The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model
The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model
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DOI：
10.1172/jci32451
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Sayegh, Mohamed H.
中科院分区：
文献类型：
--
作者：
Ueno, Takuya;Habicht, Antje;Sayegh, Mohamed H.
T细胞Ig mucin 1 （TIM-1）在自身免疫和哮喘模型的免疫应答调节中起重要作用，它在Th1和Th2细胞上均有表达。利用一种拮抗TIM-1特异性抗体，我们研究了TIM-1在同种免疫中的作用。短期的tim -1特异性抗体单药治疗延长了完全mhc错配的血管化小鼠心脏异体移植物的存活时间。这种延长与抑制同种异体Th1反应和保存Th2反应有关。与th2型细胞因子缺乏Stat6（-/-）受体相比，tim -1特异性抗体治疗在th1型细胞因子缺乏Stat（-/-）受体中更有效。亚治疗剂量的雷帕霉素加tim -1特异性抗体导致同种异体移植物接受，并阻止慢性同种异体移植物血管病变的发展。同种异体移植物通过这种治疗存活伴随着Th1-到th2型细胞因子的转换。天然Tregs的消耗消除了tim -1特异性抗体的移植物保护作用。重要的是，与初始CD4(+)CD25(+) treg相比，从长期幸存者获得的CD4(+)CD25(+) treg具有增强的调节活性。与此一致的是，tim -1特异性抗体处理既保存了Tregs，又阻止了同种异体反应效应Th1细胞在同种异体反应性TCR转基因过继转移模型中的增殖。这些研究明确了TIM-1在体内调节同种免疫反应中的未知功能，并可能为促进移植耐受提供新的途径。
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 Stat(-/-) 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.