Peripheral Mechanisms of Immunologic Tolerance

描述(由申请人提供)：诱导移植耐受和自身免疫仍然是一个难以实现的临床目标。因此，有必要更彻底地了解免疫耐受的基本机制。在这里，我们提出了一种多学科的方法，通过研究实体器官移植、骨髓移植和自身免疫的小鼠模型来研究免疫耐受的外周机制。提出了一种多学科的方法，因为导致自身和异体抗原耐受的机制重叠，而且三个临床学科之间存在显著的串扰：骨髓移植越来越多地被用于诱导对实体器官移植的耐受，移植中使用的治疗药物适用于自身免疫性患者(反之亦然)。 PPG由三个综合项目和一个核心项目组成：组织病理学。这些项目之间的整合是基于免疫学概念的共同性、研究人员之间正在进行的和未来的合作以及方法和资源的共享。项目1将探索导致骨髓移植后移植物抗宿主病(GVHD)的树突状细胞成熟的机制。项目2将研究通过产生调节性T细胞(Treg)在炎症性肠病小鼠模型中诱导耐受。项目3将通过研究宿主免疫系统持续识别移植器官的先天和适应性机制来探索免疫忽视现象。组织病理学核心(核心B)将为所有三个项目提供组织处理、染色、免疫组织化学、原位杂交、成像和解释服务。行政核心(核心A)将提供后勤、通信和数据共享支持。

DESCRIPTION (provided by applicant): The induction of tolerance in transplantation and autoimmunity remains an elusive clinical goal. A more thorough understanding of the fundamental mechanisms of immunologic tolerance is therefore necessary. We propose here a multidisciplinary approach to investigate peripheral mechanisms of immunologic tolerance by studying murine models of solid organ transplantation, bone marrow transplantation, and autoimmunity. A multidisciplinary approach is proposed because the mechanisms responsible for tolerance to self and foreign antigens overlap, and because significant cross-talk among the three clinical disciplines exists: bone marrow transplantation is increasingly employed to induce tolerance to solid organ allografts, and therapeutic agents used in transplantation are applicable to patients with autoimmunity (and vice versa). The PPG consists of three integrated projects and a core: histopathology. Integration among the projects is based on commonality of immunologic concepts, ongoing and future collaborations between the investigators, and the sharing of methods and resources. Project 1 will explore the mechanisms of dendritic cell maturation that lead to graft-versus-host disease (GVHD) following bone marrow transplantation. Project 2 will investigate tolerance induction via the generation of regulatory T cells (Treg) in a mouse model of inflammatory bowel disease. Project 3 will explore the phenomenon of immunologic ignorance by studying the innate and adaptive mechanisms that are responsible for continued recognition of a transplanted organ by the host's immune system. The Histopathology Core (Core B) will provide tissue processing, staining, immunohistochemistry, in situ hybridization, imaging, and interpretation services to all three projects. The Administrative Core (Core A) will provide logistical, communications and data sharing support.