Ueno Takuya, Habicht Antje, Clarkson Michael R, Albin Monica J, Yamaura Kazuhiro, Boenisch Olaf, Popoola Joyce, Wang Ying, Yagita Hideo, Akiba Hisaya, Ansari M Javeed, Yang Jaeseok, Turka Laurence A, Rothstein David M, Padera Robert F, Najafian Nader, Sayegh Mohamed H
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2008 Feb;118(2):742-51. doi: 10.1172/JCI32451.
T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.
T细胞免疫球蛋白黏蛋白1（TIM-1）在自身免疫和哮喘模型中调节免疫反应方面发挥着重要作用，并且在Th1和Th2细胞上均有表达。我们使用一种TIM-1特异性拮抗抗体，研究了TIM-1在同种异体免疫中的作用。短期使用TIM-1特异性抗体单一疗法可延长完全MHC不匹配的血管化小鼠心脏同种异体移植物的存活时间。这种存活时间的延长与同种异体反应性Th1反应的抑制以及Th2反应的保留有关。与Th2型细胞因子缺陷的Stat6（-/-）受体相比，TIM-1特异性抗体治疗在Th1型细胞因子缺陷的Stat4（-/-）受体中更有效。亚治疗剂量的雷帕霉素加TIM-1特异性抗体可导致同种异体移植物被接受，并预防慢性同种异体移植物血管病的发生。通过这种治疗实现的同种异体移植物存活伴随着从Th1型细胞因子向Th2型细胞因子的转变。天然调节性T细胞的耗竭消除了TIM-1特异性抗体的移植物保护作用。重要的是，与幼稚的CD4（+）CD25（+）调节性T细胞相比，从长期存活者中获得的CD4（+）CD25（+）调节性T细胞具有增强的调节活性。与此一致地，在同种异体反应性TCR转基因过继转移模型中，TIM-1特异性抗体治疗既保留了调节性T细胞，又阻止了同种异体反应性效应Th1细胞的扩增。这些研究确定了TIM-1在体内调节同种异体免疫反应方面以前未知的功能，并可能为促进移植耐受提供一种新方法。
