Immunological Ignorance as an Adjunct to Tolerance

如果抗原保留在次级淋巴组织之外，则发生免疫忽视，次级淋巴组织是免疫缺陷的部位。 成熟的抗原呈递细胞（ARC）活化初始T和B淋巴细胞。虽然无知是一种 自身反应性T细胞避免自身抗原的重要机制，忽视移植器官， 很少被观察到。即使是允许从外科手术中恢复的同种异体移植物， 在引流淋巴组织中呈递抗原，当 在一些实施方案中，免疫抑制被撤销或在外源性幼稚或效应/记忆T细胞转移后。这 表明，移植构成了免疫无知的障碍，即使在长期稳定的， 同种异体移植物功能探索这些障碍可以提供促进同种异体移植物接受的新策略 防止慢性排斥反应因此，我们建议在PPG的这个组成部分中调查为什么 免疫系统不会忽视“愈合”的同种异体移植物。具体目标将集中在两个假设上， 分别与PPG的项目1和2整合：（1）先天免疫激活在“愈合”后持续存在。 同种异体移植导致APC成熟、初始T细胞活化和效应/记忆T细胞进入增强 （2）淋巴细胞耗竭，往往伴随着耐受诱导方案是负责 通过经历淋巴细胞减少诱导的增殖（LIP）的初始T细胞持续识别移植物， 转化为记忆样淋巴细胞。在具体目标1中，我们将研究是什么使先天的 对"愈合“同种异体移植物的免疫反应，重点是先天淋巴细胞（NK和iNKT细胞）， 中性粒细胞、补体系统和通过TLR信号传导途径直接激活APC。在特定 目的2，我们将研究负责调节淋巴细胞减少诱导的增殖的机制， 天然T细胞，重点是CTLA-4和TGF β。了解这些机制将使我们能够 制定基于免疫力的策略，促进同种异体移植物的接受和预防慢性排斥反应。这 该项目严重依赖于心脏病核心的处理和分析。 同种异体移植物样品、定量同种异体移植物血管病变和树突细胞表型。

Immunological ignorance occurs if an antigen remains outside secondary lymphoid tissues, the site where mature antigen presenting cells (ARC) activate naive T and B lymphocytes. Although ignorance is an important mechanism by which autoreactive T cells avoid self-antigens, ignorance of transplanted organs is seldom observed. Even allografts that are allowed to recover from the surgical procedure continue to present antigen in the draining lymphoid tissue and undergo either acute or chronic rejection when immunosuppression is withdrawn or upon the transfer of exogenous naive or effector/memory T cells. This suggests that transplantation poses a barrier to immunologic ignorance even after long periods of stable allograft function. Exploring these barriers could provide new strategies that facilitate allograft acceptance and prevent chronic rejection. Therefore, we propose in this component of the PPG to investigate why the immune system does not ignore a 'healed' allograft. The specific aims will focus on two hypotheses that integrate with Projects 1 and 2 of the PPG, respectively: (1) Innate immune activation persists in a "healed" allograft leading to APC maturation, naive T cell activation, and enhanced entry of effector/memory T cells into the graft; and (2) lymphodepletion that often accompanies tolerance-inducing regimens is responsible for continuous recognition of the graft by naive T cells that undergo lymphopenia-induced proliferation (LIP) and transform into memory-like lymphocytes. In specific aim 1, we will investigate what perpetuates the innate immune response to a 'healed' allograft, with emphasis on innate lymphocytes (NK and iNKT cells), neutrophils, the complement system, and direct activation of APCs via TLR-signaling pathways. In specific aim 2, we will investigate the mechanisms responsible for regulating lymphophenia-induced proliferation of naTve T cells, with emphasis on CTLA-4 and TGFb. Understanding these mechanisms would allow us to develop ignorance-based strategies that facilitate allograft acceptance and prevent chronic rejection. This Project is critically dependent on the Histopathology Core for processing and analysis of cardiac allograft samples, quantitating allograft vasculopathy, and phenotyping dendritic cells.