Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.
Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.
复制标题
供体反应性T细胞的衰减可以使用调节性T细胞治疗有效控制同种异体移植的排斥。
DOI：
10.1111/ajt.12509
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Tang Q
中科院分区：
文献类型：
--
作者：
Lee K;Nguyen V;Lee KM;Kang SM;Tang Q
调节性T细胞（Treg）对于建立和维持免疫耐受至关重要，这表明Treg在移植中具有潜在的治疗作用。然而，单独施用Treg不足以在正常宿主中诱导长期同种异体移植物存活，这可能是由于同种异体反应性T细胞的高频率。我们假设靶向减少同种异体反应性T效应细胞将允许Treg功效的治疗窗口。在这里，我们表明，预处理受体小鼠与供体特异性输血后，环磷酰胺治疗删除70-80%的供体反应性T细胞，但未能延长胰岛移植物的存活。然而，输注5 ×106个具有直接供体反应性的TCLs或25 ×106个多克隆TCLs导致超过70%的预处理C57 BL/6受体中的BALB/c胰岛无限期存活。值得注意的是，在自身免疫性非肥胖糖尿病小鼠中C3 H胰岛的保护需要胰岛自身抗原特异性Tcl 4和多克隆Tcl 4。Treg治疗导致移植后早期移植物浸润细胞中CD 8 + T细胞的显著减少和伴随的内源性T细胞的增加。总之，这些结果表明，减少供体反应性T细胞将是移植中基于Treg的疗法的重要组成部分。
Regulatory T cells (Tregs) are essential for the establishment and maintenance of immune tolerance, suggesting a potential therapeutic role for Tregs in transplantation. However, Treg administration alone is insufficient in inducing long-term allograft survival in normal hosts, likely due to the high frequency of alloreactive T cells. We hypothesized that a targeted reduction of alloreactive T effector cells would allow a therapeutic window for Treg efficacy. Here we show that preconditioning recipient mice with donor-specific transfusion followed by cyclophosphamide treatment deleted 70–80% donor-reactive T cells, but failed to prolong islet allograft survival. However, infusion of either 5 ×106 Tregs with direct donor reactivity or 25 ×106 polyclonal Tregs led to indefinite survival of BALB/c islets in more than 70% of preconditioned C57BL/6 recipients. Notably, protection of C3H islets in autoimmune nonobese diabetic mice required islet autoantigen-specific Tregs together with polyclonal Tregs. Treg therapy led to significant reduction of CD8+ T cells and concomitant increase in endogenous Tregs among graft-infiltrating cells early after transplantation. Together, these results demonstrate that reduction of the donor-reactive T cells will be an important component of Treg-based therapies in transplantation.