Role of TIM Family of Molecules in Regulating Transplantation Tolerance

TIM 分子家族在调节移植耐受中的作用

• 批准号: 8378184
• 负责人: TERRY B. STROM
• 金额: $ 38.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378184
• 关键词: Agonist; Alloantigen; Allografting; Antibodies; Antigen-Presenting Cells; Apoptotic; Basic Science; Biochemical; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cell Survival; Cells; Cessation of life; Chimeric Proteins; Engraftment; Equilibrium; Family; Family member; Galactose Binding Lectin; Galectin 3; Gene Family; Goals; Graft Rejection; IL2RA gene; Immune response; Immunity; Immunoglobulins; Infusion procedures; Knowledge; Ligands; Ligation; Mitogen-Activated Protein Kinases; Molecular; Monoclonal Antibodies; Mucins; Mus; Nature; Pathway Analysis; Pathway interactions; Pattern; Peripheral; Phenotype; Population; Proteins; Reagent; Regulation; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; T-Cell Activation; T-Lymphocyte; Testing; Transplantation; Transplantation Tolerance; Wild Type Mouse; allograft rejection; allotransplant; base; in vivo; novel; prevent; research study; response; tool

We hypothesize that interaction ofT cell Immunoglobulin Mucin (TIM) proteins with their ligands regulates the aggressive and protective components of the allograft response. Both basic science and translational aspects are explored. Crucial to our proposal is knowledge that the potential to create peripheral transplant tolerance is negated in Tim-3 deficient mice and in wild type mice treated with blocking anti-Tim-3 mAb or Tim-3.Ig fusion proteins. Why? In the absence of the Tim-3-to-galectin-9 interaction, TH1 type alloimmune responses are not properly terminated and the TREG compartment does not expand. New experiments reveal that Tim-3 is expressed on CD4+ TH17 and CD8+ CTLs (Tc1) effector T cells as well as terminally differentiated TH1 cells. These findings serve to magnify the importance of the Tim-3-to-galectin-9 interaction in the effector T cell allograft response. Another Tim family member Tim-1 is expressed on all activated T cells and we have identified Tim-4 that is expressed on antigen presenting cells as the ligand for Tim-1. We have now identified antagonist .type anti-Tim-1 mAbs as well as agonist type anti-Tim-1 mAbs. The 3B3 agonist mAb and Tim-4.Ig, act as potent T cell co stimulants. In vivo administration of the agonist mAb blocks the induction of transplant tolerance by co stimulation blockade, favors polarization of the allograft response into a TH"!/ Tn17 pattern while inhibiting expansion/function of TregS. In contrast, infusion of an antagonist type anti-Tim-1 mAb (RMT 1-10) aids tolerance induction and polarizes the allograft response into a TH2/ Treg dominant mode. Using these novel tools we propose to explore the role of Tim family of molecules in the regulation of transplantation tolerance. Specifically, we hypothesize that the (i) Tim-3-togalectin- 9 interaction gates the cytopathic alloreactive TH1, Tc1 as well as the newly recognized TH17 compartments and reciprocally regulates the donor reactive TREc compartment, and (ii) Tim-1 -to-Tim-4 interaction regulates the intensity and direction of CD4+ T cell activation. The specific aims are to analyze: 1) the Tim-3-galectin 9 axis in the allograft response; 2) the Tim1-Tim-4 axis in the allograft response; and 3) T cell signaling pathways in the context of Tim-1 and Tim-3 engagement. These studies will provide a functional and mechanistic understanding of how Tim-1 and Tim-3 molecules upon interaction with their ligand regulate immune responses to allotransplants.

我们假设这种相互作用oft细胞免疫球蛋白粘蛋白（TIM）蛋白与配体 调节同种异体移植反应的侵略性和保护性成分。基础科学和 探索了翻译方面。对我们的建议至关重要的是，知道创造的潜力 在TIM-3缺乏小鼠和用阻塞治疗的野生型小鼠中，外围移植耐受性被否定 抗TIM-3 mAb或tim-3.ig融合蛋白。为什么？在没有TIM-3到Galectin-9相互作用的情况下，Th1 类型AlloMune响应未正确终止，Treg隔室没有扩展。新的 实验表明，TIM-3在CD4+ TH17和CD8+ CTL（TC1）效应T细胞以及 末端分化的Th1细胞。这些发现有助于放大TIM-3至galectin-9的重要性 效应T细胞同种异体移植反应中的相互作用。蒂姆家族成员蒂姆1对所有人表示 活化的T细胞，我们已经确定了在抗原呈递细胞上表达的TIM-4作为配体 Tim-1。现在，我们已经鉴定出拮抗剂.Type抗TIM-1 MAB以及激动剂型抗TIM-1 MAB。 3B3激动剂mAb和tim4.ig充当有效的T细胞CO刺激剂。激动剂的体内给药 mAb通过CO刺激阻断阻塞移植耐受性的诱导，有利于偏振 同种异体移植反应对TH“！/ TN17模式，同时抑制Tregs的扩张/功能。相反，输注 拮抗剂型抗TIM-1 MAB（RMT 1-10）有助于耐受性诱导并极化同种异体移植反应 进入TH2/ Treg主导模式。我们建议使用这些新颖的工具来探索蒂姆家族的作用 分子调节移植耐受性。具体而言，我们假设（i）tim-3----------------------- 9相互作用的细胞疗法同种异体反应性TH1，TC1以及新认可的TH17 隔室和相互调节的供体反应性TREC室，（ii）TIM-1-1至TIM-4 相互作用调节CD4+ T细胞活化的强度和方向。具体目的是分析： 1）同种异体移植反应中的TIM-3-甘氏蛋白9轴； 2）同种异体移植反应中的TIM1-TIM-4轴；和 3）TIM-1和TIM-3参与度的T细胞信号通路。这些研究将提供 对TIM-1和TIM-3分子与其相互作用时如何进行功能和机械理解 配体调节对同种异体植物的免疫反应。