Allograft inflammatory factor-1 and immune tolerance

同种异体移植物炎症因子-1与免疫耐受 实体器官移植是许多终末期疾病的最终治疗方法， 但其长期成功常常受到慢性免疫排斥的限制。在心脏移植中， 这种低度排斥表现为心脏同种异体移植物血管病变（CAV）。CAV病变 特征性表现为由平滑肌样组成的同心圆状血管内膜增生 细胞和相关的细胞外基质;这种内膜扩张在整个过程中弥漫性发展 移植器官的脉管系统，最终限制了它们的动脉管道功能， 导致移植物缺血和衰竭。 同种异体移植物炎性因子-1（AIF 1）是一种17 kDa的EF携带蛋白， 在移植心脏的动脉周围巨噬细胞中， 自身免疫性疾病在临床前研究中，非移植组织中AIF 1的强制表达 血管损伤模型增加了新生内膜和动脉粥样硬化病变的大小，表明 AIF 1是血管阻塞的驱动因素。另一方面，AIF 1缺乏症限制了疾病 在实验性自身免疫性脑脊髓炎（EAE）和胶原诱导的关节炎中的活性， 多发性硬化症和类风湿性关节炎的模型。这些发现表明 AIF 1的表达促进炎症并有助于自身免疫性疾病的发病机制。 炎症过程。移植后AIF 1的诱导和积累如何影响 CAV和供体器官存活率未知。 AIF 1已被表征为细胞质蛋白，其充当促凋亡蛋白的支架。 炎症信号它与肌动蛋白捆绑密切相关， 基于AIF 1的细胞骨架对巨噬细胞迁移和吞噬作用的影响，但精确的 AIF 1对细胞功能和炎症的更广泛依赖性作用的基础仍然模糊不清。 在最近的研究中，我们确定了AIF 1与已经建立的蛋白质的新相互作用， 与免疫调节有关。我们的目标与拟议的研究是确定的性质， 这些分子相互作用以及它们如何影响免疫细胞表型，并测试AIF 1 表达对于引起CAV和移植失败的同种异体反应是必需的。

Allograft inflammatory factor-1 and immune tolerance Solid organ transplantation is the ultimate therapeutic approach for many end-stage diseases, but its long-term success is often limited by chronic immune rejection. In heart transplantation, this low-grade rejection manifests as cardiac allograft vasculopathy (CAV). The lesions of CAV characteristically show concentric vascular intimal hyperplasia composed of smooth muscle-like cells and associated extracellular matrix; this intimal expansion develops diffusely throughout the vasculature of transplanted organs, eventually limiting their arterial conduit function and causing graft ischemia and failure. Allograft inflammatory factor-1 (AIF1), a 17kDa EF hand-bearing protein, is strongly expressed in peri-arterial macrophages in transplanted hearts, and is also upregulated in multiple autoimmune conditions. In preclinical studies, forced expression of AIF1 in non-transplant models of vascular injury increases neointimal and atherosclerotic lesion size, suggesting that AIF1 acts as a driver of vascular obstruction. AIF1 deficiency, on the other hand, limits disease activity in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis, models for multiple sclerosis and rheumatoid arthritis, respectively. These findings suggest that expression of AIF1 promotes inflammation and contributes to the pathogenesis of autoimmune inflammatory processes. How AIF1 induction and accumulation after transplantation affects CAV and donor organ survival is unknown. AIF1 has been characterized as a cytoplasmic protein that acts as a scaffold for pro- inflammatory signaling. It is associated most closely with actin bundling, which plausibly relates to AIF1-based cytoskeletal effects on macrophage migration and phagocytosis, but the precise basis for broader AIF1-dependent effects on cell function and inflammation remains nebulous. In recent studies, we identified novel interactions of AIF1 with proteins that have established links to immune regulation. Our goals with the proposed studies are to ascertain the nature of these molecular interactions and how they affect immune cell phenotypes, and to test if AIF1 expression is necessary for the allogeneic response that causes CAV and transplant failure.