Hotta Kiyohiko, Aoyama Akihiro, Oura Tetsu, Yamada Yohei, Tonsho Makoto, Huh Kyu Ha, Kawai Kento, Schoenfeld David, Allan James S, Madsen Joren C, Benichou Gilles, Smith Rex-Neal, Colvin Robert B, Sachs David H, Cosimi A Benedict, Kawai Tatsuo
Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts, USA.
JCI Insight. 2016 Jul 7;1(10). doi: 10.1172/jci.insight.86419.
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8 T cell responses in tolerant (TOL) recipients, while marked CD4 T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4 cells were FOXP3 in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4FOXP3 cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.
通过诱导短暂的造血嵌合，在非人类灵长类动物（NHPs）和人类中已成功实现同种异体移植耐受。由于这些受者在没有持久嵌合的情况下实现了同种异体移植耐受，因此推测外周机制起主要作用。在此，我们报告了对实现长期耐受的NHP受者与排斥同种异体移植（AR）的受者的T细胞免疫研究。所有肾、心和肺移植受者在接受非清髓性方案预处理后，接受了同步或延迟的供体骨髓移植（DBMT）。DBMT后，用CFSE进行的混合淋巴细胞培养始终显示，耐受（TOL）受者中CD8 T细胞反应出现供体特异性丧失，而对供体抗原的显著CD4 T细胞增殖持续存在。有趣的是，在TOL受者中，增殖的CD4细胞中有很大一部分是FOXP3阳性，但在AR受者或未接触过抗原的NHPs中并非如此。在TOL受者中，针对供体抗原的CD4FOXP3细胞增殖大于针对第三方抗原的增殖。最后，扩增的调节性T细胞（Tregs）似乎是由非Tregs转化而来的诱导性Tregs（iTregs）。这些数据支持了以下假设：供体抗原特异性诱导iTregs是短暂混合嵌合诱导长期同种异体移植耐受的关键。
