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Jarczak J, Bujko K, Brzeźniakiewicz-Janus K, Ratajczak M, Kucia M. Next-generation sequencing protocol of hematopoietic stem cells (HSCs). Step-by-step overview and troubleshooting guide. PLoS One 2025; 20:e0313009. [PMID: 39787063 PMCID: PMC11717189 DOI: 10.1371/journal.pone.0313009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 10/16/2024] [Indexed: 01/12/2025] Open
Abstract
Populations of very small embryonic-like stem cells (VSELs) (CD34+lin-CD45- and CD133+lin-CD45-), circulating in the peripheral blood of adults in small numbers, have been identified in several human tissues and together with the populations of hematopoietic stem cells (HSCs) (CD34+lin-CD45+) and CD133+lin-CD45+constitute a pool of cells with self-renewal and pluripotent stem cell characteristics. Using advanced cell staining and sorting strategies, we isolated populations of VSELs and HSCs for bulk RNA-Seq analysis to compare the transcriptomic profiles of both cell populations. Libraries were prepared from an extremely small number of cells; however, their good quality was preserved, and they met the criteria for sequencing. We present here a step-by-step NGS protocol for sequencing VSELs and HSC with a description of troubleshooting during library preparation and sequencing.
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Affiliation(s)
- Justyna Jarczak
- Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | - Kamila Bujko
- Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
| | | | - Mariusz Ratajczak
- Stem Cell Institute at Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States of America
| | - Magdalena Kucia
- Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland
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2
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Wang Z, Li R, Fu W, Cheng H, Zhang Y, Tang G, Yang J, Wang J, Ni X. Anti-CD4 monoclonal antibody prevents chronic graft-versus-host disease in mice by inducing immune tolerance of CD8 + T cells and alleviating thymus injury. Front Immunol 2024; 15:1460687. [PMID: 39776911 PMCID: PMC11703850 DOI: 10.3389/fimmu.2024.1460687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background Chronic graft-versus-host disease (cGVHD) manifests with characteristics of autoimmune disease with organs attacked by pathogenic helper T cells. Recent studies have highlighted the role of T cells in cGVHD pathogenesis. Due to limited understanding of underlying mechanisms, preventing cGVHD after allogenic hematopoietic cell transplantation (HCT) has become a major challenge. Materials and methods Here, we used a representative cGVHD model with the donor C57BL/6 to recipient BALB/c combination. Post-HCT, mice were treated with IgG or anti-CD4 monoclonal antibody. The severity of cGVHD was assessed by evaluating symptoms of cGVHD and histopathology examination (H&E) of target organs. Thymus gland damage and defects of the negative selection were assessed by analyzing the CD4+CD8+ double-positive thymocytes, cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs). Immunotolerance of CD8+ T cells was assessed by detecting the expression of CD80, PD-1, GRAIL and IL-7Rα. Long-term cellular and humoral immunity associated with graft-versus-leukemia (GVL) effects were evaluated through detecting the percentage of CD4+ T cells, IgG, IgM and IgA concentrations, and performing tumor challenge experiment. Results Donor CD8+ T cells caused thymic epithelial cells damage and impaired negative selection in recipients, leading to generation of autoreactive T cells and causing cGVHD. Anti-CD4 mAb treatment promoted immune incompetence of thymus-infiltrating CD8+ T cells, facilitated recovery of CD4+CD8+ thymocytes and regeneration mTECs, and preserved negative-selection, but had no effects on the long-term cellular immunity and humoral immunity, resulting in preservation of GVL effect. Conclusion Our results indicate that anti-CD4 mAb therapy early post-HCT allows thymus recovery by inducing the immune tolerance of thymus infiltrated CD8+ T cells, thereby alleviating thymic epithelial cells damage, preserving negative selection, and preserving long-term GVL effect at the same time.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiong Ni
- Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai, China
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3
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Copsel SN, Garrido VT, Barreras H, Bader CS, Pfeiffer B, Mateo-Victoriano B, Wolf D, Gallardo M, Paczesny S, Komanduri KV, Benjamin CL, Villarino AV, Saluja AK, Levy RB. Minnelide suppresses GVHD and enhances survival while maintaining GVT responses. JCI Insight 2024; 9:e165936. [PMID: 38602775 PMCID: PMC11141936 DOI: 10.1172/jci.insight.165936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 04/03/2024] [Indexed: 04/13/2024] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelide's GVHD suppression after aHSCT. Importantly, Minnelide's GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.
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Affiliation(s)
| | | | | | | | - Brent Pfeiffer
- Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | | | | | | | - Sophie Paczesny
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Krishna V. Komanduri
- Department of Microbiology and Immunology
- Sylvester Comprehensive Cancer Center
- Department of Medicine, and
| | - Cara L. Benjamin
- Sylvester Comprehensive Cancer Center
- Department of Medicine, and
| | | | - Ashok K. Saluja
- Department of Surgery, and
- Sylvester Comprehensive Cancer Center
| | - Robert B. Levy
- Department of Microbiology and Immunology
- Sylvester Comprehensive Cancer Center
- Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida, USA
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Philippen L, Schub N, Günther A, Cario G, Schrappe M, Repp R, Gramatzki M. Alemtuzumab treatment for steroid-refractory acute graft-versus-host disease leads to severe immunosuppression but not to relapse of malignant disease. Bone Marrow Transplant 2024; 59:153-155. [PMID: 37932418 PMCID: PMC10781631 DOI: 10.1038/s41409-023-02144-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 10/11/2023] [Accepted: 10/23/2023] [Indexed: 11/08/2023]
Affiliation(s)
- Lennart Philippen
- Division of Stem Cell Transplantation and Immunotherapy, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Natalie Schub
- Division of Stem Cell Transplantation and Immunotherapy, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Andreas Günther
- Division of Stem Cell Transplantation and Immunotherapy, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Gunnar Cario
- Department of Pediatrics, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Martin Schrappe
- Department of Pediatrics, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Roland Repp
- Division of Stem Cell Transplantation and Immunotherapy, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany
| | - Martin Gramatzki
- Division of Stem Cell Transplantation and Immunotherapy, University Hospital Schleswig-Holstein and Christian-Albrechts-University Kiel, Kiel, Germany.
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5
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To NH, Pilon C, Moatti A, Debesset A, Debbi K, Coraggio G, Ksouri W, Massaria V, Cohen JL, Belkacemi Y, Thiolat A. Effect of lethal total body irradiation on bone marrow chimerism, acute graft-versus-host disease, and tumor engraftment in mouse models: impact of different radiation techniques using low- and high-energy X-rays. Strahlenther Onkol 2023; 199:1242-1254. [PMID: 36932237 DOI: 10.1007/s00066-023-02066-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 02/19/2023] [Indexed: 03/19/2023]
Abstract
PURPOSE Effects of X‑ray energy levels used for myeloablative lethal total body irradiation (TBI) delivery prior to bone marrow transplantation (BMT) in preclinical mouse models were examined. MATERIALS AND METHODS In mouse models, single-fraction myeloablative TBI at a lethal dose was delivered using two different X‑ray devices, either low (160 kV cabinet irradiator) or high energy (6 MV linear accelerator), before semi-allogeneic hematopoietic stem-cell transplantation (HSCT) to ensure bone marrow (BM) chimerism, graft-versus-host disease (GVHD), and tumor engraftment. Recipient mice were clinically followed for 80 days after bone marrow transplantation (BMT). Flow cytometry was performed to assess donor chimerism and tumor engraftment in recipient mice. RESULTS Both X‑ray irradiation techniques delivered a 10 Gy single fraction of TBI, presented a lethal effect, and could allow near-complete early donor chimerism on day 13. However, low-energy irradiation increased T cells' alloreactivity compared to high-energy irradiation, leading to clinical consequences for GVHD and tumor engraftment outcomes. The alloreactive effect differences might be attributed to the distinction in inflammatory status of irradiated recipients at donor cell infusion (D0). Delaying donor cell administration (D1 after lethal TBI) attenuated T cells' alloreactivity and clinical outcomes in GVHD mouse models. CONCLUSION Different X‑ray irradiation modalities condition T cell alloreactivity in experimental semi-allogeneic BMT. Low-energy X‑ray irradiator induces a post-TBI inflammatory burst and exacerbates alloreactive reactions. This technical and biological information should be considered in interpreting GVHD/ graft-versus-leukemia effect results in mice experimental models of BMT.
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Affiliation(s)
- Nhu Hanh To
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France.
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France.
| | - Caroline Pilon
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Audrey Moatti
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Anaïs Debesset
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Kamel Debbi
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Gabriele Coraggio
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - Wassim Ksouri
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - Virginie Massaria
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
| | - José L Cohen
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
| | - Yazid Belkacemi
- AP-HP. Radiation Oncology Department and Henri Mondor Breast Center, Henri Mondor University Hospital, Créteil, France
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
| | - Allan Thiolat
- INSERM UMR 955, team I-BIOT, Institute Mondor de Recherche Biomédicale, University of Paris Est Créteil, Créteil, France
- AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Creteil, France
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Herrity E, Pereira MP, Kim DDH. Acute myeloid leukaemia relapse after allogeneic haematopoietic stem cell transplantation: Mechanistic diversity and therapeutic directions. Br J Haematol 2023; 203:722-735. [PMID: 37787151 DOI: 10.1111/bjh.19121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/28/2023] [Accepted: 09/12/2023] [Indexed: 10/04/2023]
Abstract
Emerging biological and clinical data, along with advances in new technologies, have exposed the mechanistic diversity in post-haematopoietic stem cell transplant (HCT) relapse. Post-HCT relapse mechanisms are relevant for guiding sophisticated selection of therapeutic interventions and identification of areas for further research. Clonal evolution and emergence of resistant leukemic strains is a common mechanism shared by relapse post-chemotherapy and post-HCT, other mechanisms such as leukemic immune escape and donor T cell exhaustion are unique entities to post-HCT relapse. Due to diversity in the mechanisms behind post-HCT relapse, the subsequent clinical approach relies on clinician discretion, rather than objective evidence. Lack of standardized selection based on post-HCT relapse mechanism(s) could be a contributing factor to observed poor outcomes. Therapeutic strategies including donor lymphocyte infusion (DLI), second transplant, immunotherapies, hypomethylating agents, and targeted strategies are supported options and efficacy may be enhanced when post-HCT AML relapse mechanism is established and guides treatment selection. This review aims, through compilation of supporting studies, to describe mechanisms of post-HCT relapse and their implications for subsequent treatment selection and inspiration for future research.
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Affiliation(s)
- Elizabeth Herrity
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Mariana Pinto Pereira
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Dennis Dong Hwan Kim
- Hans Messner Allogeneic Blood and Marrow Transplantation Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Leukemia Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- Department of Hematology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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7
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Riwes MM, Golob JL, Magenau J, Shan M, Dick G, Braun T, Schmidt TM, Pawarode A, Anand S, Ghosh M, Maciejewski J, King D, Choi S, Yanik G, Geer M, Hillman E, Lyssiotis CA, Tewari M, Reddy P. Feasibility of a dietary intervention to modify gut microbial metabolism in patients with hematopoietic stem cell transplantation. Nat Med 2023; 29:2805-2813. [PMID: 37857710 PMCID: PMC10667101 DOI: 10.1038/s41591-023-02587-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 09/12/2023] [Indexed: 10/21/2023]
Abstract
Evaluation of the impact of dietary intervention on gastrointestinal microbiota and metabolites after allogeneic hematopoietic stem cell transplantation (HCT) is lacking. We conducted a feasibility study as the first of a two-phase trial. Ten adults received resistant potato starch (RPS) daily from day -7 to day 100. The primary objective was to test the feasibility of RPS and its effect on intestinal microbiome and metabolites, including the short-chain fatty acid butyrate. Feasibility met the preset goal of 60% or more, adhering to 70% or more doses; fecal butyrate levels were significantly higher when participants were on RPS than when they were not (P < 0.0001). An exploratory objective was to evaluate plasma metabolites. We observed longitudinal changes in plasma metabolites compared to baseline, which were independent of RPS (P < 0.0001). However, in recipients of RPS, the dominant plasma metabolites were more stable compared to historical controls with significant difference at engraftment (P < 0.05). These results indicate that RPS in recipients of allogeneic HCT is feasible; in this study, it was associated with significant alterations in intestinal and plasma metabolites. A phase 2 trial examining the effect of RPS on graft-versus-host disease in recipients of allogeneic HCT is underway. ClinicalTrials.gov registration: NCT02763033 .
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Affiliation(s)
- Mary M Riwes
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA.
| | - Jonathan L Golob
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, MI, USA
| | - John Magenau
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Mengrou Shan
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Gregory Dick
- Department of Earth & Environmental Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Thomas Braun
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Thomas M Schmidt
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, MI, USA
| | - Attaphol Pawarode
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Sarah Anand
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Monalisa Ghosh
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - John Maciejewski
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Darren King
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Sung Choi
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Gregory Yanik
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Marcus Geer
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Ethan Hillman
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, MI, USA
| | - Costas A Lyssiotis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Muneesh Tewari
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA
| | - Pavan Reddy
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Rogel Cancer Center, Ann Arbor, MI, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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8
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Tamura S, Ishiguro H, Suwabe T, Katagiri T, Cho K, Fuse K, Shibasaki Y, Mikami T, Shindo T, Kitagawa H, Igarashi M, Sone H, Masuko M, Ushiki T. Genetic manipulation resulting in decreased donor chondroitin sulfate synthesis mitigates hepatic GVHD via suppression of T cell activity. Sci Rep 2023; 13:13098. [PMID: 37567982 PMCID: PMC10421903 DOI: 10.1038/s41598-023-40367-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 08/09/2023] [Indexed: 08/13/2023] Open
Abstract
Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.
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Affiliation(s)
- Suguru Tamura
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Hajime Ishiguro
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Tatsuya Suwabe
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takayuki Katagiri
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Kaori Cho
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Kyoko Fuse
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Yasuhiko Shibasaki
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Tadahisa Mikami
- Laboratory of Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Takero Shindo
- Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Kitagawa
- Laboratory of Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Michihiro Igarashi
- Department of Neurochemistry and Molecular Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hirohito Sone
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Masayoshi Masuko
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takashi Ushiki
- Department of Hematology, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
- Division of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
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9
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Patel DA, Crain M, Pusic I, Schroeder MA. Acute Graft-versus-Host Disease: An Update on New Treatment Options. Drugs 2023:10.1007/s40265-023-01889-2. [PMID: 37247105 DOI: 10.1007/s40265-023-01889-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2023] [Indexed: 05/30/2023]
Abstract
Acute graft-versus-host disease (GVHD) occurs in approximately 50% of patients and remains a primary driver of non-relapse and transplant-related mortality. The best treatment remains prevention with either in vivo or ex vivo T-cell depletion, with multiple strategies used worldwide based on factors such as institution preference, ability to perform graft manipulation, and ongoing clinical trials. Predicting patients at high risk for developing severe acute GVHD based on clinical and biomarker-based criteria allows for escalation or potential de-escalation of therapy. Modern therapies for treatment of the disease include JAK/STAT pathway inhibitors, which are standard of care in the second-line setting and are being investigated for upfront management of non-severe risk based on biomarkers. Salvage therapies beyond the second-line remain suboptimal. In this review, we will focus on the most clinically used GVHD prevention and treatment strategies, including the accumulating data on JAK inhibitors in both settings.
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Affiliation(s)
- Dilan A Patel
- Section of BMT & Leukemia, Division of Oncology, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Mallory Crain
- Section of BMT & Leukemia, Division of Oncology, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Iskra Pusic
- Section of BMT & Leukemia, Division of Oncology, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Mark A Schroeder
- Section of BMT & Leukemia, Division of Oncology, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, MO, USA.
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10
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Li YR, Dunn ZS, Yu Y, Li M, Wang P, Yang L. Advancing cell-based cancer immunotherapy through stem cell engineering. Cell Stem Cell 2023; 30:592-610. [PMID: 36948187 PMCID: PMC10164150 DOI: 10.1016/j.stem.2023.02.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 01/04/2023] [Accepted: 02/22/2023] [Indexed: 03/24/2023]
Abstract
Advances in cell-based therapy, particularly CAR-T cell therapy, have transformed the treatment of hematological malignancies. Although an important step forward for the field, autologous CAR-T therapies are hindered by high costs, manufacturing challenges, and limited efficacy against solid tumors. With ongoing progress in gene editing and culture techniques, engineered stem cells and their application in cell therapy are poised to address some of these challenges. Here, we review stem cell-based immunotherapy approaches, stem cell sources, gene engineering and manufacturing strategies, therapeutic platforms, and clinical trials, as well as challenges and future directions for the field.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zachary Spencer Dunn
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
| | - Yanqi Yu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Miao Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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11
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Li YR, Zhou K, Wilson M, Kramer A, Zhu Y, Dawson N, Yang L. Mucosal-associated invariant T cells for cancer immunotherapy. Mol Ther 2023; 31:631-646. [PMID: 36463401 PMCID: PMC10014234 DOI: 10.1016/j.ymthe.2022.11.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/09/2022] Open
Abstract
Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an invariant TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted TCR β chain. MAIT cells recognize microbial peptides presented by the highly conserved MHC class I-like molecule MR1 and bridge the innate and acquired immune systems to mediate augmented immune responses. Upon activation, MAIT cells rapidly proliferate, produce a variety of cytokines and cytotoxic molecules, and trigger efficient antitumor immunity. Administration of a representative MAIT cell ligand 5-OP-RU effectively activates MAIT cells and enhances their antitumor capacity. In this review, we introduce MAIT cell biology and their importance in antitumor immunity, summarize the current development of peripheral blood mononuclear cell-derived and stem cell-derived MAIT cell products for cancer treatment, and discuss the potential of genetic engineering of MAIT cells for off-the-shelf cancer immunotherapy.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Kuangyi Zhou
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Matthew Wilson
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Adam Kramer
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Niels Dawson
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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12
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Li YR, Zeng S, Dunn ZS, Zhou Y, Li Z, Yu J, Wang YC, Ku J, Cook N, Kramer A, Yang L. Off-the-shelf third-party HSC-engineered iNKT cells for ameliorating GvHD while preserving GvL effect in the treatment of blood cancers. iScience 2022; 25:104859. [PMID: 36034226 PMCID: PMC9399487 DOI: 10.1016/j.isci.2022.104859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/11/2022] [Accepted: 07/25/2022] [Indexed: 11/25/2022] Open
Abstract
Allo-HSCT is a curative therapy for hematologic malignancies owing to GvL effect mediated by alloreactive T cells; however, the same T cells also mediate GvHD, a severe side effect limiting the widespread application of allo-HSCT in clinics. Invariant natural killer T (iNKT) cells can ameliorate GvHD while preserving GvL effect, but the clinical application of these cells is restricted by their scarcity. Here, we report the successful generation of third-party HSC-engineered human iNKT (3rdHSC-iNKT) cells using a method combining HSC gene engineering and in vitro HSC differentiation. The 3rdHSC-iNKT cells closely resembled the CD4-CD8-/+ subsets of endogenous human iNKT cells in phenotype and functionality. These cells displayed potent anti-GvHD functions by eliminating antigen-presenting myeloid cells in vitro and in xenograft models without negatively impacting tumor eradication by allogeneic T cells in preclinical models of lymphoma and leukemia, supporting 3rdHSC-iNKT cells as a promising off-the-shelf cell therapy candidate for GvHD prophylaxis.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Samuel Zeng
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zachary Spencer Dunn
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
| | - Yang Zhou
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zhe Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jiaji Yu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yu-Chen Wang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Josh Ku
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Noah Cook
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Adam Kramer
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
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13
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Song Q, Nasri U, Nakamura R, Martin PJ, Zeng D. Retention of Donor T Cells in Lymphohematopoietic Tissue and Augmentation of Tissue PD-L1 Protection for Prevention of GVHD While Preserving GVL Activity. Front Immunol 2022; 13:907673. [PMID: 35677056 PMCID: PMC9168269 DOI: 10.3389/fimmu.2022.907673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/26/2022] [Indexed: 11/30/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for hematological malignancies (i.e., leukemia and lymphoma) due to the graft-versus-leukemia (GVL) activity mediated by alloreactive T cells that can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells can cause a serious side effect, known as graft-versus-host disease (GVHD). GVHD and GVL occur in distinct organ and tissues, with GVHD occurring in target organs (e.g., the gut, liver, lung, skin, etc.) and GVL in lympho-hematopoietic tissues where hematological cancer cells primarily reside. Currently used immunosuppressive drugs for the treatment of GVHD inhibit donor T cell activation and expansion, resulting in a decrease in both GVHD and GVL activity that is associated with cancer relapse. To prevent GVHD, it is important to allow full activation and expansion of alloreactive T cells in the lympho-hematopoietic tissues, as well as prevent donor T cells from migrating into the GVHD target tissues, and tolerize infiltrating T cells via protective mechanisms, such as PD-L1 interacting with PD-1, in the target tissues. In this review, we will summarize major approaches that prevent donor T cell migration into GVHD target tissues and approaches that augment tolerization of the infiltrating T cells in the GVHD target tissues while preserving strong GVL activity in the lympho-hematopoietic tissues.
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Affiliation(s)
- Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
| | - Ryotaro Nakamura
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
| | - Paul J Martin
- Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, United States
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, Unites States.,Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, Unites States
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14
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Yang X, Ma L, Zhang X, Huang L, Wei J. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia. Exp Hematol Oncol 2022; 11:11. [PMID: 35236415 PMCID: PMC8889667 DOI: 10.1186/s40164-022-00263-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/16/2022] [Indexed: 12/14/2022] Open
Abstract
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.
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Affiliation(s)
- Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.,Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, 430030, Hubei, China
| | - Ling Ma
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoying Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China.,Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, 430030, Hubei, China
| | - Liang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China. .,Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, 430030, Hubei, China.
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China. .,Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, 430030, Hubei, China.
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15
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Igarashi K, Hori T, Yamamoto M, Sohma H, Suzuki N, Tsutsumi H, Kawasaki Y, Kokai Y. CCL8 deficiency in the host abrogates early mortality of acute graft-versus-host disease in mice with dysregulated IL-6 expression. Exp Hematol 2022; 106:47-57. [PMID: 34808257 DOI: 10.1016/j.exphem.2021.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 11/30/2022]
Abstract
Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for diverse malignant and nonmalignant diseases, acute graft-versus-host disease (aGVHD) is strongly linked to mortality caused by HSCT. We previously reported that CC chemokine ligand 8 (CCL8) is closely correlated to aGVHD mortality in both humans and mice. To study the role of CCL8 in aGVHD, CCL8 knockout (CCL8-/-) mice were transplanted with fully allogeneic marrow grafts. These mice exhibited a significant reduction in mortality (90.0% vs. 23.4% survival for CCL8-/- vs. wild-type recipients at day 28, p < 0.0001). As a result, apparent prolonged median survival from 9 days in wild-type mice to 45 days in CCL8-/- mice was observed. Acute GVHD pathology and liver dysfunction in CCL8-/- mice were significantly attenuated compared with those in wild-type mice. In association with the reduced mortality, a surge of plasma interleukin (IL)-6 was observed in CCL8-/- recipients with allogeneic marrow, which was significantly increased compared with wild-type mice that received allografts. Donor T-cell expansion and plasma levels of interferon-γ and TNF-α during aGVHD were similar in both types of mice. Collectively, these findings indicate that CCL8 plays a major role in aGVHD pathogenesis with possible involvement of an IL-6 signaling cascade.
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Affiliation(s)
- Keita Igarashi
- Department of Biomedical Engineering, Research Institute of Frontier Medicine; Department of Pediatrics, Sapporo Medical University School of Medicine.
| | - Tsukasa Hori
- Department of Pediatrics, Sapporo Medical University School of Medicine
| | - Masaki Yamamoto
- Department of Pediatrics, Sapporo Medical University School of Medicine
| | - Hitoshi Sohma
- Department of Educational Development, Center for Medical Education, Sapporo Medical University, Sapporo, Japan
| | | | - Hiroyuki Tsutsumi
- Department of Pediatrics, Sapporo Medical University School of Medicine
| | - Yukihiko Kawasaki
- Department of Pediatrics, Sapporo Medical University School of Medicine
| | - Yasuo Kokai
- Department of Biomedical Engineering, Research Institute of Frontier Medicine
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16
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Wu N, Liu R, Liang S, Gao H, Xu LP, Zhang XH, Liu J, Huang XJ. γδ T Cells May Aggravate Acute Graft-Versus-Host Disease Through CXCR4 Signaling After Allogeneic Hematopoietic Transplantation. Front Immunol 2021; 12:687961. [PMID: 34335589 PMCID: PMC8316995 DOI: 10.3389/fimmu.2021.687961] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a pathology in which chemokines and their receptors play essential roles in directing the migration of alloreactive donor T cells into GVHD organs, thereby leading to further target tissue damage. Currently, acute GVHD (aGVHD) remains a major cause of high morbidity and mortality in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT). The identification of immune cells that correlate with aGVHD is important and intriguing. To date, the involvement of innate-like γδ T cells in the pathogenesis of aGVHD is unclear. Herein, we found that primary human γδ T cells did not directly trigger allogeneic reactions. Instead, we revealed that γδ T cells facilitated the migration of CD4 T cells via the SDF-1-CXCR4 axis. These results indicate indirect regulation of γδ T cells in the development of aGVHD rather than a direct mechanism. Furthermore, we showed that the expression of CXCR4 was significantly elevated in γδ T cells and CD4 and CD8 T cells in recipients who experienced grades II-IV aGVHD after alloHCT. Consistently, CXCR4-expressing γδ T cells and CD4 T cells were induced in the target organs of mice suffering aGVHD. The depletion of γδ T cells in transplant grafts and treatment with AMD3100, an inhibitor of CXCR4 signaling, delayed the onset of aGVHD and prolonged survival in mice. Taken together, these findings suggest a role for γδ T cells in recruiting alloreactive CD4 T cells to target tissues through the expression of CXCR4. Our findings may help in understanding the mechanism of aGVHD and provide novel therapeutic targets.
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MESH Headings
- Adolescent
- Adult
- Animals
- Benzylamines/pharmacology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Cells, Cultured
- Chemokine CXCL12/metabolism
- Chemotaxis, Leukocyte
- Coculture Techniques
- Cyclams/pharmacology
- Disease Models, Animal
- Female
- Graft vs Host Disease/etiology
- Graft vs Host Disease/immunology
- Graft vs Host Disease/metabolism
- Graft vs Host Disease/prevention & control
- Hematopoietic Stem Cell Transplantation/adverse effects
- Humans
- Intraepithelial Lymphocytes/drug effects
- Intraepithelial Lymphocytes/immunology
- Intraepithelial Lymphocytes/metabolism
- Male
- Mice, Inbred NOD
- Middle Aged
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Receptors, CXCR4/antagonists & inhibitors
- Receptors, CXCR4/metabolism
- Signal Transduction
- Transplantation, Homologous
- Young Adult
- Mice
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Affiliation(s)
- Ning Wu
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruoyang Liu
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Shuang Liang
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Haitao Gao
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Lan-Ping Xu
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Jiangying Liu
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - Xiao-Jun Huang
- Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
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17
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Bader CS, Barreras H, Lightbourn CO, Copsel SN, Wolf D, Meng J, Ahn J, Komanduri KV, Blazar BR, Jin L, Barber GN, Roy S, Levy RB. STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets. Sci Transl Med 2021; 12:12/552/eaay5006. [PMID: 32669421 DOI: 10.1126/scitranslmed.aay5006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 06/02/2020] [Indexed: 12/14/2022]
Abstract
The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)-mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT-induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING's potential clinical importance. STING-/- recipients experienced reduced GVHD with transplant of purified donor CD8+ T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+ T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.
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Affiliation(s)
- Cameron S Bader
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Henry Barreras
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Casey O Lightbourn
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sabrina N Copsel
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Jingjing Meng
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Jeonghyun Ahn
- Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Krishna V Komanduri
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Lei Jin
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Glen N Barber
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.,Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sabita Roy
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Robert B Levy
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. .,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.,Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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18
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Phosphorylated ERK1/2 in CD4 T cells is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation. Blood Adv 2021; 4:667-671. [PMID: 32078679 DOI: 10.1182/bloodadvances.2019000343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 01/15/2020] [Indexed: 11/20/2022] Open
Abstract
To diagnose graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is sometimes difficult. We showed previously that MEK inhibitors selectively suppress murine GVHD while retaining antiviral and antitumor immunity. Here, we asked whether the RAS/MEK/ERK pathway is activated in human allo-HSCT recipients with GVHD, and whether the phosphorylated ERK1/2 can be a biomarker of GVHD. Peripheral blood was sequentially collected from 20 allo-HSCT recipients: 1 bone marrow transplant, 7 peripheral blood stem cell transplants (PBSCT), and 12 cord blood transplants. Ten of the 20 allo-HSCT recipients developed GVHD, and phosphorylation of ERK1/2 in T and B cells was analyzed by flow cytometry. Occurrence of acute GVHD was associated with phosphorylation of ERK1/2 in CD4+ T cells at day 30 (P < .001), which was suppressed by ex vivo exposure to a MEK inhibitor trametinib at clinically achievable concentrations. In particular, ERK1/2 was phosphorylated preferentially in naive/central memory CD4+ T cells. Notably, phosphorylation of ERK1/2 fell as GVHD improved. These results suggest that phosphorylation status of ERK1/2 in peripheral blood CD4+ T cells may be a future biomarker for diagnosing human GVHD, and the potential efficacy of MEK inhibitors against human GVHD.
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19
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Ali MM, Grønvold B, Remberger M, Abrahamsen IW, Myhre AE, Tjønnfjord GE, Fløisand Y, Gedde-Dahl T. Addition of Anti-thymocyte Globulin in Allogeneic Stem Cell Transplantation With Peripheral Stem Cells From Matched Unrelated Donors Improves Graft-Versus-Host Disease and Relapse Free Survival. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:598-605. [PMID: 34158268 DOI: 10.1016/j.clml.2021.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 11/25/2022]
Abstract
Anti-thymocyte globulin (ATG) is commonly used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To evaluate the impact of ATG as part of the GvHD prophylaxis in our institution, we report the outcome of 415 patients with matched unrelated donors (MUD) transplanted for hematological malignancies with or without ATG from 2005 to 2019 at Oslo University Hospital, Norway. The following groups were compared: (1) 154 patients transplanted with peripheral blood stem cells (PBSC) without ATG 2005-2014. (2) 137 patients transplanted with bone marrow stem cells (BMSC) 2005-2019. (3) 124 patients transplanted with PBSC and ATG (PBSC + ATG) 2014-2019. Three years survival was similar in the groups, 61% following allografting with PBSC, 54% with BMSC, and 59% with PBSC + ATG. Acute GvHD grade III-IV was 14%, 14%, and 7%; chronic GvHD was 81%, 32, and 26%; and extensive cGvHD 44%, 15%, and 6% in the corresponding groups. Both acute and chronic GvHD were significantly reduced in the PBSC + ATG-versus the PBSC group (p < 0.05 and p < 0.001 respectively).Transplant-related mortality (TRM) was 33%, 25%, and 17% (p = 0.18). Graft versus host disease and relapse free survival (GRFS) at 3 years was 43 %, 43%, and 64% in the groups. Adding ATG to the GvHD prophylaxis regimen of MUD allo-HSCT with PBSC resulted in a substantial reduction of both acute and chronic GvHD without compromising the disease control, reflected in a superior 3 years GRFS.
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Affiliation(s)
- M M Ali
- Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
| | - B Grønvold
- Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway
| | - M Remberger
- Department of Haematology, Oslo University Hospital, Oslo, Norway; Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden
| | - I W Abrahamsen
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - A E Myhre
- Department of Haematology, Oslo University Hospital, Oslo, Norway
| | - G E Tjønnfjord
- Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway
| | - Y Fløisand
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; The Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom
| | - T Gedde-Dahl
- Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway
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20
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van Eck van der Sluijs J, van Ens D, Thordardottir S, Vodegel D, Hermens I, van der Waart AB, Falkenburg JHF, Kester MGD, de Rink I, Heemskerk MHM, Borst J, Schaap NPM, Jansen JH, Xiao Y, Dolstra H, Hobo W. Clinically applicable CD34 +-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses. Cancer Immunol Immunother 2021; 70:3167-3181. [PMID: 33796917 PMCID: PMC8505305 DOI: 10.1007/s00262-021-02899-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/22/2021] [Indexed: 11/24/2022]
Abstract
Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients.
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Affiliation(s)
- Jesper van Eck van der Sluijs
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Diede van Ens
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Soley Thordardottir
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Denise Vodegel
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Inge Hermens
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Anniek B van der Waart
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | | | - Michel G D Kester
- Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
| | - Iris de Rink
- Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Mirjam H M Heemskerk
- Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jannie Borst
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Nicolaas P M Schaap
- Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joop H Jansen
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Yanling Xiao
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Harry Dolstra
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Willemijn Hobo
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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21
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Keruakous AR, Holter-Chakrabarty J, Schmidt SA, Khawandanah MO, Selby G, Yuen C. Azacitidine maintenance therapy post-allogeneic stem cell transplantation in poor-risk acute myeloid leukemia. Hematol Oncol Stem Cell Ther 2021; 16:52-60. [PMID: 36634281 DOI: 10.1016/j.hemonc.2021.03.001] [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: 11/17/2020] [Revised: 01/24/2021] [Accepted: 03/06/2021] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE/BACKGROUND Allogeneic hematopoietic stem cell transplant (HSCT) is the potential curative modality for poor-risk acute myeloid leukemia (AML), relapse remains the main reason for transplant failure. Early-phase studies showed azacitidine is safe for post-transplant maintenance therapy in AML. METHODS We performed a single institutional prospective cohort study to evaluate the benefit of azacitidine maintenance therapy following allogeneic HSCT in poor-risk AML. The main objective of this study is to generate a hypothesis aiming to optimize post-transplantation outcomes in poor-risk AML. Forty-nine adults with poor-risk AML who underwent allogeneic HSCT were evaluated in a nonrandomized prospective cohort fashion. Thirty-one participants received post-transplant azacitidine (32 mg/m2) on Days 1-5 for a 28-day treatment cycle beginning approximately 40 days after transplantation. The study was controlled using 18 matched individuals who were on a noninterventional surveillance protocol. RESULTS The relapse rate was significantly higher in the control cohort (66.67%) versus (25.81%) in the azacitidine maintenance cohort (p < .005). Time to relapse was significantly prolonged by azacitidine maintenance, not reached versus 4.1 months in the control arm (p < .0001). In addition, median overall survival was lower in the control cohort at 7.6 versus 27.4 months in the interventional cohort (p < .0001). At a median follow-up of 24 months, incidence of graft-versus-host disease (GVHD) did not differ between study groups (p = .325). In both cohorts, minimal residual disease was correlated with higher hazard of relapse (95% confidence interval, 2.31-13.74; p < .001). CONCLUSION We conclude that low dose azacitidine maintenance following allogeneic HSCT in poor-risk AML, decreased relapse rate, and increased both the time to relapse and overall survival without increased risk of GVHD.
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Affiliation(s)
- Amany R Keruakous
- University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA.
| | | | - Sarah A Schmidt
- University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Mohamad O Khawandanah
- University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - George Selby
- University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Carrie Yuen
- University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USA.
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22
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Nicolle A, Zhang Y, Belguise K. The Emerging Function of PKCtheta in Cancer. Biomolecules 2021; 11:biom11020221. [PMID: 33562506 PMCID: PMC7915540 DOI: 10.3390/biom11020221] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/22/2021] [Accepted: 02/02/2021] [Indexed: 12/30/2022] Open
Abstract
Protein Kinase C theta (PKCθ) is a serine/threonine kinase that belongs to the novel PKC subfamily. In normal tissue, its expression is restricted to skeletal muscle cells, platelets and T lymphocytes in which PKCθ controls several essential cellular processes such as survival, proliferation and differentiation. Particularly, PKCθ has been extensively studied for its role in the immune system where its translocation to the immunological synapse plays a critical role in T cell activation. Beyond its physiological role in immune responses, increasing evidence implicates PKCθ in the pathology of various diseases, especially autoimmune disorders and cancers. In this review, we discuss the implication of PKCθ in various types of cancers and the PKCθ-mediated signaling events controlling cancer initiation and progression. In these types of cancers, the high PKCθ expression leads to aberrant cell proliferation, migration and invasion resulting in malignant phenotype. The recent development and application of PKCθ inhibitors in the context of autoimmune diseases could benefit the emergence of treatment for cancers in which PKCθ has been implicated.
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23
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Wölfl M, Qayed M, Benitez Carabante MI, Sykora T, Bonig H, Lawitschka A, Diaz-de-Heredia C. Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia. Front Pediatr 2021; 9:784377. [PMID: 35071133 PMCID: PMC8771910 DOI: 10.3389/fped.2021.784377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality-which is predominantly caused by severe GvHD-is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.
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Affiliation(s)
- Matthias Wölfl
- Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital, Würzburg University Hospital, Würzburg, Germany
| | - Muna Qayed
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, United States
| | - Maria Isabel Benitez Carabante
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Tomas Sykora
- Haematopoietic Stem Cell Transplantation Unit, Department of Pediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, Frankfurt, Germany.,German Red Cross Blood Service BaWüHe, Frankfurt, Germany
| | - Anita Lawitschka
- Department of Pediatrics, St. Anna Kinderspital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria
| | - Cristina Diaz-de-Heredia
- Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
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24
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Lee KH, Goh J, Kim YJ, Kim K. Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors. Sci Rep 2020; 10:20001. [PMID: 33203961 PMCID: PMC7672081 DOI: 10.1038/s41598-020-76909-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 10/07/2020] [Indexed: 01/02/2023] Open
Abstract
Molecular-targeted approaches are important for personalised cancer treatment, which requires knowledge regarding drug target specificity. Here, we used the synthetic lethality concept to identify candidate gene pairs with synergistic effects on drug responses. A synergistic chemo-sensitivity response was identified if a drug had a significantly lower half-maximal inhibitory concentration (IC50) in cell lines with a pair of mutated genes compared with those in other cell lines (wild-type or one mutated gene). Among significantly damaging mutations in the Genomics of Drug Sensitivity in Cancer database, we found 580 candidate synergistic chemo-sensitivity interaction sets for 456 genes and 54 commercial drugs. Clustering analyses according to drug/gene and drug/tissue interactions showed that BRAF/MAPK inhibitors clustered together; 11 partner genes for BRAF were identified. The combined effects of these partners on IC50 values were significant for both drug-specific and drug-combined comparisons. Survival analysis using The Cancer Genome Atlas data showed that patients who had mutated gene pairs in synergistic interaction sets had longer overall survival compared with that in patients with other mutation profiles. Overall, this analysis demonstrated that synergistic drug-responsive gene pairs could be successfully used as predictive markers of drug sensitivity and patient survival, offering new targets for personalised medicine.
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Affiliation(s)
- Kye Hwa Lee
- Department of Biomedical Informatics, Asan Medical Center, Seoul, 05505, South Korea.
| | - Jinmin Goh
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, South Korea.,Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, 37673, South Korea
| | - Yi-Jun Kim
- Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, 07985, South Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, 03080, South Korea.
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25
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Gupta V, Braun TM, Chowdhury M, Tewari M, Choi SW. A Systematic Review of Machine Learning Techniques in Hematopoietic Stem Cell Transplantation (HSCT). SENSORS (BASEL, SWITZERLAND) 2020; 20:E6100. [PMID: 33120974 PMCID: PMC7663237 DOI: 10.3390/s20216100] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/19/2020] [Accepted: 10/25/2020] [Indexed: 12/11/2022]
Abstract
Machine learning techniques are widely used nowadays in the healthcare domain for the diagnosis, prognosis, and treatment of diseases. These techniques have applications in the field of hematopoietic cell transplantation (HCT), which is a potentially curative therapy for hematological malignancies. Herein, a systematic review of the application of machine learning (ML) techniques in the HCT setting was conducted. We examined the type of data streams included, specific ML techniques used, and type of clinical outcomes measured. A systematic review of English articles using PubMed, Scopus, Web of Science, and IEEE Xplore databases was performed. Search terms included "hematopoietic cell transplantation (HCT)," "autologous HCT," "allogeneic HCT," "machine learning," and "artificial intelligence." Only full-text studies reported between January 2015 and July 2020 were included. Data were extracted by two authors using predefined data fields. Following PRISMA guidelines, a total of 242 studies were identified, of which 27 studies met the inclusion criteria. These studies were sub-categorized into three broad topics and the type of ML techniques used included ensemble learning (63%), regression (44%), Bayesian learning (30%), and support vector machine (30%). The majority of studies examined models to predict HCT outcomes (e.g., survival, relapse, graft-versus-host disease). Clinical and genetic data were the most commonly used predictors in the modeling process. Overall, this review provided a systematic review of ML techniques applied in the context of HCT. The evidence is not sufficiently robust to determine the optimal ML technique to use in the HCT setting and/or what minimal data variables are required.
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Affiliation(s)
- Vibhuti Gupta
- Michigan Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas M. Braun
- School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Mosharaf Chowdhury
- Michigan Engineering, Computer Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Muneesh Tewari
- Michigan Medicine, Department of Internal Medicine, Hematology/Oncology Division, University of Michigan, Ann Arbor, MI 48109, USA;
- Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
- Michigan Engineering, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sung Won Choi
- Michigan Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
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26
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Nguyen H, Alawieh A, Bastian D, Kuril S, Dai M, Daenthanasanmak A, Zhang M, Iamsawat S, Schutt SD, Wu Y, Sleiman MM, Shetty A, Atkinson C, Sun S, Varela JC, Tomlinson S, Yu XZ. Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease. Clin Cancer Res 2020; 26:3481-3490. [PMID: 31919135 PMCID: PMC7334060 DOI: 10.1158/1078-0432.ccr-19-1717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/03/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. EXPERIMENTAL DESIGN We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. RESULTS Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. CONCLUSIONS This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.
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Affiliation(s)
- Hung Nguyen
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
| | - Ali Alawieh
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - David Bastian
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Sandeepkumar Kuril
- Department of Pediatric, Medical University of South Carolina, Charleston, South Carolina
| | - Min Dai
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Anusara Daenthanasanmak
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Mengmeng Zhang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Supinya Iamsawat
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Steven D Schutt
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Yongxia Wu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - M Mahdi Sleiman
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Akshay Shetty
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Shaoli Sun
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Juan Carlos Varela
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, South Carolina
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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27
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Mia MB, Saxena RK. Poly dispersed acid-functionalized single walled carbon nanotubes target activated T and B cells to suppress acute and chronic GVHD in mouse model. Immunol Lett 2020; 224:30-37. [PMID: 32504776 DOI: 10.1016/j.imlet.2020.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/05/2020] [Accepted: 05/12/2020] [Indexed: 12/27/2022]
Abstract
Graft versus host disease (GVHD) results from hyper-activation of transplanted lymphocytes against the host antigens. Bone marrow transplantation in humans as well as some cases of blood transfusion and organ transplantation are associated with a strong GVH reaction resulting in GVHD that in many cases may be fatal. We had previously shown that poly-dispersed acid-functionalized single-walled carbon nanotubes (AF-SWCNTs) specifically target activated T and B lymphocytes and kill them. In the present study, efficacy of AF-SWCNTs to suppress the GVH reaction was tested in the mouse model. Acute GVHD was induced in mice by administering intravenously 30 or 60 million spleen cells from a parental strain (C57bl/6 mouse, MHC haplotype H-2b) to host (C57bl/6 x Balb/c) F1 mice (MHC haplotype H-2b/d)and waiting for 8-10 days. Chronic GVHD was similarly induced by administration of 30 million parent spleen cells to F1 mice and waiting for a period of 60 days. Our results demonstrate a marked decline in splenomegaly and recovery of spleen T (both CD4 and CD8) and B cells in GVHD mice treated with AF-SWCNTs. AF-SWCNTs treatment also limited T and B cell proliferation by restricting S-phage of cell cycle. Generation of anti-host cytotoxic T cells (CTLs) was also markedly suppressed by AF-SWCNT treatment of acute GVHD mice, and a significant reduction in the generation of anti-host antibodies could also be demonstrated. Taken together, our results suggest that the AF-SWCNTs can be considered as a potential therapeutic agent for treating GVHD.
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Affiliation(s)
- Md Babu Mia
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, 110021, India
| | - Rajiv K Saxena
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, 110021, India.
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28
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Riwes M, Reddy P. Short chain fatty acids: Postbiotics/metabolites and graft versus host disease colitis. Semin Hematol 2020; 57:1-6. [DOI: 10.1053/j.seminhematol.2020.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/07/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
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29
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Amin R, He R, Gupta D, Zheng W, Burmakin M, Mohammad DK, DePierre JW, Sadeghi B, Olauson H, Wernerson A, El-Andaloussi S, Hassan M, Abedi-Valugerdi M. The kidney injury caused by the onset of acute graft-versus-host disease is associated with down-regulation of αKlotho. Int Immunopharmacol 2020; 78:106042. [DOI: 10.1016/j.intimp.2019.106042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/24/2019] [Accepted: 11/08/2019] [Indexed: 12/11/2022]
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30
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Greenan E, Vandenberghe E, Murphy CC. Refractory recurrent ocular graft versus host disease. BMJ Case Rep 2019; 12:12/12/e232579. [PMID: 31843781 DOI: 10.1136/bcr-2019-232579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Ocular graft-versus-host disease (GVHD) is one of the most frequent and long-term complications affecting patients after haematopoietic stem cell transplantation. It is associated with significant morbidity and a marked reduction in quality of life. Although common, currently there are no widely accepted guidelines available for its management, and no suggested regime of treatment that is completely satisfactory. So far, prophylactic treatment strategies for ocular GVHD have yet to be developed and treatment is normally initiated based on symptoms often after permanent ocular tissue changes and surface damage has occurred. Here we describe a case of recurrent ocular GVHD and its associated complications that was highly refractory to treatment.
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Affiliation(s)
- Emily Greenan
- Ophthalmology, Royal College of Surgeons in Ireland, Dublin, Ireland.,Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
| | | | - Conor C Murphy
- Ophthalmology, Royal College of Surgeons in Ireland, Dublin, Ireland .,Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
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31
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Godoy JAP, Paiva RMA, Souza AM, Kondo AT, Kutner JM, Okamoto OK. Clinical Translation of Mesenchymal Stromal Cell Therapy for Graft Versus Host Disease. Front Cell Dev Biol 2019; 7:255. [PMID: 31824942 PMCID: PMC6881464 DOI: 10.3389/fcell.2019.00255] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/15/2019] [Indexed: 12/15/2022] Open
Abstract
Graft versus host disease (GVHD) is a common condition in patients subjected to allogeneic hematopoietic stem cell transplantation (HSCT). The immune cells derived from the grafted stem cells attack recipient's tissues, including those from the skin, liver, eyes, mouth, lungs, gastrointestinal tract, neuromuscular system, and genitourinary tract, may lead to severe morbidity and mortality. Acute GVHD can occur within few weeks after the allogeneic cells have engrafted in the recipient while chronic GVHD may occur any time after transplant, typically within months. Although treatable by systemic corticosteroid administration, effective responses are not achieved for a significant proportion of patients, a condition associated with poor prognosis. The use of multipotent mesenchymal stromal cells (MSCs) as an alternative to treat steroid-refractory GVHD had improved last decade, but the results are still controversial. Some studies have shown improvement in the life quality of patients after MSCs treatment, while others have found no significant benefits. In addition to variations in trial design, discrepancies in protocols for MSCs isolation, characterization, and ex vivo manipulation, account for inconsistent clinical results. In this review, we discuss the immunomodulatory properties supporting the therapeutic use of MSCs in GVHD and contextualize the main clinical findings of recent trials using these cells. Critical parameters for the clinical translation of MSCs, including consistent production of MSCs according to Good Manufacturing Practices (GMPs) and informative potency assays for product quality control (QC), are addressed.
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Affiliation(s)
- Juliana A. P. Godoy
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Raquel M. A. Paiva
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Aline M. Souza
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Andrea T. Kondo
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Jose M. Kutner
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Oswaldo K. Okamoto
- Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, São Paulo, Brazil
- Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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32
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Ingham AC, Kielsen K, Cilieborg MS, Lund O, Holmes S, Aarestrup FM, Müller KG, Pamp SJ. Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation. MICROBIOME 2019; 7:131. [PMID: 31519210 PMCID: PMC6744702 DOI: 10.1186/s40168-019-0745-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 08/29/2019] [Indexed: 05/11/2023]
Abstract
BACKGROUND Increasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), i.e., a replacement of the cellular components of the patients' immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including cancers such as acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g., at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly. RESULTS In two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) high concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances of Lactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such as Ruminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such as Enterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state. CONCLUSIONS We identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution, and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.
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Affiliation(s)
- Anna Cäcilia Ingham
- Research Group for Genomic Epidemiology, Technical University of Denmark, Kongens Lyngby, Denmark
- Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark
| | - Katrine Kielsen
- Institute for Inflammation Research, Department of Rheumatology and Spine Disease, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Malene Skovsted Cilieborg
- Comparative Pediatrics and Nutrition, Department of Clinical Veterinary and Animal Science, University of Copenhagen, Frederiksberg, Denmark
| | - Ole Lund
- Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Susan Holmes
- Department of Statistics, Stanford University, Stanford, USA
| | - Frank M Aarestrup
- Research Group for Genomic Epidemiology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Klaus Gottlob Müller
- Institute for Inflammation Research, Department of Rheumatology and Spine Disease, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Sünje Johanna Pamp
- Research Group for Genomic Epidemiology, Technical University of Denmark, Kongens Lyngby, Denmark.
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33
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Sofi MH, Wu Y, Schutt SD, Dai M, Daenthanasanmak A, Heinrichs Voss J, Nguyen H, Bastian D, Iamsawat S, Selvam SP, Liu C, Maulik N, Ogretmen B, Jin J, Mehrotra S, Yu XZ. Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease. J Clin Invest 2019; 129:2760-2774. [PMID: 31045571 DOI: 10.1172/jci122899] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Oxidative stress is elevated in the recipients of allogeneic hematopoietic transplantation (allo-HCT) and likely contributes to the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production and migration of alloreactive donor T cells, and remains a major cause of morbidity and mortality after allo-HCT. Hence, strategies to limit oxidative stress in GVHD are highly desirable. Thioredoxin1 (Trx1) counteracts oxidative stress by scavenging reactive oxygen species (ROS) and regulating other enzymes that metabolize H2O2. The present study sought to elucidate the role of Trx1 in the pathophysiology of GVHD. Using murine and xenograft models of allogeneic bone marrow transplantation (allo-BMT) and genetic (human Trx1-transgenic, Trx1-Tg) as well as pharmacologic (human recombinant Trx1, RTrx1) strategies; we found that Trx1-Tg donor T cells or administration of the recipients with RTrx1 significantly reduced GVHD severity. Mechanistically, we observed RTrx1 reduced ROS accumulation and cytokine production of mouse and human T cells in response to alloantigen stimulation in vitro. In allo-BMT settings, we found that Trx1-Tg or RTrx1 decreased downstream signaling molecules including NFκB activation and T-bet expression, and reduced proliferation, IFN-γ production and ROS accumulation in donor T cells within GVHD target organs. More importantly, administration of RTrx1 did not impair the graft-versus-leukemia (GVL) effect. Taken together, the current work provides a strong rationale and demonstrates feasibility to target the ROS pathway, which can be readily translated into clinic.
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Affiliation(s)
| | - Yongxia Wu
- Department of Microbiology and Immunology and
| | | | - Min Dai
- Department of Microbiology and Immunology and
| | | | | | - Hung Nguyen
- Department of Microbiology and Immunology and
| | | | | | - Shanmugam Panneer Selvam
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Chen Liu
- Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
| | - Nilanjana Maulik
- Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Junfei Jin
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | | | - Xue-Zhong Yu
- Department of Microbiology and Immunology and.,Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
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34
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Haug T, Aigner M, Peuser MM, Strobl CD, Hildner K, Mougiakakos D, Bruns H, Mackensen A, Völkl S. Human Double-Negative Regulatory T-Cells Induce a Metabolic and Functional Switch in Effector T-Cells by Suppressing mTOR Activity. Front Immunol 2019; 10:883. [PMID: 31105702 PMCID: PMC6498403 DOI: 10.3389/fimmu.2019.00883] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/05/2019] [Indexed: 01/07/2023] Open
Abstract
The recently discovered population of TCRαβ+ CD4–/CD8– (double-negative, DN) T-cells are highly potent suppressor cells in mice and humans. In preclinical transplantation models, adoptive transfer of DN T-cells specifically inhibits alloreactive T-cells and prevents transplant rejection or graft-vs.-host disease (GvHD). Interestingly, clinical studies in patients who underwent allogeneic stem cell transplantation reveal an inverse correlation between the frequency of circulating DN T-cells and the severity of GvHD, suggesting a therapeutic potential of human DN T-cells. However, their exact mode of action has not been elucidated yet. Investigating the impact of DN T-cells on conventional T-cells, we found that human DN T-cells selectively inhibit mTOR signaling in CD4 T-cells. Given that mTOR is a critical regulator of cellular metabolism, we further determined the impact of DN T-cells on the metabolic framework of T-cells. Intriguingly, DN T-cells diminished expression of glucose transporters and glucose uptake, whereas fatty acid uptake was not modified, indicating that DN T-cells prevent metabolic adaptation of CD4 T-cells upon activation (i.e., glycolytic switch) thereby contributing to their suppression. Further analyses demonstrated that CD4 T-cells also do not upregulate homing receptors associated with inflammatory processes. In contrast, expression of central memory-cell associated cell surface markers and transcription factors were increased by DN T-cells. Moreover, CD4 T-cells failed to produce inflammatory cytokines after co-culture with DN T-cells, whereas IL-2 secretion was enhanced. Taken together DN T-cells impair metabolic reprogramming of conventional CD4 T-cells by abrogating mTOR signaling, thereby modulating CD4 T-cell functionality. These results uncover a new mechanism of DN T-cell-mediated suppression, pointing out that DN T-cells could serve as cell-based therapy to limit alloreactive immune response.
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Affiliation(s)
- Tabea Haug
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Michael Aigner
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Moritz M Peuser
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Carolin D Strobl
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Kai Hildner
- Department of Internal Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Dimitrios Mougiakakos
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Heiko Bruns
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Andreas Mackensen
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Simon Völkl
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
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35
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Kim HK, Chung H, Kwon J, Castro E, Johns C, Hawk NV, Hwang S, Park JH, Gress RE. Differential Cytokine Utilization and Tissue Tropism Results in Distinct Repopulation Kinetics of Naïve vs. Memory T Cells in Mice. Front Immunol 2019; 10:355. [PMID: 30886618 PMCID: PMC6409349 DOI: 10.3389/fimmu.2019.00355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 02/12/2019] [Indexed: 02/06/2023] Open
Abstract
Naïve and memory T cells co-exist in the peripheral T cell pool, but the cellular mechanisms that maintain the balance and homeostasis of these two populations remain mostly unclear. To address this question, here, we assessed homeostatic proliferation and repopulation kinetics of adoptively transferred naïve and memory T cells in lymphopenic host mice. We identified distinct kinetics of proliferation and tissue-distribution between naïve and memory donor T cells, which resulted in the occupancy of the peripheral T cell pool by mostly naïve-origin T cells in short term (<1 week), but, in a dramatic reversal, by mostly memory-origin T cells in long term (>4 weeks). To explain this finding, we assessed utilization of the homeostatic cytokines IL-7 and IL-15 by naïve and memory T cells. We found different efficiencies of IL-7 signaling between naïve and memory T cells, where memory T cells expressed larger amounts of IL-7Rα but were significantly less potent in activation of STAT5 that is downstream of IL-7 signaling. Nonetheless, memory T cells were superior in long-term repopulation of the peripheral T cell pool, presumably, because they preferentially migrated into non-lymphoid tissues upon adoptive transfer and additionally utilized tissue IL-15 for rapid expansion. Consequently, co-utilization of IL-7 and IL-15 provides memory T cells a long-term survival advantage. We consider this mechanism important, as it permits the memory T cell population to be maintained in face of constant influx of naïve T cells to the peripheral T cell pool and under competing conditions for survival cytokines.
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Affiliation(s)
- Hye Kyung Kim
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Hyunsoo Chung
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Juntae Kwon
- Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Ehydel Castro
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Johns
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Nga V Hawk
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - SuJin Hwang
- Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Jung-Hyun Park
- Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Ronald E Gress
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
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36
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Antigenic Targets for the Immunotherapy of Acute Myeloid Leukaemia. J Clin Med 2019; 8:jcm8020134. [PMID: 30678059 PMCID: PMC6406328 DOI: 10.3390/jcm8020134] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 01/10/2019] [Accepted: 01/20/2019] [Indexed: 12/18/2022] Open
Abstract
One of the most promising approaches to preventing relapse is the stimulation of the body’s own immune system to kill residual cancer cells after conventional therapy has destroyed the bulk of the tumour. In acute myeloid leukaemia (AML), the high frequency with which patients achieve first remission, and the diffuse nature of the disease throughout the periphery, makes immunotherapy particularly appealing following induction and consolidation therapy, using chemotherapy, and where possible stem cell transplantation. Immunotherapy could be used to remove residual disease, including leukaemic stem cells from the farthest recesses of the body, reducing, if not eliminating, the prospect of relapse. The identification of novel antigens that exist at disease presentation and can act as targets for immunotherapy have also proved useful in helping us to gain a better understand of the biology that belies AML. It appears that there is an additional function of leukaemia associated antigens as biomarkers of disease state and survival. Here, we discuss these findings.
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37
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Cassady K, Martin PJ, Zeng D. Regulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80. Front Immunol 2018; 9:3061. [PMID: 30622541 PMCID: PMC6308317 DOI: 10.3389/fimmu.2018.03061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/10/2018] [Indexed: 12/18/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e. leukemia and lymphoma), because graft-versus-leukemia (GVL) activity mediated by alloreactive T cells can eliminate residual malignant cells and prevent relapse. However, the same alloreactive T cells also mediate a severe side effect, graft-versus-host disease (GVHD), and prevention of GVHD while preserving GVL activity remains an elusive goal. The immune checkpoint molecule PD-L1 and its interaction with PD-1 receptor in regulating cancer immunity is under intensive and wide-spread study, but knowledge about this interaction in regulating GVHD and GVL activity is very limited. In this review, we summarize the literature exploring how PD-L1 interaction with its receptors PD-1 and CD80 regulate GVHD and GVL activities, how PD-L1 signaling regulates T cell metabolic profiles, and how a differential role of PD-L1 interaction with PD-1, CD80 or both may provide a novel avenue to prevent GVHD while preserving strong GVL effects.
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Affiliation(s)
- Kaniel Cassady
- Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, United States.,Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA, United States.,Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Paul J Martin
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.,Department of Medicine, University of Washington, Seattle, WA, United States
| | - Defu Zeng
- Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, United States.,Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA, United States.,Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
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38
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Hilger N, Mueller C, Stahl L, Mueller AM, Zoennchen B, Dluczek S, Halbich C, Wickenhauser C, Gerloff D, Wurm AA, Behre G, Kretschmer A, Fricke S. Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia. Front Immunol 2018; 9:2408. [PMID: 30405611 PMCID: PMC6204383 DOI: 10.3389/fimmu.2018.02408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 09/28/2018] [Indexed: 12/24/2022] Open
Abstract
Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3ITD AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG1 prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3ITD AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.
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Affiliation(s)
- Nadja Hilger
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.,Institute for Clinical Immunology, University of Leipzig, Leipzig, Germany
| | - Claudia Mueller
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Lilly Stahl
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Anne M Mueller
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Bianca Zoennchen
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Sarah Dluczek
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Christoph Halbich
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | | | - Dennis Gerloff
- Department of Dermatology and Venereology, University Hospital Halle, Halle, Germany
| | - Alexander A Wurm
- Division of Hematology and Medical Oncology, Leipzig University Hospital, Leipzig, Germany
| | - Gerhard Behre
- Division of Hematology and Medical Oncology, Leipzig University Hospital, Leipzig, Germany
| | - Anna Kretschmer
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Stephan Fricke
- Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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39
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Brick C, Atouf O, Ouadghiri S, Drissi Bourhanbour A, Bougar S, Yakhlef I, Essakalli M. HLA typing and haematopoietic stem cell transplantation in the histocompatibility unit of the Ibn Sina University Hospital in Rabat (Morocco). Transfus Clin Biol 2018; 26:293-298. [PMID: 30366818 DOI: 10.1016/j.tracli.2018.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 09/27/2018] [Indexed: 11/17/2022]
Abstract
PURPOSE OF STUDY This study focuses on the search for a suitable related HLA-matched donor of haematopoietic stem cells in the context of allogeneic transplantation in Morocco. The aim of this work is to establish whether the related donor can meet graft needs in Moroccan patients. PATIENTS AND METHODS 429 families (429 recipients and 965 donors) benefited from HLA typing, using microlymphocytotoxicity, polymerase chain reaction-sequence specific primer and/or high-resolution polymerase chain reaction-specific sequence oligonucleotide. RESULTS The recipients and donors are mostly men over 18 years of age. In total, 86.8% of the recipients have between 1 and 3 donors who are 96% of the collaterals. Malignant haemopathies account for 54% of allograft indications. Benign haemopathies are more frequent than malignant in children, whereas the profile is reversed in adults. Fifty percent of recipients have an HLA identical donor in their siblings and 42% and HLA haplo identical donor. The HLA typing of the recipients and the donors reveals very large polymorphism of the population. CONCLUSION The related donor of haematopoietic stem cells represents an important source of grafts but will not be able to satisfy all the needs of Morocco. The creation of national unrelated voluntary donors will open up new possibilities for recipients who do not have a compatible donor within his relatives.
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Affiliation(s)
- C Brick
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco.
| | - O Atouf
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco; UPR of immunology, faculty of medicine and pharmacy, university Mohamed V Rabat, Rabat, Morocco
| | - S Ouadghiri
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco
| | | | - S Bougar
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco
| | - I Yakhlef
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco; UPR of immunology, faculty of medicine and pharmacy, university Mohamed V Rabat, Rabat, Morocco
| | - M Essakalli
- Department of immunology and transfusion, CHU Ibn Sina Rabat, Rabat, Morocco; UPR of immunology, faculty of medicine and pharmacy, university Mohamed V Rabat, Rabat, Morocco
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40
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Saleem MS, Aljurf M, Srivastava A, Shamsi T, Lu PH, Hamidieh AA, El Haddad A, Hashmi SK. Challenges in managing graft-versus-host disease in developing countries: a perspective. Bone Marrow Transplant 2018; 54:641-647. [PMID: 30237541 DOI: 10.1038/s41409-018-0333-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 08/27/2018] [Accepted: 08/29/2018] [Indexed: 01/07/2023]
Abstract
Hematopoietic cell transplant (HCT) activity is increasing worldwide due to safer techniques, widening indications, and more availability of donors. New HCT centers have recently been established in many developing countries including Asian and African countries. Due to limited resources, logistic, political, and social issues in developing countries, the treatment of orphan diseases like graft-versus-host disease (GVHD) can be challenging. We intended to delineate the current issues that institutions and clinicians face in managing GVHD. We conducted a comprehensive systematic electronic review of peer-reviewed published articles on GVHD management in developing countries. We used PubMed, Cochrane, and Embase databases as our primary source of data. Studies that were included described the treatments for both acute and chronic GVHD. Consensus on the use of high-dose methyl-prednisone and prednisolone as the initial therapy was widely accepted and used in practice. Socio-economic factors were found to be the major factor involved in GVHD management in lower income patients. Delayed diagnosis and treatment, lack of availability of healthcare professionals, lack of knowledge among cancer patients, and poverty are major concerns in the developing world. For optimal management, HCT programs should develop systems in place for long-term follow-up of HCT survivors and have a low threshold to initiate treatments for GVHD early. Awareness and health policy programs must be initiated at the grass-root level for long-term management of these survivors in developing countries.
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Affiliation(s)
| | - Mahmoud Aljurf
- Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Alok Srivastava
- Department of Hematology, Christian Medical College, Vellore, India
| | - Tahir Shamsi
- Department of Hematology, National Institutes of Blood Diseases, Karachi, Pakistan
| | - Pei Hua Lu
- Department of Hematology, Dao Pei Lu Hospital, Beijing, China
| | - Amir Ali Hamidieh
- Department of Pediatric Hematology/Oncology, Tehran University of Medical Sciences, Tehran, Iran
| | - Alaa El Haddad
- National Cancer Institute, Cairo University, Cairo, Egypt
| | - Shahrukh K Hashmi
- Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. .,Department of Internal Medicine, Mayo Clinic, Rochester, NY, USA.
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41
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Huang F, Cao FL, Zheng SG. Update of humanized animal disease models in studying Graft-versus-host disease. Hum Vaccin Immunother 2018; 14:2618-2623. [PMID: 30130452 DOI: 10.1080/21645515.2018.1512454] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a severe adverse effect that results from bone marrow or peripheral blood cells transplantation and has a high rate of mortality. About 50% of the patients are accompanied with acute Graft-versus-Host Disease (aGVHD) after bone marrow cell transplantation and need systematic treatment. It has an important clinical significance to evaluate the prevention and treatment effects of GVHD. The stable and reliable approaches of humanized animal models are crucial for advancing on the study the biology of GVHD. Relative models transplanting the human immune cells into the mouse body can trigger immunoreaction similar to the humans. As it is a disease triggered by human immune cells, any intervention research prior to clinical treatment has more clinical interrelations compared with the general animal models. In this review, we update the current understanding on humanized animal disease models on studying Graft-versus-host disease and expect to provide more theoretical basis to further study on Graft-versus-host disease.
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Affiliation(s)
- Feng Huang
- a Department of Clinical Immunology , Third Hospital at Sun Yat-sen University , Guangzhou , China
| | - Feng Lin Cao
- b Hematology Department , The First Hospital of Harbin Medical University , Harbin , China
| | - Song Guo Zheng
- c Department of Medicine , Milton S. Hershey Medical Center, Penn State University , Hershey , PA , USA
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42
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Ben Nasr M, D'Addio F, Malvandi AM, Faravelli S, Castillo-Leon E, Usuelli V, Rocchio F, Letizia T, El Essawy AB, Assi E, Mameli C, Giani E, Macedoni M, Maestroni A, Dassano A, Loretelli C, Paroni M, Cannalire G, Biasucci G, Sala M, Biffi A, Zuccotti GV, Fiorina P. Prostaglandin E2 Stimulates the Expansion of Regulatory Hematopoietic Stem and Progenitor Cells in Type 1 Diabetes. Front Immunol 2018; 9:1387. [PMID: 29971065 PMCID: PMC6018202 DOI: 10.3389/fimmu.2018.01387] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/04/2018] [Indexed: 12/29/2022] Open
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only “experimental therapy” that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes.
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Affiliation(s)
- Moufida Ben Nasr
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.,International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Amir Mohammad Malvandi
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Silvia Faravelli
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Eduardo Castillo-Leon
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Vera Usuelli
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.,International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Francesca Rocchio
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Teresa Letizia
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | | | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Chiara Mameli
- Department of Pediatrics, Buzzi Children Hospital, Milan, Italy.,Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.,Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Elisa Giani
- Department of Pediatrics, Buzzi Children Hospital, Milan, Italy.,Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.,Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Maddalena Macedoni
- Department of Pediatrics, Diabetes Service Studies, University of Milan, Ospedale dei Bambini Vittore Buzzi, Milan, Italy
| | - Anna Maestroni
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Alice Dassano
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Moira Paroni
- Department of Bioscience, University of Milan, Milan, Italy
| | - Giuseppe Cannalire
- Department of Pediatrics and Neonatology, Ospedale Guglielmo da Saliceto, Piacenza, Italy
| | - Giacomo Biasucci
- Department of Pediatrics and Neonatology, Ospedale Guglielmo da Saliceto, Piacenza, Italy
| | - Marco Sala
- Department of Pediatrics, Tradate Hospital, Tradate, Italy
| | - Alessandra Biffi
- Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Gian Vincenzo Zuccotti
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.,Department of Pediatrics, Buzzi Children Hospital, Milan, Italy.,Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.,Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.,International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.,Division of Endocrinology, ASST Sacco Fatebenefratelli-Sacco, Milan, Italy
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43
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Illhardt T, Toporski J, Feuchtinger T, Turkiewicz D, Teltschik HM, Ebinger M, Schwarze CP, Holzer U, Lode HN, Albert MH, Gruhn B, Urban C, Dykes JH, Teuffel O, Schumm M, Handgretinger R, Lang P. Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma. Biol Blood Marrow Transplant 2018; 24:1005-1012. [DOI: 10.1016/j.bbmt.2017.12.805] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 12/30/2017] [Indexed: 12/25/2022]
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44
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Kamiya T, Wong D, Png YT, Campana D. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. Blood Adv 2018; 2:517-528. [PMID: 29507075 PMCID: PMC5851418 DOI: 10.1182/bloodadvances.2017012823] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 02/01/2018] [Indexed: 12/11/2022] Open
Abstract
Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19+ leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies.
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Affiliation(s)
- Takahiro Kamiya
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Desmond Wong
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yi Tian Png
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Dario Campana
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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45
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Alloantigen expression on malignant cells and healthy host tissue influences graft-versus-tumor reactions after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2018; 53:807-819. [PMID: 29362503 DOI: 10.1038/s41409-017-0071-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/27/2017] [Accepted: 11/28/2017] [Indexed: 11/08/2022]
Abstract
Durable remissions of hematological malignancies regularly observed following allogeneic hematopoietic stem cell transplantation (aHSCT) are due to the conditioning regimen, as well as an immunological phenomenon called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. The development of GVL is closely linked to graft-versus-host disease (GVHD), the main side effect associated with aHSCT. Both, GVHD and GVL are mediated by donor T cells that are initially activated by antigen-presenting cells that present recipient-derived alloantigens in the context of either matched or mismatched MHC class I molecules. Using murine models of aHSCT we show that ubiquitously expressed minor histocompatibility alloantigens (mHAg) are no relevant target for GVT effects. Interestingly, certain ubiquitously expressed MHC alloantigens augmented GVT effects early after transplantation, while others did not. The magnitude of GVT effects correlated with tumor infiltration by CD8+ cytotoxic T cells and tumor cell apoptosis. Furthermore, the immune response underlying GVHD and GVT was oligoclonal, highlighting that immunodominance is an important factor during alloimmune responses. These results emphasize that alloantigen expression on non-hematopoietic tissues can influence GVT effects in a previously unrecognized fashion. These findings bear significance for harnessing optimal GVL effects in patients receiving aHSCT.
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46
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Reddy P, Ferrara JL. Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00108-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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47
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Porrata LF. Autograft immune effector cells and survival in autologous peripheral blood hematopoietic stem cell transplantation. J Clin Apher 2017; 33:324-330. [PMID: 29232011 DOI: 10.1002/jca.21611] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 11/30/2017] [Accepted: 12/04/2017] [Indexed: 12/31/2022]
Abstract
In addition to stem cells, T-cells, natural killer cells, dendritic cells, and monocytes are also collected and infused from the autograft in patients undergoing autologous peripheral blood hematopoietic stem cell transplantation. Recent reports have shown that these autograft immune effector cells can affect the clinical outcome postautologous peripheral blood hematopoietic stem cell transplantation. In this article, I will review the clinical impact on the survival of these autograft immune effector cells conferring the concept of autologous graft versus tumor effect.
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Affiliation(s)
- Luis F Porrata
- Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota
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48
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Tsamadou C, Fürst D, Vucinic V, Bunjes D, Neuchel C, Mytilineos D, Gramatzki M, Arnold R, Wagner EM, Einsele H, Müller C, Schrezenmeier H, Mytilineos J. Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients. Haematologica 2017; 102:1947-1955. [PMID: 28883078 PMCID: PMC5664399 DOI: 10.3324/haematol.2017.169805] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 09/04/2017] [Indexed: 01/18/2023] Open
Abstract
The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48-0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs 18%, P=0.005; HR=0.40, CI 95%=0.22-0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post-transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.
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MESH Headings
- Adolescent
- Adult
- Aged
- Alleles
- Bone Marrow Transplantation
- Female
- Genotype
- Hematopoietic Stem Cell Transplantation/adverse effects
- Hematopoietic Stem Cell Transplantation/methods
- Histocompatibility Antigens Class I/genetics
- Histocompatibility Antigens Class I/immunology
- Histocompatibility Testing
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/therapy
- Male
- Middle Aged
- Potassium Channels, Inwardly Rectifying/genetics
- Prognosis
- Survival Analysis
- Transplantation Conditioning
- Transplantation, Homologous
- Treatment Outcome
- Young Adult
- HLA-E Antigens
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Affiliation(s)
- Chrysanthi Tsamadou
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg - Hessen, and University Hospital Ulm, Germany
- Institute of Transfusion Medicine, University of Ulm, Germany
| | - Daniel Fürst
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg - Hessen, and University Hospital Ulm, Germany
- Institute of Transfusion Medicine, University of Ulm, Germany
| | - Vladan Vucinic
- Department of Hematology/Oncology, University of Leipzig, Germany
| | - Donald Bunjes
- Department of Internal Medicine III, University of Ulm, Germany
| | - Christine Neuchel
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg - Hessen, and University Hospital Ulm, Germany
- Institute of Transfusion Medicine, University of Ulm, Germany
| | | | - Martin Gramatzki
- Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University of Kiel, Germany
| | - Renate Arnold
- Hematology/Oncology Department, Charité Campus Virchow-Klinikum, Berlin, Germany
| | - Eva Maria Wagner
- Department of Internal Medicine III, Johannes Gutenberg-University Mainz, Germany
| | - Hermann Einsele
- Department of Internal Medicine II, University Hospital Würzburg, Germany
| | - Carlheinz Müller
- ZKRD - Zentrale Knochenmarkspender-Register für Deutschland, German National Bone Marrow Donor Registry, Germany
- DRST - German Registry for Stem Cell Transplantation, Ulm, Germany
| | - Hubert Schrezenmeier
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg - Hessen, and University Hospital Ulm, Germany
- Institute of Transfusion Medicine, University of Ulm, Germany
| | - Joannis Mytilineos
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg - Hessen, and University Hospital Ulm, Germany
- Institute of Transfusion Medicine, University of Ulm, Germany
- DRST - German Registry for Stem Cell Transplantation, Ulm, Germany
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49
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Giebel B, Kordelas L, Börger V. Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig 2017; 4:84. [PMID: 29167805 DOI: 10.21037/sci.2017.09.06] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 08/27/2017] [Indexed: 12/12/2022]
Abstract
Within the last two decades mesenchymal stem/stromal cells (MSCs) emerged after hematopoietic stem cells as the second most investigated and applied somatic stem cell entity so far. MSCs mediate immunosuppressive as well as pro-regenerative activities. Against the initial assumption, MSCs may not primarily exert their therapeutic functions in a cellular but rather in a paracrine manner. Here, extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as major mediators of these paracrine effects. Meanwhile, MSC-EVs have been applied to an increasing amount of different animal models and were tested in a patient suffering from steroid-refractory acute graft-versus-host disease (acute GvHD) as well as in a patient cohort with chronic kidney disease. So far, the MSC-EV administration appears to be safe in humans and all tested animal models. Improvements were reported in all settings. Thus, MSC-EVs appear as promising novel therapeutic agents which might help to improve disease associated symptoms in millions of patients. Here, we review some of the milestones in the field, briefly discuss challenges and highlight clinical aspects of acute GvHD and its treatment with MSCs and MSC-EVs.
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Affiliation(s)
- Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Lambros Kordelas
- Department of Bone Marrow Transplantation, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Verena Börger
- Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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50
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Dukat-Mazurek A, Bieniaszewska M, Hellmann A, Moszkowska G, Trzonkowski P. Association of cytokine gene polymorphisms with the complications of allogeneic haematopoietic stem cell transplantation. Hum Immunol 2017; 78:672-683. [PMID: 28987962 DOI: 10.1016/j.humimm.2017.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/12/2017] [Accepted: 09/29/2017] [Indexed: 10/18/2022]
Abstract
The purpose of our study was to confirm the prevalence of the association between single nucleotide polymorphisms present in genes encoding cytokines and the complications occurring after haematopoietic stem cell transplantation (HSCT). 108 recipients and 81 donors were typed for TNF-α (-308), TGF-β1 (codon 10, 25), IL-10 (-1082, -819, -592), IL-6 (-174) and INF-γ (+874). Our studies have shown a tendency toward association between the occurrence of acute form of graft versus host disease (aGVHD) and IL-6 genotype. Homozygote C/C was less likely to develop aGVHD (p=0,09). Genotype GCC/ATA in IL-10 recipient gene alone had protective effect against the occurrence of aGVHD (p=0,01). Furthermore, GCC/ATA protected the host against developing the disease in the clinically relevant grades (II-IV) (p=0,03). In addition, the recipient's T/T G/G genotype (TGF-β1) predisposed to the development of both acute (p=0,06 - trend) and chronic (p=0,04) GVHD and also severe aGVHD (p=0,004). We also observed a statistically significant association between the genotype of recipient and the risk of infection - the protective function of the G/C IL-6 in the bloodstream infections (p=0,001). Our results suggest that IL-6, IL-10 and TGF-β1 genotypes of recipient are the most associated with the risk of complications after HSCT.
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Affiliation(s)
- Anna Dukat-Mazurek
- Department of Hematology and Transplantology, Medical University of Gdansk, Debinki 7 Street, 80-211 Gdansk, Poland.
| | - Maria Bieniaszewska
- Department of Hematology and Transplantology, Medical University of Gdansk, Debinki 7 Street, 80-211 Gdansk, Poland.
| | - Andrzej Hellmann
- Department of Hematology and Transplantology, Medical University of Gdansk, Debinki 7 Street, 80-211 Gdansk, Poland.
| | - Grażyna Moszkowska
- Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Debinki 7 Street, 80-211 Gdansk, Poland.
| | - Piotr Trzonkowski
- Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Debinki 7 Street, 80-211 Gdansk, Poland.
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