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

TIM-1：TIM-4 通路在同种异体移植排斥和耐受中的作用

• 批准号: 8099446
• 负责人: Mohamed H Sayegh
• 金额: $ 40.45万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099446
• 关键词: Acute; Address; Adverse effects; Affect; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animals; Antibody Therapy; Antigen-Presenting Cells; Antigens; Apoptosis; Asthma; Autoimmunity; Behavior; Blocking Antibodies; Breeding; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiac; Cell Death; Cell Differentiation process; Cells; Chimeric Proteins; Chronic; Clinical; Clonal Expansion; Collaborations; Complex; Data; Development; Engraftment; Experimental Autoimmune Encephalomyelitis; Family; Fibrosis; Functional disorder; Gene Expression; Gene Targeting; Generations; Goals; Graft Rejection; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL2RA gene; Immune response; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; In Vitro; Knock-in Mouse; Laboratories; Lead; Life; Ligands; Link; MHC Class II Genes; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic Diseases; Modeling; Mucin 1 protein; Mucins; Mus; Opportunistic Infections; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Play; Primates; Procedures; Process; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Reporter; Research Personnel; Rodent; Role; STAT4 gene; STAT6 gene; Signal Transduction; Sirolimus; Skin; Skin Transplantation; Solid; Specificity; Survival Rate; T cell differentiation; T cell regulation; T cell response; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Th1 Cells; Th1/Th2 Differentiation Pathway; Th2 Cells; Transgenic Animals; Transgenic Mice; Transgenic Model; Translating; Transplantation; Transplantation Tolerance; Universities; Vascular Diseases; Withdrawal; allograft rejection; anergy; base; cardiovascular disorder risk; chemokine; clinically relevant; cytokine; design; end-stage organ failure; graft failure; heart allograft; immunoregulation; improved; in vivo; innovation; insight; isoimmunity; knockout gene; nonhuman primate; novel; novel strategies; peripheral tolerance; prevent; programs; receptor; response; skin allograft; tool; Acute; Address; Adverse effects; Affect; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animals; Antibody Therapy; Antigen-Presenting Cells; Antigens; Apoptosis; Asthma; Autoimmunity; Behavior; Blocking Antibodies; Breeding; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiac; Cell Death; Cell Differentiation process; Cells; Chimeric Proteins; Chronic; Clinical; Clonal Expansion; Collaborations; Complex; Data; Development; Engraftment; Experimental Autoimmune Encephalomyelitis; Family; Fibrosis; Functional disorder; Gene Expression; Gene Targeting; Generations; Goals; Graft Rejection; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL2RA gene; Immune response; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; In Vitro; Knock-in Mouse; Laboratories; Lead; Life; Ligands; Link; MHC Class II Genes; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic Diseases; Modeling; Mucin 1 protein; Mucins; Mus; Opportunistic Infections; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Play; Primates; Procedures; Process; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Reporter; Research Personnel; Rodent; Role; STAT4 gene; STAT6 gene; Signal Transduction; Sirolimus; Skin; Skin Transplantation; Solid; Specificity; Survival Rate; T cell differentiation; T cell regulation; T cell response; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Th1 Cells; Th1/Th2 Differentiation Pathway; Th2 Cells; Transgenic Animals; Transgenic Mice; Transgenic Model; Translating; Transplantation; Transplantation Tolerance; Universities; Vascular Diseases; Withdrawal; allograft rejection; anergy; base; cardiovascular disorder risk; chemokine; clinically relevant; cytokine; design; end-stage organ failure; graft failure; heart allograft; immunoregulation; improved; in vivo; innovation; insight; isoimmunity; knockout gene; nonhuman primate; novel; novel strategies; peripheral tolerance; prevent; programs; receptor; response; skin allograft; tool

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.

描述（由申请人提供）：T细胞免疫球蛋白粘蛋白（TIM）新型受体配体对家族在T细胞激活，分化和效应子功能以及自身免疫和过敏/哮喘中免疫反应的调节中起着重要作用，但是它在AlloMmune响应中的功能较差。我们的中心假设得到了广泛的初步数据的支持，是tim-1：tim-4途径通过影响T辅助细胞分化，在体内中扮演着重要的作用，在体内发挥重要作用。此外，我们小组和其他人的数据表明，TIM分子家族在调节T细胞功能中的可能作用。该提案的主要目的是定义角色并了解TIM-1：TIM-4途径在调节体内同种免疫反应方面的作用机制，以作为在鼠类移植模型中实现耐用且可再现的耐受性的一种手段。独特的工具，包括抗TIM激动剂和阻断抗体和融合蛋白，以及基因敲除和TCR转基因动物，用于使用急性和慢性抑制模型的血管化移植模型的血管化移植模型，以及皮肤移植的严格模型，在同种免疫性中剖析TIM-1：TIM-4途径的功能。更具体地说，该项目的目的是：1。研究TIM-1：TIM-4途径在体内响应中的功能。 2。研究慢性排斥反应中TIM-1：TIM-4途径的功能。 3。通过定义体内同种反应性T细胞的命运，研究靶向TIM-1：TIM-1：TIM-1：TIM-4途径的作用机制。 4。研究TIM-1：TIM-4途径在体内Foxp3调节T细胞的发电/功能中的作用。总体而言，我们的具体目的描述了免费的方法，这些方法应导致创新策略的发展，以允许固体器官移植的接受而无需长期拒绝以转化为灵长类动物和人类。