Cytokine Regulation in Experimental Arthritis

实验性关节炎中的细胞因子调节

基本信息

批准号：
7633814
负责人：
ALISON FINNEGAN
金额：
$ 33.3万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633814
关键词：
Affect Alleles Animal Model Antigen Presentation Antigen-Presenting Cells Antigens Area Arthritis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes CD4 Positive T Lymphocytes Cartilage Cell Differentiation process Cells Chronic Data Dendritic Cells Dermal Development Diagnosis Disease Environment Environmental Risk Factor Etiology Event Experimental Arthritis Fostering Frequencies Generations Genes Genetic Goals Greater sac of peritoneum Helper-Inducer T-Lymphocyte Heterogeneity Histopathology Human Immune Immune response Immune system Immunization Inbred BALB C Mice Infectious Agent Inflammatory Inherited Investigation Joints Kinetics Lead Leukocytes Light Link Literature Lymphoid Lymphoid Cell Lymphoid Tissue Mediating Modeling Mus Pattern Phenotype Population Process Production Proteoglycan Regulation Reporting Rheumatoid Arthritis Route Signal Transduction Site System T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Th1 Cells Th2 Cells Therapeutic Tissues Transgenic Mice base bone cell type chemokine chemokine receptor cytokine human disease immunopathology in vivo insight intraperitoneal monocyte novel programs public health relevance receptor expression response

项目摘要

DESCRIPTION (provided by applicant): The genetics of rheumatoid arthritis suggest that a combination of inherited alleles and environmental factors contribute to the development of arthritis. T cell reactivity is implicated in RA based on the linkage of RA to particular MHC alleles. Our animal model, proteoglycan-induced arthritis (PGIA) has many similarities to RA and so has the potential to provide important information on the mechanism of human disease. Similar to RA, PGIA is critically dependent on auto reactive T cell activation. In PGIA, activation of Th1 cells and the production of IFN3 are critical for development of severe arthritis. In this, the "conventional" model of PGIA, the route of antigen exposure is intraperitoneal. We demonstrate that altering the route of antigen exposure from intraperitoneal to intradermal induces a Th17 instead of a Th1 T cell response. These findings suggest that antigen presentation changes the early events in T cell polarization and that the innate microenvironment at these different tissue sites may provide unique signals that foster T cell differentiation. Very little is known about how autoimmune responses initiated at different tissue sites might affect disease. The overall goal is to understand the rules governing T cell differentiation at distinct tissue sites. Our strategy in aim 1 is to determine the cytokine environment which contributes to Th cell polarization and to determine if the immunopathology of the resulting arthritis is similar (or different) in Th1- versus Th17-mediated PGIA. In aim 2 and aim 3 we will begin to dissect the mechanism by which the route of antigen exposure contributes to T cell polarization. In aim 2 we will locate the lymphoid tissue sites where T cells are initially primed and produce cytokines and attempt to redirect the differentiating T cell population by altering the cytokine environment. In aim 3 we will identify the antigen presenting cells which drive Th1/Th17 mediated PGIA and determine the cytokines and co-stimulatory molecules involved in T cell polarization. If we can begin to understand how these T cell subsets are initiated we may be able to identify different subtypes of RA which could lead to the development of more effective therapeutic strategies for selective blockade of disease. This is an important and exciting area of investigation, which is expected to shed new light on the mechanisms of CD4+T cell mediated disease in RA, and more generally in autoimmune disease. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovial proliferation and infiltrating of leukocytes which leads to destruction of cartilage and bone. Pro-inflammatory effector T helper cells have been divided into three subsets designated as T helper (Th) 1, Th2 and Th17. Th subsets are distinct subsets based on their cytokine secretion pattern, chemokine receptor expression, and clearance of infectious organisms. Models of autoimmune disease can be divided into either Th1-dependent or Th17-dependent. It is presently unclear what causes this heterogeneity in effector T cell differentiation. Based on preliminary results we hypothesize that the context in which the antigen is first encountered in the immune system determines the T cell effector choice. We hypothesize that contact with environmental antigens or infectious agents at different tissue sites predispose T helper cells to differentiation into Th1 or Th17 cells. Different tissue sites have unique cytokine and co-stimulatory microenvironments that are predisposed to the generation of specific Th cytokine phenotypes. The activation of different CD4+ T cell subsets in RA may contribute to disease heterogeneity. This proposal will elucidate the mechanism (s) by which the route of antigen exposure affect/modify fundamental T cell polarization. These studies aim to develop novel insights into the autoimmune disease process that will facilitate the diagnosis and treatment of RA.

描述（由申请人提供）：类风湿性关节炎的遗传学表明，遗传等位基因和环境因素的结合导致了关节炎的发生。基于 RA 与特定 MHC 等位基因的连接，T 细胞反应性与 RA 相关。我们的动物模型蛋白多糖诱导性关节炎 (PGIA) 与 RA 有许多相似之处，因此有可能提供有关人类疾病机制的重要信息。与 RA 类似，PGIA 严重依赖于自身反应性 T 细胞的激活。在 PGIA 中，Th1 细胞的激活和 IFN3 的产生对于严重关节炎的发展至关重要。在这种 PGIA 的“传统”模型中，抗原暴露的途径是腹膜内。我们证明，将抗原暴露途径从腹膜内改为皮内会诱导 Th17 T 细胞反应，而不是 Th1 T 细胞反应。这些发现表明，抗原呈递改变了 T 细胞极化的早期事件，并且这些不同组织部位的先天微环境可能提供促进 T 细胞分化的独特信号。关于不同组织部位引发的自身免疫反应如何影响疾病，人们知之甚少。总体目标是了解控制不同组织部位 T 细胞分化的规则。我们的目标 1 策略是确定导致 Th 细胞极化的细胞因子环境，并确定 Th1 介导的 PGIA 与 Th17 介导的 PGIA 所导致的关节炎的免疫病理学是否相似（或不同）。在目标 2 和目标 3 中，我们将开始剖析抗原暴露途径导致 T 细胞极化的机制。在目标 2 中，我们将找到 T 细胞最初启动并产生细胞因子的淋巴组织部位，并尝试通过改变细胞因子环境来重新定向分化的 T 细胞群。在目标 3 中，我们将鉴定驱动 Th1/Th17 介导的 PGIA 的抗原呈递细胞，并确定参与 T 细胞极化的细胞因子和共刺激分子。如果我们能够开始了解这些 T 细胞亚群是如何启动的，我们也许能够识别 RA 的不同亚型，从而开发出更有效的选择性阻断疾病的治疗策略。这是一个重要且令人兴奋的研究领域，有望为 RA 以及更广泛的自身免疫性疾病中 CD4+T 细胞介导的疾病机制提供新的线索。公共健康相关性：公共健康相关性声明类风湿性关节炎 (RA) 是一种慢性炎症性自身免疫性疾病，其特征是滑膜增殖和白细胞浸润，导致软骨和骨骼破坏。促炎效应 T 辅助细胞已分为三个亚群，称为 T 辅助细胞 (Th) 1、Th2 和 Th17。 Th 子集是基于其细胞因子分泌模式、趋化因子受体表达和感染性生物体清除的不同子集。自身免疫性疾病模型可分为 Th1 依赖性或 Th17 依赖性。目前尚不清楚是什么原因导致效应 T 细胞分化的这种异质性。根据初步结果，我们假设免疫系统中首次遇到抗原的环境决定了 T 细胞效应器的选择。我们假设，在不同组织部位与环境抗原或感染因子接触会使 T 辅助细胞易于分化为 Th1 或 Th17 细胞。不同的组织部位具有独特的细胞因子和共刺激微环境，易于产生特定的 Th 细胞因子表型。 RA 中不同 CD4+ T 细胞亚群的激活可能导致疾病异质性。该提案将阐明抗原暴露途径影响/改变基本 T 细胞极化的机制。这些研究旨在对自身免疫性疾病过程产生新的见解，从而促进 RA 的诊断和治疗。