Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients.
Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients.
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DOI：
10.1126/scitranslmed.3010760
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发表时间：
2015-01-28
影响因子：
17.1
通讯作者：
Sykes M
中科院分区：
文献类型：
--
作者：
Morris H;DeWolf S;Robins H;Sprangers B;LoCascio SA;Shonts BA;Kawai T;Wong W;Yang S;Zuber J;Shen Y;Sykes M
T细胞对同种异体主要组织相容性(MHC)抗原的反应是器官移植的一个巨大障碍，需要长期的免疫抑制以减少排斥反应。慢性排斥反应和药物致病是可通过诱导同种异体移植耐受克服的主要限制因素。肾和骨髓联合移植(CKBMT)首次在人类体内故意诱导耐受，但这些患者的耐受机制尚不完全清楚。我们现在建立了一种鉴定供者反应性T细胞的方法，并测试缺失在CKBMT后耐受性中的作用。使用TCRB链CDR3区域的高通量测序，我们定义了移植前供者反应性T细胞谱系的指纹，并在移植后跟踪这些克隆。我们观察到了三名耐受性CKBMT患者移植后供者反应性T细胞克隆的减少；在第四名非耐受性CKBMT患者或两名接受标准免疫抑制方案的传统肾移植受者中没有观察到这种减少。淋巴细胞耗竭调节导致的T细胞库周转仅部分解释了观察到的耐受性患者T细胞库的减少；事实上，传统的移植受者表现出循环中供体反应性克隆的扩大，尽管有广泛的库周转。此外，与体外功能分析相比，供体反应性T细胞克隆的缺失与耐受诱导的关系更密切。我们的分析支持克隆性缺失是CKBMT患者移植耐受的一种机制。这些结果验证了我们的方法在移植前识别的供者反应性T细胞克隆的重要性，支持进一步探索作为移植结果的潜在生物标记物。
T cell responses to allogeneic major histocompatibility (MHC) antigens present a formidable barrier to organ transplantation, necessitating long-term immunosuppression to minimize rejection. Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally induced in humans via combined kidney and bone marrow transplantation (CKBMT), but the mechanisms of tolerance in these patients are incompletely understood. We now establish an assay to identify donor-reactive T cells and test the role of deletion in tolerance after CKBMT. Using high-throughput sequencing of the TCRB chain CDR3 region, we define a fingerprint of the donor-reactive T cell repertoire prior to transplantation and track those clones post-transplant. We observed post-transplant reductions in donor-reactive T cell clones in three tolerant CKBMT patients; such reductions were not observed in a fourth, non-tolerant, CKBMT patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens. T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients; in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in CKBMT patients. The results validate the significance of donor-reactive T cell clones identified pre-transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes.
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人T细胞的稳态膨胀和表型转化取决于与APC的外周相互作用。
DOI：
10.4049/jimmunol.0901711
发表时间：
2010-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Onoe T;Kalscheuer H;Chittenden M;Zhao G;Yang YG;Sykes M
通讯作者：
Sykes M
影响因子：
8.8
作者：
Dziubianau, M.;Hecht, J.;Babel, N.
通讯作者：
Babel, N.
影响因子：
6.2
作者：
GOULMY, E;PERSIJN, G;VANROOD, JJ
通讯作者：
VANROOD, JJ
影响因子：
6.2
作者：
Manilay, JO;Pearson, DA;Sykes, M
通讯作者：
Sykes, M
影响因子：
6.2
作者：
Leventhal J;Abecassis M;Miller J;Gallon L;Tollerud D;Elliott MJ;Bozulic LD;Houston C;Sustento-Reodica N;Ildstad ST
通讯作者：
Ildstad ST