The Role of TIM-1: TIM-4 Pathway in Allograft Rejection and Tolerance

描述(申请人提供)：T细胞免疫球蛋白粘蛋白(TIM)家族是一类新的受体-配体对，在T细胞激活、分化和效应功能以及自身免疫和过敏/哮喘的免疫反应调节中发挥重要作用，但其在同种异体免疫反应中的功能尚不清楚。我们的中心假设得到了大量初步数据的支持，即TIM-1：TIM-4通路通过影响T辅助细胞的分化，在体内的同种异体免疫反应和耐受中发挥重要作用。此外，来自我们团队和其他人的数据表明，TIM家族分子可能在调节性T细胞的功能中发挥作用。该方案的主要目的是明确TIM-1：TIM-4通路在体内调节同种异体免疫反应中的作用和作用机制，作为在小鼠移植模型中实现持久和可重复性耐受的一种手段。独特的工具，包括抗TIM激动剂和阻断性抗体和融合蛋白，以及基因敲除和TCR转基因动物，将被用来剖析TIM-1：TIM-4通路在同种异体免疫中的功能，包括急性和慢性排斥的血管化移植模型，以及严格的皮肤移植模型。更具体地说，该项目的目的是：1.研究TIM-1：TIM-4通路在体内同种异体免疫反应中的作用。2.探讨TIM-1：TIM-4信号通路在慢性排斥反应中的作用。3.通过确定同种异体反应性T细胞在体内的命运，探讨靶向TIM-1：TIM-4通路在同种异体反应性和耐受性中的作用机制。4.研究TIM-1：TIM-4通路在体内Foxp3调节性T细胞生成/功能中的作用。总体而言，我们的具体目标描述了互补的方法，这些方法应该导致创新策略的开发，允许固体器官移植接受而不会出现慢性排斥反应，转化为灵长类动物和人类。

DESCRIPTION (provided by applicant): The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cell activation, differentiation and effector function, and in regulation of immune responses in autoimmunity and allergy/asthma, but its functions in alloimmune responses are poorly defined. Our central hypothesis, supported by extensive preliminary data, is that the TIM-1 :TIM-4 pathway, by affecting T helper cell differentiation, play important roles in alloimmune responses and tolerance in vivo. In addition, data from our group and others suggest a possible role of the TIM family of molecules in the function of regulatory T cells. The main goal of this proposal is to define the role and understand the mechanisms of action of the TIM-1:TIM-4 pathway in regulating alloimmune responses in vivo as a means of achieving durable and reproducible tolerance in murine transplant models. Unique tools, including anti-TIM agonistic and blocking antibodies and fusion proteins, and gene knockout and TCR transgenic animals will be used to dissect the functions of the TIM-1 :TIM-4 pathway in alloimmunity using vascularized transplant models of acute and chronic rejection, and stringent models of skin transplantation. More specifically, the aims of the project are: 1. To investigate the functions of the TIM-1 :TIM-4 pathway in alloimmune responses in vivo. 2. To investigate the functions of the TIM-1 :TIM-4 pathway in chronic rejection. 3. To investigate the mechanisms of action of targeting the TIM-1 :TIM-4 pathway in alloreactivity and tolerance via defining the fate of alloreactive T cells in vivo. 4. To study the role of the TIM-1 :TIM-4 pathway in generation/function of Foxp3 regulatory T cells in vivo. Overall, our specific aims describe complimentary approaches that should lead to the development of innovative strategies to permit solid organ graft acceptance without chronic rejection to translate to primates and humans.