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）：同种异体移植排斥反应是由受体对供体抗原的免疫反应介导的，该反应由CD4+ T细胞启动和协调。一旦T细胞遇到同种抗原，它们就会扩展并分化为效应子和/或记忆T细胞。激活还导致调节性T细胞的扩展，该细胞功能控制免疫反应，并提出这种免疫调节过程对于长期同种异体移植生存至关重要。在T细胞中，已经发现几种适配器蛋白在T细胞受体诱导的信号转导中起着核心作用，并且发现有几个是在形成信号复合物中的活跃参与者，从而调节T细胞激活响应。 T细胞特异性衔接蛋白（TSAD）是一个含有细胞内衔接子分子的SH2结构域，最初据报道其表达对T细胞受到限制。越来越多的证据表明，TSAD在T细胞中的功能很复杂，并且在效应子以及调节反应中都很重要。但是，尚未解决有关同种异体移植排斥和/或同种免疫反应中TSAD生物学的问题。这项探索性研究建议基于新的初步观察结果，我们观察到心脏同种异体移植的TSAD基因敲除接受者在同种异体免疫调节中具有严重的缺陷。我们研究的总体目标是表征TSAD在移植后如何介导免疫调节。具体而言，我们计划使用TSAD基因敲除小鼠作为同种异体移植物的接受者，以确定其在排斥过程中的功能，以确定其在同种反应性T细胞的产生和功能中的作用，并确定同种异体T调节细胞中TSAD活性的假定靶标。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，此外，TSAD在免疫调节中的生物学作用是通过其在T细胞中的表达介导的。我们将以两个具体目标来检验这一假设：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性同种异体免疫反应中的作用，而2），确定TSAD在同种免疫调节中的功能效应是否取决于其在T细胞中的表达。我们认为，这些研究是R21机制的理想选择，因为它们将启动对该领域的新分子的探索，并且它们具有巨大的潜力，从而导致高影响结果。了解该衔接子在T细胞中的作用和功能在移植中也很重要，因为它们可能导致鉴定将免疫反应从免疫/炎症中的一种转移到一种耐受性的靶标。 公共卫生相关性：器官移植是对终阶段器官衰竭患者的挽救生命疗法，但由于一个称为慢性同种异体移植拒绝的过程，所有移植物最终都会失败。正在进行的研究集中在对基本机制的理解上，导致慢性排斥和机制的发展，从而引起同种免疫反应会导致移植物损伤。在这项研究建议中，我们计划确定适配蛋白（称为TSAD在同种免疫力中的功能）是否可以学习如何操纵依赖TSAD的信号以在将来实现长期移植生存。