Ana F David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, Rainer Oberbauer
{"title":"联合细胞疗法会导致肾移植受者体内捐献者特异性 T 细胞的克隆性缺失。","authors":"Ana F David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, Rainer Oberbauer","doi":"10.1016/j.ebiom.2024.105239","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.</p><p><strong>Methods: </strong>We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.</p><p><strong>Findings: </strong>Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4<sup>+</sup> T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4<sup>+</sup> and CD8<sup>+</sup> TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.</p><p><strong>Interpretation: </strong>Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.</p><p><strong>Funding: </strong>This study was funded by the Vienna Science and Technology Fund (WWTF).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284950/pdf/","citationCount":"0","resultStr":"{\"title\":\"Combination cell therapy leads to clonal deletion of donor-specific T cells in kidney transplant recipients.\",\"authors\":\"Ana F David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, Rainer Oberbauer\",\"doi\":\"10.1016/j.ebiom.2024.105239\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.</p><p><strong>Methods: </strong>We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.</p><p><strong>Findings: </strong>Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4<sup>+</sup> T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4<sup>+</sup> and CD8<sup>+</sup> TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.</p><p><strong>Interpretation: </strong>Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.</p><p><strong>Funding: </strong>This study was funded by the Vienna Science and Technology Fund (WWTF).</p>\",\"PeriodicalId\":11494,\"journal\":{\"name\":\"EBioMedicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.7000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284950/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EBioMedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ebiom.2024.105239\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/13 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2024.105239","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/13 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Combination cell therapy leads to clonal deletion of donor-specific T cells in kidney transplant recipients.
Background: Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.
Methods: We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.
Findings: Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4+ T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4+ and CD8+ TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.
Interpretation: Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.
Funding: This study was funded by the Vienna Science and Technology Fund (WWTF).
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍:
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.