Regulatory Mechanisms in Autoimmune Arthritis

描述(由申请人提供)： 类风湿性关节炎(RA)是一种折磨着全球数百万人的致残性疾病。它的进行性、破坏性的病理显著影响活动能力和生活质量。RA是一个复杂的疾病过程，涉及人类白细胞抗原分子和免疫细胞的相互作用，导致滑膜炎症、软骨和骨破坏，以及关节功能丧失。虽然其病因仍是一个谜，但很明显，RA的易感性与介导免疫反应的人类白细胞抗原基因之间存在强烈的关联，这表明该病是一种自身免疫基础。调节性T细胞(Tregs)是一种新发现的抑制细胞亚群，对免疫稳态起着绝对关键的作用。如果没有特雷格的适当赞扬，多种形式的自身免疫就会迅速发展。很明显，Tregs可以调节自身免疫，但我们对Tregs在体内如何发挥作用，以及如何利用它们来开发治疗自身免疫性疾病的新治疗方法的理解存在很大差距。我们将在我们的关节炎动物模型的背景下使用Foxp3gfp/IL-17Frfp双重报告读数，为我们提供一个独特的机会来剖析Treg细胞在自身免疫中的作用，使我们能够直接检查这些细胞调节自身免疫反应的能力，我们可以直接测量这些操作如何可以预防疾病病理。到目前为止，我们的研究表明，脊椎动物的免疫系统非肠道暴露在没有共刺激的情况下提供的可溶性抗原可以导致预先存在的调节性T细胞群的激活和扩张。我们的假设是，这种激活提供了必要的承诺，以防止这些nTregs在随后暴露于其同源配体时可能转化为Th17细胞，在促炎条件下，如在类风湿关节中发现的那样。我们建议使用体外和体内模型来确定肠外抗原诱导的免疫调节阻止Th17细胞反应发展的机制(S)，从而提供对RA特有的衰弱关节病理的保护。我们还将确定适当的Tregs刺激是否可以防止它们在促炎介质存在的情况下转化为Th17细胞。成功阐明这些问题的答案将使我们能够为那些患有RA和其他炎症性自身免疫性疾病的衰弱效应的退伍军人设计基于细胞的治疗方法。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a crippling disease afflicting millions of people worldwide. Its progressive, destructive pathology significantly affects mobility and quality of life. RA is a complex disease process that involves the interaction of HLA molecules and immune cells that results in synovial inflammation, cartilage and bone destruction, and loss of joint function. Although its etiology is still a mystery, it is clear that there is a strong association between susceptibility to RA and the HLA genes that mediate immune responses, suggesting an autoimmune basis for the disease. Regulatory T cells (Tregs) are a newly described subset of suppressive cells that are absolutely critical for immune homeostasis. Without a proper compliment of Tregs, multiple forms of autoimmunity develop quickly. It is clear that Tregs can modulate autoimmunity, but there are large gaps in our understanding of how Tregs function in vivo, and how they can be manipulated for the development of new therapeutic approaches to the treatment of autoimmune diseases. We will use a Foxp3gfp/IL-17Frfp dual reporter readout in the context of our well- characterized animal model for arthritis to give us a unique opportunit to dissect the role of Treg cells in autoimmunity, allowing us to directly examine the ability of these cells to regulate an autoimmune response and we can directly measure how these manipulations can prevent disease pathology. Our research to date has suggested that parenteral exposure of the vertebrate immune system to a soluble antigen supplied without co-stimulation can result in an activation and expansion of a pre-existing population of regulatory T cells. It is our hypothesis that this activation provides the commitment necessary to prevent the possible conversion of these nTregs into Th17 cells upon subsequent exposure to their cognate ligand under pro-inflammatory conditions such as those found in the rheumatoid joint. We propose to use both in vitro and in vivo models to determine the mechanism(s) by which parenteral antigen induced immunoregulation prevents the development of the Th17 cell response, thereby providing protection from the debilitating joint pathologies characteristic of RA. We will also determine if the proper stimulation of Tregs can prevent them from converting to Th17 cells in the presence of pro-inflammatory mediators. Successful elucidation of the answers to these problems will allow us to design cell-based therapeutic treatments for those veterans suffering from the debilitating effects of RA and other inflammatory autoimmune diseases.