TIM molecules and the innate: adaptive interface in alloimmunity

TIM 分子和先天性：同种免疫中的适应性界面

基本信息

批准号：
8707632
负责人：
NADER NAJAFIAN
金额：
$ 31.24万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-20 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707632
关键词：
Address Adoptive Transfer Adverse effects Affect Alloantigen Allograft Tolerance Allografting Antibodies Antigens Apoptotic Autoimmunity B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell Communication Cells Chimera organism Chimeric Proteins Chronic Coculture Techniques Conflict (Psychology)Cytokine Signaling Data Development Effector Cell Engraftment Equilibrium Eragrostis Exposure to Family member Functional disorder Goals Graft Rejection Graft Survival Helper-Inducer T-Lymphocyte Human Hypersensitivity ITGAX gene Immune Immune response Immune system Immunity Immunobiology Immunodeficiency and Cancer Immunosuppression In Vitro Incidence Infection Inflammation Inflammatory Interleukin-17 Interleukin-2 Interleukin-4 Interruption Investigation Life Ligands Ligation Maps Mediating Modeling Morbidity - disease rate Mus Nature Outcome Patients Pattern recognition receptor Phagocytosis Phenotype Physiological Play Procedures Process Production Receptor Signaling Regulation Regulatory T-Lymphocyte Relative (related person)Reporter Role Signal Transduction Source T cell differentiation T cell response T-Lymphocyte Testing Th2 Cells Therapeutic Therapeutic Agents Tissues Transplant Recipients Transplantation anergy base congenic end-stage organ failure improved in vivo insight islet allograft isoimmunity macrophage novel phosphatidylserine receptor prevent response therapeutic target uptake vaccine development

项目摘要

DESCRIPTION (provided by applicant): Transplantation is a life-saving procedure for patients with end-stage organ failure. Current immuno- suppression is associated with significant morbidity and a high incidence of chronic transplant dysfunction, rendering the induction of antigen-specific tolerance a desirable alternative. Therapeutic manipulation of the TIM molecules is thought to have great tolerogenic potential. In contrast to the other TIM family members, TIM- 4 is primarily expressed on APCs, including CD11c+ DCs and macrophages. Although in vitro studies utilizing TIM-4 Ig fusion proteins demonstrate that it binds costimulator ligands on T cells, the results are conflicting and the nature of costimulatory signals not well defined. Furthermore, as these co-cultures lacked APCs, the physiological role of TIM-4 on DCs was not examined. TIM-4 has also recently been identified as a phosphatidylserine receptor, capable of modulating the immune system by directing engulfment of apoptotic bodies. The relative contribution of these roles in directing immune responses remains unclear. The primary objective of this application is to address the role of TIM-4 in alloimmunity. We show that antibody-mediated blockade of TIM-4 induces long-term islet allograft survival, suggesting that TIM-4 plays a major role in regulating alloimmunity in vivo. We have also discovered that TIM-4 defines functionally distinct DC subsets involved in the determination of T helper cell fate. Furthermore, TIM-4 blockade inhibits both TIM-4 signaling initiated by TIM-4+ DCs and phagocytosis mediated by macrophages, resulting in the splenic accumulation of apoptotic bodies and a shift of phagocytic duty from macrophages to DCs. The relative contribution of these functions to the marked effect of anti-TIM-4 on graft survival is unknown and is the central focus of this proposal. We hypothesize that the graft prolongation achieved by anti-TIM-4 is due to inhibition of TIM-4 signaling to DCs and/or inhibition of T cell costimulation. Alternatively, TM-4 blockade may alter the activation status of DCs/macrophages and, consequently, allograft survival, by shifting the responsibility of apoptotic cell phagocytosis from macrophages to DCs. Thus, the specific aims are: 1. What is the role of TIM-4 in the regulation of DC phenotype and function? 2. What is the role of TIM-4 on DCs versus macrophages in allograft survival? 3. What are the mechanisms whereby TIM-4 regulates the fate of alloreactive T cells in vivo? These studies will not only provide brand new basic insight into the immunobiology of DCs and Th differentiation, but will allow us to optimize strategies for promoting allograft survival, by selectively inhibiting TIM-4 function on DCs and/or macrophages. Moreover, the insights gained from the proposed studies will have broad therapeutic potential, including the development of tolerogenic strategies in autoimmunity and allergy, while manipulation of this molecule could also be used to enhance the immune response, which would be useful in states of relative immunodeficiency (cancer and chronic infection) and in vaccine development.

描述（由申请人提供）：移植对于终末期器官衰竭患者来说是一种挽救生命的手术。目前的免疫抑制与显着的发病率和慢性移植功能障碍的高发生率相关，这使得诱导抗原特异性耐受成为理想的替代方案。 TIM 分子的治疗操作被认为具有巨大的耐受性潜力。与其他 TIM 家族成员相比，TIM-4 主要在 APC 上表达，包括 CD11c+ DC 和巨噬细胞。尽管利用 TIM-4 Ig 融合蛋白的体外研究表明它与 T 细胞上的共刺激配体结合，但结果是相互矛盾的，并且共刺激信号的性质尚未明确定义。此外，由于这些共培养物缺乏 APC，因此未检查 TIM-4 对 DC 的生理作用。 TIM-4 最近还被鉴定为一种磷脂酰丝氨酸受体，能够通过引导吞噬凋亡小体来调节免疫系统。这些作用在指导免疫反应中的相对贡献仍不清楚。本申请的主要目的是阐明 TIM-4 在同种免疫中的作用。我们发现抗体介导的 TIM-4 阻断可诱导长期胰岛同种异体移植物存活，这表明 TIM-4 在调节体内同种免疫中发挥着重要作用。我们还发现 TIM-4 定义了功能不同的 DC 子集，这些 DC 子集参与 T 辅助细胞命运的决定。此外，TIM-4阻断同时抑制TIM-4+ DC发起的TIM-4信号传导和巨噬细胞介导的吞噬作用，导致脾脏中凋亡小体的积累以及吞噬职责从巨噬细胞转移到DC。这些功能对抗TIM-4对移植物存活的显着影响的相对贡献尚不清楚，并且是该提案的中心焦点。我们假设抗TIM-4实现的移植物延长是由于抑制TIM-4向DC的信号传导和/或抑制T细胞共刺激。或者，TM-4阻断可能通过将凋亡细胞吞噬作用从巨噬细胞转移到DC来改变DC/巨噬细胞的激活状态，从而改变同种异体移植物的存活。因此，具体目标是： 1. TIM-4在DC表型和功能调节中的作用是什么？ 2. TIM-4 对 DC 与巨噬细胞在同种异体移植物存活中的作用是什么？ 3. TIM-4在体内调节同种反应性T细胞命运的机制是什么？这些研究不仅将为 DC 和 Th 分化的免疫生物学提供全新的基本见解，而且使我们能够通过选择性抑制 DC 和/或巨噬细胞上的 TIM-4 功能来优化促进同种异体移植物存活的策略。此外，从拟议的研究中获得的见解将具有广泛的治疗潜力，包括开发自身免疫和过敏的耐受策略，而对该分子的操纵也可用于增强免疫反应，这在相对免疫缺陷的状态下将是有用的（癌症和慢性感染）和疫苗开发。