Immunological Ignorance as an Adjunct to Tolerance

如果抗原残留在次级淋巴组织之外，就会发生免疫学上的无知 成熟的抗原提呈细胞(ARC)激活幼稚的T和B淋巴细胞。尽管无知是一种 自身反应性T细胞避免自身抗原的重要机制是忽视移植器官 很少被观察到。即使是被允许从手术中恢复的同种异体移植物也会继续 在引流的淋巴组织中存在抗原，并在以下情况下发生急性或慢性排斥反应 免疫抑制被撤销或在外源性幼稚T细胞或效应/记忆T细胞转移时。这 这表明，即使在长期的稳定期之后，移植也对免疫学的无知构成了障碍 同种异体移植功能。探索这些障碍可以提供新的策略，促进同种异体移植的接受 并防止慢性排斥反应。因此，我们建议在PPG的这一部分中调查为什么 免疫系统不会忽视‘治愈’的同种异体移植物。具体目标将集中在以下两个假设上 分别与PPG的项目1和2相结合：(1)先天免疫激活持续在一种“治愈”状态 同种异体移植导致APC成熟、幼稚T细胞活化和增强效应/记忆T细胞进入 进入移植物；和(2)经常伴随耐受诱导方案的淋巴枯竭是 经历淋巴细胞减少诱导增殖(LIP)的幼稚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，我们将调查是什么使先天的 对“愈合”的同种异体移植物的免疫反应，重点是天然淋巴细胞(NK和iNKT细胞)， 中性粒细胞、补体系统，以及通过TLR信号通路直接激活APC。具体而言 目的2，我们将研究调节淋巴酚诱导的细胞增殖的机制。 NATve T细胞，重点是CTLA-4和TGFb。了解这些机制将使我们能够 制定基于无知的策略，促进同种异体移植的接受，防止慢性排斥反应。这 项目严重依赖于心脏组织病理学核心的处理和分析 同种异体移植样本，同种异体血管病变的量化，以及树突状细胞的表型。

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present antigen in the draining lymphoid tissue and undergo either acute or chronic rejection when immunosuppression is withdrawn or upon the transfer of exogenous naive or effector/memory T cells.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.