol 2023; 14:1164284. [PMID: 37287988 PMCID: PMC10242110 DOI: 10.3389/fimmu.2023.1164284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 04/24/2023] [Indexed: 06/09/2023] Open
Abstract
Introduction Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). Methods In this study, we separately investigated the differentiation of CD8+ regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing de-novo NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7+CD45RA+CD31+ recent thymic emigrant (RTE) cells differentiate via CD45RA-CD31+ memory (CD31+ memory) cells, via resting mature naïve (MN) cells or via direct proliferation into CD45RA-CD31- memory (CD31- memory) cells, consisting of both CCR7+CD45RA- central memory (CM) and CCR7-CD45RA- effector memory (EM) cells. Results We found that both RTE Treg and Tresp differentiation via CD31+ memory Tregs/Tresps was age-independently increased in KTR, who developed de novo NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8+ Treg/Tresp ratio, suggesting this ratio as a reliable marker for de-novo NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained via conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. Discussion In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8+ Tregs more than that of CD8+ Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.
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Affiliation(s)
- Jonas Leonhard
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Matthias Schaier
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Florian Kälble
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Andrea Steinborn
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
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2
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Llinàs-Mallol L, Raïch-Regué D, Pascual J, Crespo M. Alloimmune risk assessment for antibody-mediated rejection in kidney transplantation: A practical proposal. Transplant Rev (Orlando) 2023; 37:100745. [PMID: 36572001 DOI: 10.1016/j.trre.2022.100745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022]
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although an improvement in graft survival has been observed in the last decades with the use of different immunosuppressive drugs, this is still limited in time with antibody-mediated rejection being a main cause of graft-loss. Immune monitoring and risk assessment of antibody-mediated rejection before and after kidney transplantation with useful biomarkers is key to tailoring treatments to achieve the best outcomes. Here, we provide a review of the rationale and several accessible tools for immune monitoring, from the most classic to the modern ones. Finally, we end up discussing a practical proposal for alloimmune risk assessment in kidney transplantation, including histocompatibility leukocyte antigen (HLA) and non-HLA antibodies, HLA molecular mismatch analysis and characterization of peripheral blood immune cells.
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Affiliation(s)
- Laura Llinàs-Mallol
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Dàlia Raïch-Regué
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Julio Pascual
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
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3
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Mehranzadeh E, Crende O, Badiola I, Garcia-Gallastegi P. What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors? Biomedicines 2022; 10:biomedicines10123292. [PMID: 36552048 PMCID: PMC9776400 DOI: 10.3390/biomedicines10123292] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/28/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases such as Alzheimer's and cancer. Cancer cells are secretory cells that send signals to the tumor microenvironment (TME), remodeling the surrounding space for their own benefits. One of the most important components of the TME is the immune system of the tumor. In this review, we describe recent discoveries that link PCs to the immune escape of tumors. Among PCs, many findings have determined the role of Furin (PC3) as a paramount enzyme causing the TME to induce tumor immune evasion. The overexpression of various cytokines and proteins, for instance, IL10 and TGF-B, moves the TME towards the presence of Tregs and, consequently, immune tolerance. Furthermore, Furin is implicated in the regulation of macrophage activity that contributes to the increased impairment of DCs (dendritic cells) and T effector cells. Moreover, Furin interferes in the MHC Class_1 proteolytic cleavage in the trans-Golgi network. In tumors, the T cytotoxic lymphocytes (CTLs) response is impeded by the PD1 receptor (PD1-R) located on CTLs and its ligand, PDL1, located on cancer cells. The inhibition of Furin is a subtle means of enhancing the antitumor response by repressing PD-1 expression in tumors or macrophage cells. The impacts of other PCs in tumor immune escape have not yet been clarified to the extent that Furin has. Accordingly, the influence of other types of PCs in tumor immune escape is a promising topic for further consideration.
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Affiliation(s)
- Elham Mehranzadeh
- Cell Biology and Histology Department, Faculty of Medicine and Nursery, University of the Basque Country (UPV/EHU), Barrio Sarriena, sn., 48940 Leioa, Spain
| | - Olatz Crende
- Cell Biology and Histology Department, Faculty of Medicine and Nursery, University of the Basque Country (UPV/EHU), Barrio Sarriena, sn., 48940 Leioa, Spain
| | - Iker Badiola
- Cell Biology and Histology Department, Faculty of Medicine and Nursery, University of the Basque Country (UPV/EHU), Barrio Sarriena, sn., 48940 Leioa, Spain
- Nanokide Therapeutics SL, Ed. ZITEK, Barrio Sarriena, sn., 48940 Leioa, Spain
| | - Patricia Garcia-Gallastegi
- Physiology Department, Faculty of Medicine and Nursery, University of the Basque Country (UPV/EHU), Barrio Sarriena, sn., 48940 Leioa, Spain
- Correspondence:
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4
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Bottomley MJ, Massey PR, Thuraisingham R, Doyle A, Rao S, Bibee KP, Bouwes Bavinck JN, Jambusaria-Pahlajani A, Harwood CA. Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework. Transpl Int 2022; 35:10880. [PMID: 36484063 PMCID: PMC9722441 DOI: 10.3389/ti.2022.10880] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/10/2022] [Indexed: 11/23/2022]
Abstract
Cutaneous squamous cell carcinoma (CSCC) is a major cause of morbidity and mortality after organ transplant. Many patients subsequently develop multiple CSCC following a first CSCC, and the risk of metastasis and death is significantly increased compared to the general population. Post-transplant CSCC represents a disease at the interface of dermatology and transplant medicine. Both systemic chemoprevention and modulation of immunosuppression are frequently employed in patients with multiple CSCC, yet there is little consensus on their use after first CSCC to reduce risk of subsequent tumors. While relatively few controlled trials have been undertaken, extrapolation of observational data suggests the most effective interventions may be at the time of first CSCC. We review the need for intervention after a first post-transplant CSCC and evidence for use of various approaches as secondary prevention, before discussing barriers preventing engagement with this approach and finally highlight areas for future research. Close collaboration between specialties to ensure prompt deployment of these interventions after a first CSCC may improve patient outcomes.
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Affiliation(s)
- Matthew J. Bottomley
- Chinese Academy of Medical Sciences Oxford Institute (CAMS-COI), Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom,Oxford Transplant Unit, Oxford University Hospitals, NHS Foundation Trust, Oxford, United Kingdom,*Correspondence: Matthew J. Bottomley,
| | | | - Raj Thuraisingham
- Department of Renal Medicine and Transplantation, Barts Health NHS Trust, London, United Kingdom
| | - Alden Doyle
- Department of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Swati Rao
- Department of Medicine, University of Virginia, Charlottesville, VA, United States
| | - Kristin P. Bibee
- Department of Dermatology, School of Medicine, John Hopkins University, Baltimore, MD, United States
| | | | - Anokhi Jambusaria-Pahlajani
- Division of Dermatology, Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, United States
| | - Catherine A. Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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5
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Bernaldo-de-Quirós E, Pion M, Martínez-Bonet M, Correa-Rocha R. A New Generation of Cell Therapies Employing Regulatory T Cells (Treg) to Induce Immune Tolerance in Pediatric Transplantation. Front Pediatr 2022; 10:862807. [PMID: 35633970 PMCID: PMC9130702 DOI: 10.3389/fped.2022.862807] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Kidney transplantation is the most common solid organ transplant and the preferred treatment for pediatric patients with end-stage renal disease, but it is still not a definitive solution due to immune graft rejection. Regulatory T cells (Treg) and their control over effector T cells is a crucial and intrinsic tolerance mechanism in limiting excessive immune responses. In the case of transplants, Treg are important for the survival of the transplanted organ, and their dysregulation could increase the risk of rejection in transplanted children. Chronic immunosuppression to prevent rejection, for which Treg are especially sensitive, have a detrimental effect on Treg counts, decreasing the Treg/T-effector balance. Cell therapy with Treg cells is a promising approach to restore this imbalance, promoting tolerance and thus increasing graft survival. However, the strategies used to date that employ peripheral blood as a Treg source have shown limited efficacy. Moreover, it is not possible to use this approach in pediatric patients due to the limited volume of blood that can be extracted from children. Here, we outline our innovative strategy that employs the thymus removed during pediatric cardiac surgeries as a source of therapeutic Treg that could make this therapy accessible to transplanted children. The advantageous properties and the massive amount of Treg cells obtained from pediatric thymic tissue (thyTreg) opens a new possibility for Treg therapies to prevent rejection in pediatric kidney transplants. We are recruiting patients in a clinical trial to prevent rejection in heart-transplanted children through the infusion of autologous thyTreg cells (NCT04924491). If its efficacy is confirmed, thyTreg therapy may establish a new paradigm in preventing organ rejection in pediatric transplants, and their allogeneic use would extend its application to other solid organ transplantation.
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Affiliation(s)
- Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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6
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Rossi E, Schinzari G, Maiorano BA, Esposito I, Acampora A, Romagnoli J, Stefani AD, Regno LD, Lancellotta V, Fionda B, Tagliaferri L, Peris K, Tortora G. Immune-checkpoint inhibitors in renal transplanted patients affected by melanoma: a systematic review. Immunotherapy 2021; 14:65-75. [PMID: 34751039 DOI: 10.2217/imt-2021-0195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Kidney transplantation leads to an increased risk of cancer. Melanoma is one of the most frequent neoplasms in kidney transplant recipients. Transplanted patients were excluded from trials with checkpoint inhibitors in melanoma. The authors performed a systematic review regarding the use of anti-PD1 and anti-CTLA4 agents in renal transplanted patients with melanoma. Thirty-four cases were included (24 progressive disease, eight partial responses and one stable disease) but no complete response were reported. Fourteen graft rejections were observed, especially with anti-PD1 agent. The median time from the start of immune-checkpoint inhibitor and rejection was 21 days. Response rate was similar between patients with rejection and patients without rejection. The benefit of immune-checkpoint inhibitors versus the risk of allograft rejection should be carefully weighted for each patient. A multidisciplinary approach should be considered to discuss the most appropriate treatment for every case, given the aggressiveness of melanoma in these subsets of patients.
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Affiliation(s)
- Ernesto Rossi
- Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Giovanni Schinzari
- Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia.,Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, 00168, Italia
| | - Brigida Anna Maiorano
- Unità di Oncologia, Fondazione Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo (FG), 71013, Italia
| | - Ilaria Esposito
- Dermatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Anna Acampora
- Sezione di Igiene, Dipartimento Universitario di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Jacopo Romagnoli
- Trapianti di Rene, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia.,Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, 00168, Italia
| | - Alessandro Di Stefani
- Dermatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Laura Del Regno
- Dermatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Valentina Lancellotta
- Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Bruno Fionda
- Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Luca Tagliaferri
- Radioterapia Oncologica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia
| | - Ketty Peris
- Dermatologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia.,Dermatologia, Università Cattolica del Sacro Cuore, Roma, 00168, Italia
| | - Giampaolo Tortora
- Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, 00168, Italia.,Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, 00168, Italia
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7
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Thet Z, Lam AK, Ranganathan D, Aung SY, Han T, Khoo TK. Reducing non-melanoma skin cancer risk in renal transplant recipients. Nephrology (Carlton) 2021; 26:907-919. [PMID: 34240786 DOI: 10.1111/nep.13939] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/11/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022]
Abstract
With an increasing number of renal transplant recipients (RTRs) and improving patient survival, a higher incidence of non-melanoma skin cancer (NMSC) has been observed. NMSC in RTRs are often more numerous and biologically more aggressive than the general population, thus contributing towards an increase in morbidity and to a lesser degree, mortality. The resultant cumulative health and financial burden is a recognized concern. Proposed strategies in mitigating risks of developing NMSC and early therapeutic options thereof include tailored modification of immunosuppressants in conjunction with sun protection in all transplant patients. This review highlights the clinical and financial burden of transplant-associated skin cancers, carcinogenic mechanisms in association with immunosuppression, importance of skin cancer awareness campaign and integrated transplant skin clinic, and the potential role of chemoprotective agents. A scheme is proposed for primary and secondary prevention of NMSC based on the available evidence.
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Affiliation(s)
- Zaw Thet
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia.,Department of Nephrology, Central Queensland Hospital and Health Service, Rockhampton, Queensland, Australia
| | - Alfred K Lam
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.,Pathology Queensland, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Dwarakanathan Ranganathan
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia.,Department of Nephrology, Metro North Hospital and Health Service, Herston, Queensland, Australia
| | - Soe Yu Aung
- Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.,Department of Oncology, Central Queensland Hospital and Health Service, Rockhampton, Queensland, Australia
| | - Thin Han
- Department of Nephrology, Central Queensland Hospital and Health Service, Rockhampton, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Tien K Khoo
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia.,School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia
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8
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Desai R, Coxon AT, Dunn GP. Therapeutic applications of the cancer immunoediting hypothesis. Semin Cancer Biol 2021; 78:63-77. [PMID: 33711414 DOI: 10.1016/j.semcancer.2021.03.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/15/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer.
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Affiliation(s)
- Rupen Desai
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrew T Coxon
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
| | - Gavin P Dunn
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
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9
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Early Posttransplant Mobilization of Monocytic Myeloid-derived Suppressor Cell Correlates With Increase in Soluble Immunosuppressive Factors and Predicts Cancer in Kidney Recipients. Transplantation 2021; 104:2599-2608. [PMID: 32068661 DOI: 10.1097/tp.0000000000003179] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) increase in patients with cancer and are associated with poor prognosis; however, their role in transplantation is not yet understood. Here we aimed to study the MDSC effects on the evolution of kidney transplant recipients (KTRs). METHODS A cohort of 229 KTRs was prospectively analyzed. Two myeloid cells subsets. CD11bCD33CD14CD15HLA-DR (monocytic MDSC [M-MDSC]) and CD11bCD33CD14CD15HLA-DR (monocytes), were defined by flow cytometry. The suppressive capacity of myeloid cells was tested in cocultures with autologous lymphocytes. Suppressive soluble factors, cytokines, anti-HLA antibodies, and total antioxidant capacity were quantified in plasma. RESULTS Pretransplant, M-MDSC, and monocytes were similar in KTRs and healthy volunteers. M-MDSCs increased immediately posttransplantation and suppressed CD4 and CD8 T cells proliferation. M-MDSCs remained high for 1 y posttransplantation. Higher M-MDSC counts at day 14 posttransplant were observed in patients who subsequently developed cancer, and KTRs with higher M-MDSC at day 14 had significantly lower malignancy-free survival. Day 14 M-MDSC >179.2 per microliter conferred 6.98 times (95% confidence interval, 1.28-37.69) more risk to develop cancer, independently from age, gender, and immunosuppression. Early posttransplant M-MDSCs were lower in patients with enhanced alloimmune response as represented by anti-HLA sensitization. M-MDSC counts correlated with higher circulatory suppressive factors arginase-1 and interleukin-10, and lower total antioxidant capacity. CONCLUSIONS Early posttransplant mobilization of M-MDSCs predicts cancer and adds risk as an independent factor. M-MDSC may favor an immunosuppressive environment that promotes tumoral development.
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10
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Courivaud C, Bamoulid J, Crepin T, Gaiffe E, Laheurte C, Saas P, Ducloux D. Pre-transplant Thymic Function Predicts Is Associated With Patient Death After Kidney Transplantation. Front Immunol 2020; 11:1653. [PMID: 32903778 PMCID: PMC7438875 DOI: 10.3389/fimmu.2020.01653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022] Open
Abstract
Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54–4.39 for each decrease of 1 log in RTE; p < 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43–12.13; p = 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11–3.51 for each decrease of 1 log in RTE; p = 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.
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Affiliation(s)
- Cécile Courivaud
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,Univ. Bourgogne Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon, France.,Structure Fédérative de Recherche, SFR FED4234, Besançon, France.,CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France
| | - Jamal Bamoulid
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,Univ. Bourgogne Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon, France.,Structure Fédérative de Recherche, SFR FED4234, Besançon, France.,CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France
| | - Thomas Crepin
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,Univ. Bourgogne Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon, France.,Structure Fédérative de Recherche, SFR FED4234, Besançon, France.,CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France
| | - Emilie Gaiffe
- CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France.,CHU Besançon, CIC Biothérapie, INSERM CIC1431, Besançon, France
| | - Caroline Laheurte
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,EFS Bourgogne Franche-Comté, Plateforme de Biomonitoring, CIC 1431/UMR1098, Besançon, France
| | - Philippe Saas
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,Univ. Bourgogne Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon, France.,Structure Fédérative de Recherche, SFR FED4234, Besançon, France.,CHU Besançon, CIC Biothérapie, INSERM CIC1431, Besançon, France.,EFS Bourgogne Franche-Comté, Plateforme de Biomonitoring, CIC 1431/UMR1098, Besançon, France
| | - Didier Ducloux
- Inserm, UMR1098, Federation Hospitalo-Universitaire INCREASE, Besançon, France.,Univ. Bourgogne Franche-Comté, Faculté de Médecine et de Pharmacie, LabEx LipSTIC, Besançon, France.,Structure Fédérative de Recherche, SFR FED4234, Besançon, France.,CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, Besançon, France.,CHU Besançon, CIC Biothérapie, INSERM CIC1431, Besançon, France
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11
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Pontrelli P, Rascio F, Zaza G, Accetturo M, Simone S, Infante B, Furian L, Castellano G, Ditonno P, Battaglia M, Cormio L, Carrieri G, Lupo A, Rigotti P, Gesualdo L, Stallone G, Grandaliano G. Interleukin-27 is a potential marker for the onset of post-transplant malignancies. Nephrol Dial Transplant 2019; 34:157-166. [PMID: 30059989 DOI: 10.1093/ndt/gfy206] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022] Open
Abstract
Background Malignancies represent the third leading cause of post-transplant mortality worldwide. The main challenge for transplant physicians is a timely diagnosis of this condition. The aim of the study was to identify a soluble diagnostic marker for monitoring the development of post-transplant malignancies. Methods This is a multicentre, observational, perspective, case-control study. We enrolled 47 patients with post-transplant solid neoplasia. As a control group we employed 106 transplant recipients without a history of neoplasia and matched them with cases for the main demographic and clinical features. We investigated the transcriptomic profiles of peripheral blood mononuclear cells from kidney graft recipients with and without post-transplant malignancies enrolled in two of the participating centres, randomly selected from the whole study population. Microarray results were confirmed by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in the remaining patients from the same transplant centres and validated in a further independent group enrolled in two different transplant centres. Results We identified 535 differentially expressed genes comparing patients with and without post-transplant malignancies (fold change ≥2.5; false discovery rate <5%). The cancer pathway was closely related to gene expression data, and one of the most down-regulated genes in this pathway was interleukin-27 (IL-27), a cytokine regulating anti-tumour immunity. Quantitative PCR and ELISA confirmed the microarray data. Interestingly, IL-27 plasma levels were able to discriminate patients with post-transplant neoplasia with a specificity of 80% and a sensitivity of 81%. This observation was confirmed in an independent set of patients from two different transplant centres. Conclusions Our data suggest that IL-27 may represent a potential immunological marker for the timely identification of post-transplant neoplasia.
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Affiliation(s)
- Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Federica Rascio
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Department of Clinical Medicine, University of Verona, Verona, Italy
| | - Matteo Accetturo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Simona Simone
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Lucrezia Furian
- Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Pasquale Ditonno
- Andrology, Urology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Michele Battaglia
- Andrology, Urology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Luigi Cormio
- Urology and Kidney Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Carrieri
- Urology and Kidney Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Lupo
- Department of Clinical Medicine, University of Verona, Verona, Italy
| | - Paolo Rigotti
- Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Grandaliano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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12
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Abstract
Cancer is the second most common cause of mortality and morbidity in kidney transplant recipients after cardiovascular disease. Kidney transplant recipients have at least a twofold higher risk of developing or dying from cancer than the general population. The increased risk of de novo and recurrent cancer in transplant recipients is multifactorial and attributed to oncogenic viruses, immunosuppression and altered T cell immunity. Transplant candidates and potential donors should be screened for cancer as part of the assessment process. For potential recipients with a prior history of cancer, waiting periods of 2-5 years after remission - largely depending on the cancer type and stage of initial cancer diagnosis - are recommended. Post-transplantation cancer screening needs to be tailored to the individual patient, considering the cancer risk of the individual, comorbidities, overall prognosis and the screening preferences of the patient. In kidney transplant recipients diagnosed with cancer, treatment includes conventional approaches, such as radiotherapy and chemotherapy, together with consideration of altering immunosuppression. As the benefits of transplantation compared with dialysis in potential transplant candidates with a history of cancer have not been assessed, current clinical practice relies on evidence from observational studies and registry analyses.
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Affiliation(s)
- Eric Au
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia
| | - Germaine Wong
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia.,Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia
| | - Jeremy R Chapman
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia.
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13
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Bottomley MJ, Thomson J, Harwood C, Leigh I. The Role of the Immune System in Cutaneous Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:E2009. [PMID: 31022866 PMCID: PMC6515307 DOI: 10.3390/ijms20082009] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/16/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. In immunosuppressed populations it is a source of considerable morbidity and mortality due to its enhanced recurrence and metastatic potential. In common with many malignancies, leucocyte populations are both protective against cancer development and also play a role in 'sculpting' the nascent tumor, leading to loss of immunogenicity and tumor progression. UV radiation and chronic viral carriage may represent unique risk factors for cSCC development, and the immune system plays a key role in modulating the response to both. In this review, we discuss the lessons learned from animal and ex vivo human studies of the role of individual leucocyte subpopulations in the development of cutaneous SCC. We then discuss the insights into cSCC immunity gleaned from studies in humans, particularly in populations receiving pharmacological immunosuppression such as transplant recipients. Similar insights in other malignancies have led to exciting and novel immune therapies, which are beginning to emerge into the cSCC clinical arena.
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Affiliation(s)
- Matthew J Bottomley
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
| | - Jason Thomson
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
| | - Irene Leigh
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
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14
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Garnier AS, Planchais M, Riou J, Jacquemin C, Ordonez L, Saint-André JP, Croue A, Saoudi A, Delneste Y, Devys A, Boutin I, Subra JF, Duveau A, Augusto JF. Pre-transplant CD45RC expression on blood T cells differentiates patients with cancer and rejection after kidney transplantation. PLoS One 2019; 14:e0214321. [PMID: 30925186 PMCID: PMC6440623 DOI: 10.1371/journal.pone.0214321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/11/2019] [Indexed: 01/11/2023] Open
Abstract
Background Biological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence. Methods We performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively. Results After a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24–11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh<51.9% were 84.0, 54.7, 89.8 and 42.0% respectively. Confirming our previous results, frequency of CD8+CD45RChigh T cells above 52.1% was associated with AR, conferring a 20-fold increased risk (HR 21.7 [2.67–176.2], p = 0.0004). The sensibility, specificity, negative predictive and positive predictive values of CD8+CD45RChigh>52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (p<0.0001), suggesting that recipients with high AR risk display a low cancer risk. Conclusion High frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation.
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Affiliation(s)
- Anne-Sophie Garnier
- LUNAM Université, Angers, France
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France
| | - Martin Planchais
- LUNAM Université, Angers, France
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France
| | - Jérémie Riou
- MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, IBS- CHU, Angers, France
| | - Clément Jacquemin
- INSERM U1035, BMGIC, Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France
| | - Laurence Ordonez
- Université de Toulouse, Centre de physiopathologie de Toulouse Purpan, Toulouse, France
| | - Jean-Paul Saint-André
- LUNAM Université, Angers, France
- CHU Angers, Laboratoire d’anatomopathologie, Angers, France
| | - Anne Croue
- CHU Angers, Laboratoire d’anatomopathologie, Angers, France
| | - Abdelhadi Saoudi
- Université de Toulouse, Centre de physiopathologie de Toulouse Purpan, Toulouse, France
| | - Yves Delneste
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Angers, France
| | - Anne Devys
- Laboratoire HLA, Etablissement Français du Sang Pays de Loire, Angers, France
| | - Isabelle Boutin
- Centre de Sante, Etablissement Français du Sang Pays de Loire, Angers, France
| | - Jean-François Subra
- LUNAM Université, Angers, France
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Angers, France
| | - Agnès Duveau
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France
| | - Jean-François Augusto
- LUNAM Université, Angers, France
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France
- CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France
- LabEx IGO “Immunotherapy, Graft, Oncology”, Angers, France
- * E-mail:
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15
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McCallion O, Hester J, Issa F. Deciphering the Contribution of γδ T Cells to Outcomes in Transplantation. Transplantation 2018; 102:1983-1993. [PMID: 29994977 PMCID: PMC6215479 DOI: 10.1097/tp.0000000000002335] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
γδ T cells are a subpopulation of lymphocytes expressing heterodimeric T-cell receptors composed of γ and δ chains. They are morphologically and functionally heterogeneous, innate yet also adaptive in behavior, and exhibit diverse activities spanning immunosurveillance, immunomodulation, and direct cytotoxicity. The specific responses of γδ T cells to allografts are yet to be fully elucidated with evidence of both detrimental and tolerogenic roles in different settings. Here we present an overview of γδ T-cell literature, consider ways in which their functional heterogeneity contributes to the outcomes after transplantation, and reflect on methods to harness their beneficial properties.
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Affiliation(s)
- Oliver McCallion
- Transplantation Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Joanna Hester
- Transplantation Research Immunology Group, University of Oxford, Oxford, United Kingdom
| | - Fadi Issa
- Transplantation Research Immunology Group, University of Oxford, Oxford, United Kingdom
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16
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Abikhair Burgo M, Roudiani N, Chen J, Santana AL, Doudican N, Proby C, Felsen D, Carucci JA. Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma. JCI Insight 2018; 3:120750. [PMID: 30185657 PMCID: PMC6171807 DOI: 10.1172/jci.insight.120750] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 07/26/2018] [Indexed: 01/05/2023] Open
Abstract
Organ transplant recipients (OTRs) on cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK1/2 inhibitor, ruxolitinib. In human SCC cells, the greatest proliferative response to IL-22 and CSA treatment occurred in nonmetastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs and in SCC with high risk for metastasis. Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1, and STAT1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.
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Affiliation(s)
- Melody Abikhair Burgo
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Nazanin Roudiani
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Jie Chen
- Institute for Pediatric Urology, Department of Urology, Weill Cornell Medicine, New York, New York, USA
| | - Alexis L. Santana
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Nicole Doudican
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
| | - Charlotte Proby
- Division of Cancer Research, Jacqui Wood Cancer Centre, University of Dundee, Dundee, Scotland, United Kingdom
| | - Diane Felsen
- Institute for Pediatric Urology, Department of Urology, Weill Cornell Medicine, New York, New York, USA
| | - John A. Carucci
- Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA
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17
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Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients. Transplantation 2017; 101:2102-2110. [PMID: 28403126 DOI: 10.1097/tp.0000000000001759] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response. METHODS Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months. RESULTS Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients. CONCLUSIONS Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.
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18
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Sirolimus Increases T-Cell Abundance in the Sun Exposed Skin of Kidney Transplant Recipients. Transplant Direct 2017; 3:e171. [PMID: 28706974 PMCID: PMC5498012 DOI: 10.1097/txd.0000000000000694] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 04/26/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Kidney transplant recipients (KTRs) receiving the mammalian target of rapamycin inhibitor sirolimus may display a reduced risk of skin cancer development compared to KTRs receiving calcineurin inhibitors. Despite studies investigating the effects of these 2 drug classes on T cells in patient blood, the effect these drugs may have in patient skin is not yet known. METHODS Fifteen patients with chronic kidney disease (not recipients of immunosuppressive drugs), and 30 KTRs (15 receiving a calcineurin inhibitor, and 15 receiving sirolimus) provided matched samples of blood, sun exposed (SE) and non-SE skin. The abundance of total CD8+ and CD4+ T cells, memory CD8+ and CD4+ T cells, and regulatory T (Treg) cells in each sample was then assessed by flow cytometry. RESULTS Sirolimus treatment significantly increased absolute numbers of CD4+ T cells, memory CD8+- and CD4+ T cells, and Treg cells in SE skin versus paired samples of non-SE skin. No differences were found in the absolute number of any T cell subset in the blood. Correlation analysis revealed that the percentage of T cell subsets in the blood does not always accurately reflect the percentage of T-cell subsets in the skin of KTRs. Furthermore, sirolimus significantly disrupts the balance of memory CD4+ T cells in the skin after chronic sun exposure. CONCLUSIONS This study demonstrated that immunosuppressive drug class and sun exposure modify the abundance of multiple T-cell subsets in the skin of KTRs. Correlation analysis revealed that the prevalence of Treg cells in KTR blood does not accurately reflect the prevalence of Treg cells in KTR skin.
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19
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Daunting but Worthy Goal: Reducing the De Novo Cancer Incidence After Transplantation. Transplantation 2017; 100:2569-2583. [PMID: 27861286 DOI: 10.1097/tp.0000000000001428] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Solid-organ transplant recipients are at increased risk of developing de novo malignancies compared with the general population, and malignancies become a major limitation in achieving optimal outcomes. The prevention and the management of posttransplant malignancies must be considered as a main goal in our transplant programs. For these patients, immunosuppression plays a major role in oncogenesis by both impairement of immunosurveillance, enhancement of chronic viral infection, and by direct prooncogenic effects. It is essential to manage the recipient with a long-term adapted screening program beginning before transplantation to use a prophylaxis to decrease infection-related cancer, to propose a viral monitoring, and to modulate the immunosuppression toward lower doses especially for calcineurin inhibitors. Indeed, strategies to induce tolerance or to allow a dramatic reduction of the immunosuppression burden are the more promising approaches for the reduction of the posttransplant malignancies.
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20
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Bamoulid J, Crépin T, Courivaud C, Rebibou JM, Saas P, Ducloux D. Antithymocyte globulins in renal transplantation-from lymphocyte depletion to lymphocyte activation: The doubled-edged sword. Transplant Rev (Orlando) 2017; 31:180-187. [PMID: 28456447 DOI: 10.1016/j.trre.2017.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/11/2017] [Accepted: 02/13/2017] [Indexed: 11/18/2022]
Abstract
Compelling data suggest that lymphocyte depletion following T cell depleting therapy may induce prolonged CD4 T cell lymphopenia and trigger lymphocyte activation in some patients. These profound and non-reversible immune changes in T cell pool subsets are the consequence of both impaired thymic renewal and peripheral homeostatic proliferation. Chronic viral challenges by CMV play a major role in these immune alterations. Even when the consequences of CD4 T cell lymphopenia have been now well described, recent studies shed new light on the clinical consequences of immune activation. In this review, we will first focus on the mechanisms involved in T cell pool reconstitution after T cell depletion and further consider the clinical consequences of ATG-induced T cell activation and senescence in renal transplant recipients.
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Affiliation(s)
- Jamal Bamoulid
- CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, F-25030 Besançon, France; UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; Université de Franche-Comté, Faculté de Médecine et de Pharmacie, Besançon F-25020, France; Structure Fédérative de Recherche, SFR FED4234, Besançon F-25000, France
| | - Thomas Crépin
- CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, F-25030 Besançon, France; UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; Université de Franche-Comté, Faculté de Médecine et de Pharmacie, Besançon F-25020, France; Structure Fédérative de Recherche, SFR FED4234, Besançon F-25000, France
| | - Cécile Courivaud
- CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, F-25030 Besançon, France; UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; Université de Franche-Comté, Faculté de Médecine et de Pharmacie, Besançon F-25020, France; Structure Fédérative de Recherche, SFR FED4234, Besançon F-25000, France
| | - Jean-Michel Rebibou
- UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; CHU Dijon, Department of Nephrology, Dialysis and Renal Transplantation, 21000 Dijon, France
| | - Philippe Saas
- UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; Université de Franche-Comté, Faculté de Médecine et de Pharmacie, Besançon F-25020, France; Structure Fédérative de Recherche, SFR FED4234, Besançon F-25000, France
| | - Didier Ducloux
- CHU Besançon, Department of Nephrology, Dialysis, and Renal Transplantation, F-25030 Besançon, France; UMR1098, Federation hospitalo-universitaire INCREASE, Besançon F-25020, France; Université de Franche-Comté, Faculté de Médecine et de Pharmacie, Besançon F-25020, France; Structure Fédérative de Recherche, SFR FED4234, Besançon F-25000, France.
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21
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Xing YF, Cai RM, Lin Q, Ye QJ, Ren JH, Yin LH, Li X. Expansion of polymorphonuclear myeloid-derived suppressor cells in patients with end-stage renal disease may lead to infectious complications. Kidney Int 2017; 91:1236-1242. [PMID: 28215666 DOI: 10.1016/j.kint.2016.12.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 12/01/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are recently identified immune suppressive cells in multiple chronic inflammations. Here, we investigated MDSCs in patients with end-stage renal disease (ESRD) and their clinical significance in these patients and healthy individuals (49 each). Polymorphonuclear and mononuclear MDSCs were investigated by flow cytometry. Patients with ESRD before hemodialysis presented a significantly higher level of polymorphonuclear MDSCs. Depletion of polymorphonuclear-MDSCs resolved T cell IFN-γ responses. By co-culture, T cell proliferation and the production of IFN-γ were abrogated by the addition of polymorphonuclear MDSCs in a dose-dependent manner. Both of these effects were reversed by a reactive oxygen species inhibitor. The levels of reactive oxygen species were higher in polymorphonuclear MDSCs derived from patients with ESRD than from normal individuals. The mRNA level of NOX2, the key protein complex responsible for reactive oxygen species production, was higher in ESRD-related polymorphonuclear MDSCs. The phospho-STAT3 level, a key activator of MDSCs, was higher in ESRD-related polymorphonuclear MDSCs. Finally, the polymorphonuclear MDSC level before and after hemodialysis was positively related to infectious diseases. Patients with ESRD were dichotomized into 2 groups by the amount of polymorphonuclear MDSCs. Patients with high levels of polymorphonuclear MDSCs presented with a higher incidence of infectious events. Thus, polymorphonuclear MDSCs were elevated in ESRD patients with strong immune-suppressive capability through a phospho-STAT3/reactive oxygen species pathway. Hence, polymorphonuclear MDSCs might increase the risk of infectious complications.
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Affiliation(s)
- Yan-Fang Xing
- Department of Nephrology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China; The First Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Rui-Ming Cai
- Department of Urology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Qu Lin
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Qing-Jian Ye
- Department of Gynecology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jian-Hua Ren
- Department of Orthopedics, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Liang-Hong Yin
- The First Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Xing Li
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
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22
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Neuberger JM, Bechstein WO, Kuypers DRJ, Burra P, Citterio F, De Geest S, Duvoux C, Jardine AG, Kamar N, Krämer BK, Metselaar HJ, Nevens F, Pirenne J, Rodríguez-Perálvarez ML, Samuel D, Schneeberger S, Serón D, Trunečka P, Tisone G, van Gelder T. Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation 2017; 101:S1-S56. [PMID: 28328734 DOI: 10.1097/tp.0000000000001651] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
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Affiliation(s)
- James M Neuberger
- 1 Liver Unit, Queen Elizabeth Hospital Birmingham, United Kingdom. 2 Department of General and Visceral Surgery, Frankfurt University Hospital and Clinics, Germany. 3 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Campus Gasthuisberg, Belgium. 4 Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy. 5 Renal Transplantation Unit, Department of Surgical Science, Università Cattolica Sacro Cuore, Rome, Italy. 6 Department of Public Health, Faculty of Medicine, Institute of Nursing Science, University of Basel, Switzerland. 7 Department of Public Health, Faculty of Medicine, Centre for Health Services and Nursing Research, KU Leuven, Belgium. 8 Department of Hepatology and Liver Transplant Unit, Henri Mondor Hospital (AP-HP), Paris-Est University (UPEC), France. 9 Department of Nephrology, University of Glasgow, United Kingdom. 10 Department of Nephrology and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, Toulouse, France. 11 Vth Department of Medicine & Renal Transplant Program, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium. 14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. 16 Hepatobiliary Centre, Hospital Paul-Brousse (AP-HP), Paris-Sud University, Université Paris-Saclay, Villejuif, France. 17 Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria. 18 Nephrology Department, Hospital Vall d'Hebrón, Autonomous University of Barcelona, Spain. 19 Transplant Center, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. 20 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy. 21 Department of Hospital Pharmacy and Internal Medicine, Erasmus MC, the Netherlands
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23
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Bestard O, Cravedi P. Monitoring alloimmune response in kidney transplantation. J Nephrol 2016; 30:187-200. [PMID: 27245689 DOI: 10.1007/s40620-016-0320-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 05/15/2016] [Indexed: 01/22/2023]
Abstract
Currently, immunosuppressive therapy in kidney transplant recipients is generally performed by protocols and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients are likely to receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. Developing reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival. Emerging data indicate that many assays, likely used in panels rather than single assays, have potential to be diagnostic and predictive of short and also long-term outcome. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Of note, some prospective, randomized, multicenter biomarker-driven studies are currently on-going aiming at confirming such preliminary data. These works as well as other future studies are highly warranted to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.
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Affiliation(s)
- Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, IDIBELL, Barcelona, Spain
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Annenberg Building, New York, NY, 10029, USA.
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24
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Abstract
The incidence of cancer is markedly increased in organ transplant patients. A better understanding of underlying mechanisms and the identification of biomarkers for diagnosis and prognosis are major challenges. Hope et al. report expansion of regulatory T cells to be associated with the presence and severity of cancer. Although relevant, these results raise several questions.
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25
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Natural Killer Lymphocytes Are Dysfunctional in Kidney Transplant Recipients on Diagnosis of Cancer. Transplantation 2016; 99:2422-30. [PMID: 26798861 DOI: 10.1097/tp.0000000000000792] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND The incidence of cancer is increased after solid organ transplantation. Natural killer (NK) cells are key effectors of the tumor immune response. METHODS We conducted a cross sectional multicentre matched case-control study including 42 kidney transplant recipients (KTRs) on diagnosis of cancer and 41 KTRs without cancer. Extensive phenotyping of NK cells populations and functional tests of NK cells were performed. RESULTS Kidney transplant recipients with cancer had a higher incidence of acute rejection (P = 0.02) and cytomegalovirus (CMV) infection (P = 0.03) than controls. They had more lymphopenia than control KTRs (1020/mm3 +/- 32 vs 1218/mm3 +/- 34; P = 0.001) including a CD4+ lymphopenia (P = 0.01). Total CD3-/CD56+ NK cell counts were similar in both groups. However, KTRs with cancer had a lower frequency of the cytokine-enriched CD56bright NK cell subset (P = 0.001). The percentage of NK cells expressing NKp46 was decreased in KTRs with cancer (45% vs 53 %, P = 0.001). Furthermore, the ability of NK cells to degranulate CD107a+ cytolytic vesicles was reduced (11% vs 22%; P = 0.02), and the percentage of NK cells secreting IFN[gamma] was decreased (7.5% vs 28.8%; P = 0.01) in KTRs with cancer. CONCLUSIONS These results reveal an imbalance between NK cell subpopulations and functional NK cell defects in KTRs at the diagnosis of malignancy, including a decreased expression of NKp46 and decreased numbers of NK cells producing INF[gamma]. This study highlights the role of NKp46, a major activating NK cell receptor, which could be considered as a potential marker during immunological follow-up of KTRs.
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26
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Bottomley MJ, Harden PN, Wood KJ. CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients. J Am Soc Nephrol 2015; 27:1505-15. [PMID: 26563386 DOI: 10.1681/asn.2015030250] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 08/05/2015] [Indexed: 01/19/2023] Open
Abstract
Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8(+) T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8(+) T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8(+) T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8(+) T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.
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Affiliation(s)
- Matthew J Bottomley
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; and Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom
| | - Paul N Harden
- Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom
| | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; and
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27
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Peripheral natural killer cell and allo-stimulated T-cell function in kidney transplant recipients associate with cancer risk and immunosuppression-related complications. Kidney Int 2015; 88:1374-1382. [PMID: 26266834 DOI: 10.1038/ki.2015.237] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 06/05/2015] [Accepted: 06/12/2015] [Indexed: 12/12/2022]
Abstract
Reducing immunosuppression has been proposed as a means of preventing cancer in kidney transplant recipients but this can precipitate graft rejection. Here we tested whether anti-tumor natural killer (NK) cell and allo-responsive T-cell function in kidney transplant recipients may predict cancer risk and define risk of rejection. NK cell function was measured by the release of lactate dehydrogenase and T-cell allo-response by interferon-γ quantification using a panel of reactive T-cell enzyme-linked immunospot (ELISPOT) in 56 kidney transplant recipients with current or past cancer and 26 kidney transplant recipients without cancer. NK function was significantly impaired and the allo-response was significantly lower in kidney transplant recipients with cancer. With prospective follow-up, kidney transplant recipients with poor NK cell function had a hazard ratio of 2.1 (95% confidence interval 0.97-5.00) for the combined end point of metastatic cancer, cancer-related death, or septic death. Kidney transplant recipients with low interferon-γ release were also more likely to reach this combined end point. Thus, posttransplant monitoring of allo-immunity and NK cell function is useful for assessing the risk of over immunosuppression for the development of malignancy and/or death from cancer or sepsis.
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28
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Abstract
Renal cancer occurs more frequently in renal transplanted patients than in the general population, affecting native kidneys in 90% of cases and the graft in 10 %. In addition to general risk factors, malignancy susceptibility may be influenced by immunosuppressive therapy, the use of calcineurin inhibitors (CNI) as compared with mammalian target of rapamycin inhibitors, and the length of dialysis treatment. Acquired cystic kidney disease may increase the risk for renal cancer after transplantation, while autosomal dominant polycystic kidney disease does not seem to predispose to cancer development. Annual ultrasound evaluation seems appropriate in patients with congenital or acquired cystic disease or even a single cyst in native kidneys, and every 2 years in patients older than 60 years if they were on dialysis for more than 5 years before transplantation. Immunosuppression should be lowered in patients who develop renal cancer, by reduction or withdrawal of CNI. Although more evidence is still needed, it seems reasonable to shift patients from CNI to everolimus or sirolimus if not already treated with one of these drugs, with due caution in subjects with chronic allograft nephropathy.
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29
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Sivanathan KN, Rojas-Canales DM, Hope CM, Krishnan R, Carroll RP, Gronthos S, Grey ST, Coates PT. Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. Stem Cells 2015; 33:2850-63. [PMID: 26037953 DOI: 10.1002/stem.2075] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 04/14/2015] [Accepted: 05/16/2015] [Indexed: 12/29/2022]
Abstract
Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4(+) CD25(high) CD127(low) FoxP3(+) regulatory T cells (iTregs) from PHA-activated CD4(+) CD25(-) T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.
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Affiliation(s)
- Kisha Nandini Sivanathan
- School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.,Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.,Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia
| | - Darling M Rojas-Canales
- School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.,Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia
| | - Christopher M Hope
- School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.,Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia
| | - Ravi Krishnan
- School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia
| | - Robert P Carroll
- Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.,Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Stan Gronthos
- Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.,Mesenchymal Stem Cell Group Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Shane T Grey
- Transplant Immunology Group, Garvin Institute of Medical Research, Sydney, New South Wales, Australia
| | - Patrick T Coates
- School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.,Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.,Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.,Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia
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30
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Hope CM, Coates PTH, Carroll RP. Immune profiling and cancer post transplantation. World J Nephrol 2015; 4:41-56. [PMID: 25664246 PMCID: PMC4317627 DOI: 10.5527/wjn.v4.i1.41] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/03/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Half of all long-term (> 10 year) australian kidney transplant recipients (KTR) will develop squamous cell carcinoma (SCC) or solid organ cancer (SOC), making cancer the leading cause of death with a functioning graft. At least 30% of KTR with a history of SCC or SOC will develop a subsequent SCC or SOC lesion. Pharmacological immunosuppression is a major contributor of the increased risk of cancer for KTR, with the cancer lesions themselves further adding to systemic immunosuppression and could explain, in part, these phenomena. Immune profiling includes; measuring immunosuppressive drug levels and pharmacokinetics, enumerating leucocytes and leucocyte subsets as well as testing leucocyte function in either an antigen specific or non-specific manner. Outputs can vary from assay to assay according to methods used. In this review we define the rationale behind post-transplant immune monitoring assays and focus on assays that associate and/or have the ability to predict cancer and rejection in the KTR. We find that immune monitoring can identify those KTR of developing multiple SCC lesions and provide evidence they may benefit from pharmacological immunosuppressive drug dose reductions. In these KTR risk of rejection needs to be assessed to determine if reduction of immunosuppression will not harm the graft.
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31
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Jung JW, Overgaard NH, Burke MT, Isbel N, Frazer IH, Simpson F, Wells JW. Does the nature of residual immune function explain the differential risk of non-melanoma skin cancer development in immunosuppressed organ transplant recipients? Int J Cancer 2015; 138:281-92. [DOI: 10.1002/ijc.29450] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 01/08/2015] [Indexed: 12/12/2022]
Affiliation(s)
- Ji-Won Jung
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute; Brisbane QLD
| | - Nana H. Overgaard
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute; Brisbane QLD
- Center for Cancer Immune Therapy (CCIT), Department of Hematology; Copenhagen University Hospital; Herlev Denmark
| | - Michael T. Burke
- Department of Renal Medicine; The University of Queensland, Princess Alexandra Hospital; Brisbane QLD
| | - Nicole Isbel
- Department of Renal Medicine; The University of Queensland, Princess Alexandra Hospital; Brisbane QLD
| | - Ian H. Frazer
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute; Brisbane QLD
| | - Fiona Simpson
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute; Brisbane QLD
| | - James W. Wells
- The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute; Brisbane QLD
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32
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Mehrotra A, Leventhal J, Purroy C, Cravedi P. Monitoring T cell alloreactivity. Transplant Rev (Orlando) 2014; 29:53-9. [PMID: 25475045 DOI: 10.1016/j.trre.2014.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 10/03/2014] [Accepted: 11/09/2014] [Indexed: 01/06/2023]
Abstract
Currently, immunosuppressive therapy in kidney transplant recipients is center-specific, protocol-driven, and adjusted according to functional or histological evaluation of the allograft and/or signs of drug toxicity or infection. As a result, a large fraction of patients receive too much or too little immunosuppression, exposing them to higher rates of infection, malignancy and drug toxicity, or increased risk of acute and chronic graft injury from rejection, respectively. The individualization of immunosuppression requires the development of assays able to reliably quantify and/or predict the magnitude of the recipient's immune response toward the allograft. As alloreactive T cells are central mediators of allograft rejection, monitoring T cell alloreactivity has become a priority for the transplant community. Among available assays, flow cytometry based phenotyping, T cell proliferation, T cell cytokine secretion, and ATP release (ImmuKnow), have been the most thoroughly tested. While numerous cross-sectional studies have found associations between the results of these assays and the presence of clinically relevant post-transplantation outcomes, data from prospective studies are still scanty, thereby preventing widespread implementation in the clinic. Future studies are required to test the hypothesis that tailoring immunosuppression on the basis of results offered by these biomarkers leads to better outcomes than current standard clinical practice.
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Affiliation(s)
- Anita Mehrotra
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Jeremy Leventhal
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Carolina Purroy
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
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33
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Sherston SN, Vogt K, Schlickeiser S, Sawitzki B, Harden PN, Wood KJ. Demethylation of the TSDR is a marker of squamous cell carcinoma in transplant recipients. Am J Transplant 2014; 14:2617-22. [PMID: 25250867 PMCID: PMC4497351 DOI: 10.1111/ajt.12899] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 01/25/2023]
Abstract
Malignancy is an important cause of death in transplant recipients. Cutaneous squamous cell carcinoma (cSCC) causes significant morbidity and mortality as 30% of transplant recipients will develop cSCC within 10 years of transplantation. Previously we have shown that high numbers of regulatory T cells (Tregs) are associated with the development of cSCC in kidney transplant recipients (KTRs). Demethylation analysis of the Treg-specific demethylated region (TSDR) provides a more accurate association with cSCC risk after transplantation. Age, gender and duration of immunosuppression matched KTRs with (n=32) and without (n=27) cSCC, were re-analyzed for putative clinical and immunological markers of cancer risk. The proportion of FOXP3+ CD4+ cells was higher in the population with a previous SCC. Major T cell subsets remained stable over time; although B cell, CD8 and CD4 subpopulations demonstrated age-related changes. TSDR methylation analysis allowed clarification of Treg numbers, enhancing the association of high Treg levels in KTRs with cSCC compared to the cSCC-free cohort. These data validate and expand on previous findings in long-term KTRs, and show that immune markers remain stable over time. TSDR demethylation analysis provides a more accurate biomarker of cancer posttransplantation.
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Affiliation(s)
- S N Sherston
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of OxfordOxford, United Kingdom
| | - K Vogt
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany
| | - S Schlickeiser
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany
| | - B Sawitzki
- Institute for Medical Immunology, Charité–University MedicineBerlin, Germany,BCRT Berlin Brandenburg Center for Regenerative Therapies, Charite University MedicineBerlin, Germany
| | - P N Harden
- Oxford Transplant Centre, Churchill HospitalOxford, United Kingdom
| | - K J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of OxfordOxford, United Kingdom,*Corresponding author: Kathryn J. Wood,
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34
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Comparative immune phenotypic analysis of cutaneous Squamous Cell Carcinoma and Intraepidermal Carcinoma in immune-competent individuals: proportional representation of CD8+ T-cells but not FoxP3+ Regulatory T-cells is associated with disease stage. PLoS One 2014; 9:e110928. [PMID: 25340823 PMCID: PMC4207854 DOI: 10.1371/journal.pone.0110928] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/20/2014] [Indexed: 11/19/2022] Open
Abstract
Squamous Cell Carcinoma (SCC) is a type of non-melanoma skin cancer prevalent in immune-suppressed transplant recipients and older individuals with a history of chronic sun-exposure. SCC itself is believed to be a late-stage manifestation that can develop from premalignant lesions including Intraepidermal Carcinoma (IEC). Notably, while SCC regression is rare, IEC typically regresses in response to immune modifying topical treatments, however the underlying immunological reasons for these differential responses remain unclear. This study aimed to define whether IEC and SCC are associated with distinct immune profiles. We investigated the immune cell infiltrate of photo-damaged skin, IEC, and SCC tissue using 10-colour flow cytometry following fresh lesion digest. We found that IEC lesions contain higher percentages of CD3+ T-cells than photo-damaged skin, however, the abundance of CD3−CD56+ Natural Killer (NK) cells, CD11c+HLA-DR+ conventional Dendritic Cells (cDC), BDCA-2+HLA-DR+ plasmacytoid DC (pDC), FoxP3+ Regulatory T-cells (T-reg), Vα24+Vβ11+ invariant NKT-cells, and γδ Tcells did not alter with disease stage. Within the total T-cell population, high percentages of CD4+ T-cells were associated with SCC, yet CD8+ T-cells were less abundant in SCC compared with IEC. Our study demonstrates that while IEC lesions contain a higher proportion of T-cells than SCC lesions in general, SCC lesions specifically display a lower abundance of CD8+ T-cells than IEC. We propose that differences in CD8+ T-cell abundance contribute critically to the different capacity of SCC and IEC to regress in response to immune modifying topical treatments. Our study also suggests that a high ratio of CD4+ T-cells to CD8+ T-cells may be a immunological diagnostic indicator of late-stage SCC development in immune-competent patients.
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35
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Abstract
Immunosuppressive drugs commonly used in transplantation and autoimmune diseases are unfortunately associated with increased cancer incidence. Now, a new study reports a direct relationship between the number of regulatory T cells in the blood and the risk of developing invasive skin cancer in kidney transplant recipients.
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36
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Maguire O, Tario JD, Shanahan TC, Wallace PK, Minderman H. Flow cytometry and solid organ transplantation: a perfect match. Immunol Invest 2014; 43:756-74. [PMID: 25296232 PMCID: PMC4357273 DOI: 10.3109/08820139.2014.910022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the field of transplantation, flow cytometry serves a well-established role in pre-transplant crossmatching and monitoring immune reconstitution following hematopoietic stem cell transplantation. The capabilities of flow cytometers have continuously expanded and this combined with more detailed knowledge of the constituents of the immune system, their function and interaction and newly developed reagents to study these parameters have led to additional utility of flow cytometry-based analyses, particularly in the post-transplant setting. This review discusses the impact of flow cytometry on managing alloantigen reactions, monitoring opportunistic infections and graft rejection and gauging immunosuppression in the context of solid organ transplantation.
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Affiliation(s)
- Orla Maguire
- Laboratory of Flow and Image Cytometry, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Joseph D. Tario
- Laboratory of Flow and Image Cytometry, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Thomas C. Shanahan
- Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, New York, USA
| | - Paul K. Wallace
- Laboratory of Flow and Image Cytometry, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Hans Minderman
- Laboratory of Flow and Image Cytometry, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
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