Regulatory Mechanisms in Autoimmune Arthritis

自身免疫性关节炎的调节机制

• 批准号: 8597917
• 负责人: DAVID D. BRAND
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597917
• 关键词: Address; Affect; Animal Model; Antigens; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Cartilage; Cells; Characteristics; Clinic; Collagen; Collagen Arthritis; Complement Factor B; Complex; Development; Disease; Disease remission; Employee Strikes; Etiology; Exposure to; Green Fluorescent Proteins; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-17; Interleukin-6; Interruption; Joints; Label; Ligands; Measures; Mediating; Modality; Modeling; Mus; Nature; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Predisposition; Prevention; Process; Quality of life; Reaction; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Research Project Grants; Resistance; Rheumatoid Arthritis; Role; Severities; Signal Transduction; Synovial Fluid; System; T-Lymphocyte; Therapeutic; Transforming Growth Factors; Transgenic Organisms; Translating; Veterans; Work; autoimmune arthritis; base; bone; cell type; design; human leukocyte antigen gene; immunoregulation; in vivo; in vivo Model; interest; joint function; joint injury; lymph nodes; novel therapeutic intervention; precursor cell; prevent; promoter; red fluorescent protein; response; tool

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.

描述（由申请人提供）： 类风湿关节炎（RA）是一种残酷的疾病，遭受了全世界数百万人的困扰。它的进步，破坏性的病理极大地影响了流动性和生活质量。 RA是一个复杂的疾病过程，涉及HLA分子和免疫细胞的相互作用，导致滑膜炎症，软骨和骨骼破坏以及关节功能的丧失。尽管其病因仍然是一个谜，但很明显，RA的敏感性与介导免疫反应的HLA基因之间存在很强的联系，这表明该疾病的自身免疫基础。调节性T细胞（TREG）是一个新描述的抑制细胞的子集，对于免疫稳态至关重要。如果没有适当的treg夸奖，多种形式的自身免疫力很快就会发展。显然，Tregs可以调节自身免疫性，但是我们对Treg在体内的功能以及如何操纵新型治疗方法来治疗自身免疫性疾病的方法有很大的差距。在我们特征性的关节炎动物模型的背景下，我们将使用FOXP3GFP/IL-17FRFP双重记者读数，以使我们有一个独特的机会，可以剖析Treg细胞在自身免疫性中的作用，从而使我们可以直接检查这些细胞的能力，可以直接检查自身免疫性反应，我们可以直接测量这些疾病的病理学方法。迄今为止，我们的研究表明，脊椎动物免疫系统暴露于未共刺激的可溶性抗原上，可能会导致调节性T细胞的激活和扩展。我们的假设是，这种激活提供了必要的承诺，以防止这些Ntreg在随后在促炎条件下（例如在类风湿关节中发现的）下暴露于其同源配体后可能转化为Th17细胞。我们建议同时使用体外和体内模型来确定肠胃外抗原诱导的免疫调节的机制阻止Th17细胞反应的发展，从而保护RA的衰弱的关节病理特征。我们还将确定在存在促炎性介体的情况下，适当的Treg刺激是否可以防止它们转化为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退伍军人设计基于细胞的治疗方法。