1/23/2024 0 Comments Rit color grabber![]() ![]() The objective was to assess the evolution of the T-cell immune repertoire in peripheral blood samples and their patterns in the context of allograft phenotypes. Having found no significant changes in the TCR repertoire in acute rejection in pediatric recipients of renal allografts, in this study, we evaluated the TCR immune repertoires in a large cohort of adult renal transplant patients so as to be able to discern low frequency changes between T-cell clones and transplant time, histologically confirmed acute rejection episodes, and any specific variations with T cell or antibody mediated rejections. In children and young infants, a diverse B-cell pre-transplant repertoire correlated with post-transplant rejection risk, but no differences were found in the TCR immune repertoire ( 13). Recent exploratory studies tracking peripheral blood T cells using TCR sequencing after kidney transplantation ( 5, 7– 10) have observed low-frequency immune repertoires alterations with small sample sizes ( 11, 12). To assess the evolution of the T-cell immune repertoire in peripheral blood samples and their patterns in the context of allograft phenotypes, we compared peripheral blood samples from demographically matched renal transplant recipients who had either protocol or clinically indicated biopsies and paired blood samples for immune repertoire analysis group comparisons were conducted between patients with histologically clean protocol biopsies (designated as the stable group (STA)) and histologically confirmed acute rejection as graded by the Banff classification on either protocol or indicated biopsies (designated as the acute rejection group (AR)) ( 5, 6). Accurate and high-throughput sequencing of the third complementarity-determining region (CDR3) of the TCRβ chain, which is the crucial segment for antigen specificity, allowed us to profile the T-cell repertoire in peripheral blood samples, coincident with the occurrence of acute renal transplant rejection on a paired allograft biopsy, and to evaluate if rejection could be predicted prior to histological evaluation by peripheral blood sampling before transplantation and if specific changes in the TCR repertoire can define different phenotypes of acute rejection, such as antibody mediated rejection ( 4). Recent developments in T-cell receptor (TCR) sequencing allow for analysis of alloreactive human T-cell populations both before and after engraftment ( 2– 4). Transplanted kidneys fail due to both immune and nonimmune causes including primarily anti-donor alloimmunity via recruitment of activated T cells, but also due to other contributing factors such as activation of innate immunity by triggers such as cold ischemia time, donor co-morbidities, heterologous immunity from infections, and drug toxicities ( 1). In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk. Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover p=0.0016) of their T-cell repertoire. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. 2Adaptive Biotechnologies, Seattle, WA, United States. ![]() ![]()
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