Role of T cell Specific Adaptor Protein in Alloimmunity

T 细胞特异性衔接蛋白在同种免疫中的作用

• 批准号: 8190975
• 负责人: David M. Briscoe
• 金额: $ 21.71万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190975
• 关键词: Adaptor Signaling Protein; Adaptor Signaling Protein Gene; Address; Age; Alloantigen; Allografting; Antigens; Autoimmune Diseases; B-Lymphocytes; Biological; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular Immunity; Chronic; Clinical; Complex; Defect; Development; Exploratory/Developmental Grant; Future; Generations; Goals; Graft Rejection; Graft Survival; IL2RA gene; Immune response; Immunity; Individual; Inflammation; Inflammatory; Injury; Interleukin-2; Interleukin-4; Investigation; Knock-out; Knockout Mice; Lead; Learning; Life; Mediating; Mitogens; Modeling; Mus; Organ Transplantation; Outcome; Participant; Pathway interactions; Peripheral; Play; Process; Production; Protein Tyrosine Kinase; RANTES; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Proposals; Role; Self Tolerance; Signal Transduction; Small Interfering RNA; Stimulus; Stromal Cell-Derived Factor 1; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Transplantation; Transplantation Tolerance; Tyrosine; Vascular Endothelial Cell; adapter protein; allograft rejection; base; cell type; chemokine; clinically relevant; clinically significant; cytokine; end-stage organ failure; heart allograft; immunoregulation; in vivo; isoimmunity; lupus-like; migration; novel; prevent; protein function; response; src Homology Region 2 Domain; therapeutic development

DESCRIPTION (provided by applicant): Allograft rejection is mediated by the recipient's immunological response to donor antigen, initiated and coordinated by CD4+ T cells. Once T cells encounter alloantigen, they undergo expansion and differentiation into effectors and/or memory T cells. Activation also results in the expansion of regulatory T cells that function to control the immune response, and it is proposed that this process of immunoregulation is critical for long term allograft survival. Within T cells, several adapter proteins have been found to play central roles in T cell receptor-induced signal transduction, and several have been found to be active participants in the formation of signaling complexes, which modulate the T cell activation response. T-cell-Specific Adaptor Protein (TSAd) is a SH2 domain containing intracellular adaptor molecule that was initially reported to be restricted in its expression to T cells. Increasing evidence suggests that the function of TSAd in T cells is complex, and that it is of importance in both effector as well as well as regulatory responses. However, no study has addressed questions about the biology of TSAd in allograft rejection and/or in the alloimmune response. This exploratory research proposal is based on novel preliminary observations in which we observed that TSAd knockout recipients of cardiac allografts have a profound defect in alloimmune regulation. The overall goal of our research is to characterize how TSAd mediates immunoregulation following transplantation. Specifically, we plan to use TSAd knockout mice as recipients of allografts to determine its function in the rejection process, to identify its role in the generation and function of alloreactive T cells and to identify putative targets of TSAd activity within alloimmune T regulatory cells. Our hypothesis is that TSAd activity is critical for the generation of alloimmune T regulatory cell function, and further, that the biological effect(s) of TSAd in immunoregulation are mediated via its expression within T cells. We will test this hypothesis in two specific aims in which we will: 1), determine the function of TSAd in allograft rejection, and evaluate its role in regulatory alloimmune responses in vivo, and 2), determine if the functional effect of TSAd in alloimmune regulation is dependent on its expression within T cells. We believe that these studies are ideal for the R21 mechanism, as they will initiate the exploration of a new molecule in the field, and they have significant potential to result in high impact findings. Understanding roles and function(s) for this adaptor in T cells is also likely to be of great clinical importance in transplantation, as they may lead to the identification of targets that shift the immune response from one of immunity/inflammation to one of tolerance. PUBLIC HEALTH RELEVANCE: Organ transplantation is a life saving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. Ongoing research is focused on the understanding of basic mechanisms leading to the development of chronic rejection and mechanisms whereby the alloimmune response causes graft injury. In this research proposal, we plan to determine if an adaptor protein, called TSAd functions in alloimmunity and if we can learn how TSAd-dependent signals can be manipulated in order to achieve long term graft survival in the future.

描述（由申请人提供）：同种异体移植物排斥是由受体对供体抗原的免疫反应介导的，由 CD4+ T 细胞启动和协调。一旦 T 细胞遇到同种异体抗原，它们就会扩增并分化为效应 T 细胞和/或记忆 T 细胞。激活还会导致调节性 T 细胞的扩增，从而控制免疫反应，并且有人提出，这种免疫调节过程对于同种异体移植物的长期存活至关重要。在 T 细胞内，一些接头蛋白被发现在 T 细胞受体诱导的信号转导中发挥核心作用，并且一些接头蛋白被发现是信号复合物形成的积极参与者，从而调节 T 细胞激活反应。 T 细胞特异性接头蛋白 (TSAd) 是一种含有 SH2 结构域的细胞内接头分子，最初报道其表达仅限于 T 细胞。越来越多的证据表明 T 细胞中 TSAd 的功能很复杂，并且它对于效应反应和调节反应都很重要。然而，尚无研究解决有关 TAd 在同种异体移植排斥和/或同种免疫反应中的生物学问题。这项探索性研究计划基于新的初步观察，我们观察到心脏同种异体移植物的 TSAd 敲除受体在同种免疫调节方面存在严重缺陷。我们研究的总体目标是表征 TAd 如何介导移植后的免疫调节。具体来说，我们计划使用 TSAd 敲除小鼠作为同种异体移植物的受体，以确定其在排斥过程中的功能，确定其在同种异体反应性 T 细胞的生成和功能中的作用，并确定同种免疫 T 调节细胞内 TSAd 活性的假定目标。我们的假设是，TSAd 活性对于同种免疫 T 调节细胞功能的产生至关重要，而且，TSAd 在免疫调节中的生物学效应是通过其在 T 细胞内的表达介导的。我们将在两个具体目标中测试这一假设，其中我们将：1）确定 TSAd 在同种异体移植排斥中的功能，并评估其在体内调节同种免疫反应中的作用，以及 2）确定 TSAd 在同种免疫反应中的功能作用是否调节依赖于其在 T 细胞内的表达。我们相信这些研究对于 R21 机制来说是理想的，因为它们将启动该领域新分子的探索，并且具有产生高影响力发现的巨大潜力。了解该接头在 T 细胞中的作用和功能也可能在移植中具有重要的临床意义，因为它们可能导致识别靶标，将免疫反应从免疫/炎症之一转变为耐受性之一。 公众健康相关性：器官移植对于终末期器官衰竭的个体来说是一种挽救生命的疗法，但所有移植最终都会由于一种称为慢性同种异体移植排斥的过程而失败。正在进行的研究重点是了解导致慢性排斥反应发生的基本机制以及同种免疫反应导致移植物损伤的机制。在这项研究计划中，我们计划确定一种称为 TSAd 的接头蛋白是否在同种免疫中发挥作用，以及我们是否可以了解如何操纵 TSAd 依赖性信号，以便在未来实现长期移植物存活。