Role of Novel T Cell Costimulatory Pathways in Allograft Rejection and Tolerance

新型 T 细胞共刺激途径在同种异体移植物排斥和耐受中的作用

• 批准号: 7644026
• 负责人: Mohamed H Sayegh
• 金额: $ 50.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644026
• 关键词: Acute; Address; Affect; Alloantigen; Allografting; Animals; Apoptosis; Asthma; Autoimmune Diabetes; Autoimmune Process; Autoimmune Responses; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiac; Cell Death; Cell Differentiation process; Cells; Chimeric Proteins; Data; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Failure; Family; Generations; Goals; Graft Rejection; Graft Survival; Hand; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; Immune response; Immunity; Immunoglobulins; Inbred NOD Mice; Islets of Langerhans Transplantation; Knock-in Mouse; Knock-out; Ligands; Maintenance; Mediating; Memory; Modeling; Mucin 1 protein; Mucins; Mus; Outcome; Pathway interactions; Peripheral; Personal Satisfaction; Play; Primates; Process; Publishing; Recurrence; Regulation; Reporter; Research Personnel; Role; Sirolimus; Skin; Specificity; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Th1/Th2 Differentiation Pathway; Th2 Cells; Transgenic Animals; Translating; Transplantation; anergy; autoreactive T cell; base; clinically relevant; cytokine; design; in vivo; islet; islet allograft; isoimmunity; novel; novel strategies; prevent; programs; receptor; research study; response; tool; transplantation typing

The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cell activation, differentiation and effector/memory function, and in regulation of immune responses in auto- immunity and allergy/asthma. TIM-1 is expressed by activated Th1 and Th2 cells and its expression is sustained preferentially in terminally differentiated Th2 cells. The ligand for TIM-1 is TIM-4, which is predominantly expressed on APCs. Recent studies indicate that TIM-1 may differentially regulate T helper cell (Th1/Th2) differentiation in asthma/allergy, and autoimmune encephalomyelitis. At present, little is known about the role of the TIM-1 :TIM-4 pathway in alloimmune responses and autoimmune diabetes. Preliminary studies from our group indicate that the TIM-1:TIM-4 pathway plays an important role in alloimmunity, particularly alloreactive T helper cell differentiation and possibly regulatory T cell generation/function. Furthermore, it is well established that the balance of autoreactive Th1 cells on one hand and regulatory T cells and Th2 cells on the other is critical in determining the outcome of autoimmune diabetes in NOD mice. Our central hypothesis is that the TIM-1:TIM-4 pathway, by modulating Th1/Th2 cell differentiation and possibly regulatory T cell generation and function, plays an important role in alloimmune and autoimmune responses, and tolerance. The main goal of this proposal is to define the functions and mechanisms of the TIM-1:TIM-4 pathway in regulating immune responses in vivo as a means of developing novel strategies to achieve durable and reproducible tolerance, and preventing the development of recurrent autoimmunity to islet allografts. In that regard, our approach is to test and explore the mechanisms of novel rational combination strategies that target multiple pathways resulting in silencing of alloreactive and autoreactive T cells, and tipping the balance towards regulation by cells and/or cytokines in NOD recipients of islet allo- grafts. In Specific Aim 1 we will investigate the effects of targeting the TIM-1 :TIM-4 pathway on alloimmune and autoimmune responses in vivo in models of islet allograft rejection. In Specific Aim 2 we will dissect the mechanisms of action of TIM-1:TIM-4 pathway in alloimmunity, autoimmunity and tolerance, focusing on T cell expansion, differentiation, and apoptosis. These studies will utilize CD4+ and CD8+ TCR transgenic animals with defined allo- (B6 background) and auto- (NOD background) specificities. MHC tetramers will also be used to study the mechanisms of targeting TIM-1 on autoreactive CD4+ and CD8+ T cells in NOD mice. Finally, in Specific Aim 3 we will focus specifically on the role of TIM-1:TIM-4 pathway in the generation and/or function of regulatory T cells in vivo. Using foxp3-GFP knock-in reporter mice on B6 and NOD backgrounds, we will test the hypothesis, based on initial preliminary data, that the TIM-1:TIM-4 pathwaymay have an important role in the generation and/or function of CD4+CD25+ regulatory T cells in vivo. Overall, our studies shouldyield useful new data that maylead to development of novel strategies to induce tolerance to islet alloarafts to translate to orimates and humans.

T细胞免疫球蛋白粘蛋白（TIM）新型受体配体对在T细胞中起重要作用 激活，分化和效应子/记忆函数，以及自身的免疫反应调节 免疫力和过敏/哮喘。 TIM-1由活化的Th1和Th2细胞表达，其表达为 在终末分化的Th2细胞中优先持续。 Tim-1的配体是Tim-4，是 主要在APC上表达。最近的研究表明，TIM-1可能会差异调节T辅助细胞 （TH1/TH2）哮喘/过敏和自身免疫性脑脊髓炎的分化。目前，鲜为人知 关于TIM-1：TIM-4途径在同种免疫反应和自身免疫性糖尿病中的作用。初步的 来自我们小组的研究表明，tim-1：tim-4途径在同种免疫力中起重要作用， 特别是同种异体T辅助细胞分化，可能是调节性T细胞的产生/功能。 此外，众所周知，自动反应性Th1细胞的平衡和调节t 另一个细胞和Th2细胞对于确定NOD小鼠自身免疫性糖尿病的结局至关重要。 我们的中心假设是通过调节TH1/TH2细胞分化和 可能是调节性T细胞的生成和功能，在同种免疫和自身免疫中起重要作用 回应和宽容。该提案的主要目标是定义 TIM-1：TIM-4在体内调节免疫反应的途径，作为制定新型策略的一种手段 实现耐用且可重复的耐受性，并防止复发自身免疫的发展 胰岛同种异体移植。在这方面，我们的方法是测试和探索新颖理性的机制 针对多种途径的组合策略导致同种反应性和自动反应性T 细胞，并将平衡倾斜到由细胞和/或细胞因子调节的胰岛接受者中的细胞和/或细胞因子的调节。 移植物。在特定目的1中，我们将研究靶向TIM-1：TIM-4途径对同种免疫的影响 在同种异体移植抑制模型中，体内自身免疫反应。在特定目标2中，我们将剖析 TIM-1的作用机制：TIM-4途径在同种免疫，自身免疫性和耐受性，重点放在T细胞上 扩展，分化和凋亡。这些研究将利用CD4+和CD8+ TCR转基因动物 具有定义的Allo-（B6背景）和自动（NOD背景）特异性。 MHC四聚体也将 用于研究NOD小鼠中靶向TIM-1对自动反应性CD4+和CD8+ T细胞的机制。 最后，在特定目标3中，我们将专门关注Tim-1：Tim-4途径在一代中的作用 和/或体内调节性T细胞的功能。在B6上使用FOXP3-GFP敲门记者小鼠并点头 背景，我们将基于初始初步数据测试假设，即tim-1：tim-4 pathwaymay 在体内CD4+ CD25+调节T细胞的产生和/或功能中具有重要作用。 总体而言，我们的研究尤其是有用的新数据，这些数据可以发展出新的策略的发展 诱导对胰岛同种异体的耐受性，以转化为Orimates和人类。