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终极治疗方法， 但它的长期成功往往受到慢性免疫排斥的限制。在心脏移植中， 这种低度排斥反应表现为心脏移植物血管病变(CAV)。CAV的病变 特征性表现为向心性血管内膜增生，由平滑肌样组织构成 细胞和相关的细胞外基质；这种内膜扩张在整个过程中扩散发展 移植器官的血管系统，最终限制了它们的动脉管道功能 导致移植物缺血和衰竭。 同种异体移植物炎症因子-1(AIF1)是一种17 kDa的EF手承载蛋白，它强烈表达 在移植心脏的动脉周围巨噬细胞中，并在多发性 自身免疫性疾病。在临床前研究中，AIF1在非移植患者中强制表达 血管损伤模型会增加新生内膜和动脉粥样硬化病变的大小，这表明 AIF1在血管阻塞中起驱动作用。另一方面，缺乏AIF1限制了疾病的发生 实验性自身免疫性脑脊髓炎(EAE)和胶原性关节炎的活性， 多发性硬化症和类风湿性关节炎的模型。这些发现表明， AIF1的表达促进炎症并参与自身免疫的发病机制 炎症过程。移植后AIF1的诱导和蓄积对移植的影响 CAV和供体器官存活尚不清楚。 AIF1是一种细胞质蛋白，可作为前体细胞的支架。 炎症信号。它与肌动蛋白捆绑关系最密切，这似乎与 以AIF1为基础的细胞骨架对巨噬细胞迁移和吞噬的影响，但精确的 AIF1对细胞功能和炎症的更广泛依赖作用的基础仍然模糊。 在最近的研究中，我们发现了AIF1与已建立的蛋白质之间的新的相互作用 与免疫调节有关。我们建议进行的研究的目的是确定 这些分子相互作用及其如何影响免疫细胞表型，并测试AIF1 表达是导致CAV和移植失败的同种异体反应所必需的。

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.