Cytokine Regulation in Experimental Arthritis

实验性关节炎中的细胞因子调节

• 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
• 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

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）： 类风湿关节炎的遗传学表明，遗传等位基因和环境因素的结合有助于关节炎的发展。根据RA与特定MHC等位基因的联系，T细胞反应性与RA有关。我们的动物模型，蛋白聚糖引起的关节炎（PGIA）与RA有许多相似之处，因此有可能提供有关人类疾病机理的重要信息。与RA相似，PGIA严重取决于自动反应性T细胞激活。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。在这种情况下，PGIA的“常规”模型，抗原暴露的途径是腹膜内的。我们证明，从腹膜内改变抗原暴露到皮内的途径会诱导Th17而不是Th1 T细胞反应。这些发现表明，抗原呈递改变了T细胞极化中的早期事件，并且在这些不同组织部位的先天微环境可能会提供促进T细胞分化的独特信号。关于在不同组织部位启动的自身免疫反应如何影响疾病，知之甚少。总体目标是了解有关不同组织部位的T细胞分化的规则。我们目标1中的策略是确定有助于细胞极化的细胞因子环境，并确定所得关节炎的免疫病理学是否相似（或不同），而Th1-与Th17介导的PGIA相似。在AIM 2和AIM 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AIM 2中，我们将定位淋巴组织部位，其中T细胞最初被灌注并产生细胞因子，并试图通过改变细胞因子环境来重定向分化的T细胞群体。在AIM 3中，我们将确定驱动Th1/Th17介导的PGIA的抗原呈递细胞，并确定与T细胞极化有关的细胞因子和共刺激分子。如果我们可以开始了解如何启动这些T细胞子集，我们可能能够识别RA的不同亚型，这可能导致发展更有效的疾病障碍治疗策略。这是一个重要且令人兴奋的研究领域，预计该领域将为RA中CD4+T细胞介导的疾病的机制以及更一般的自身免疫性疾病提供新的启示。公共卫生相关性：公共卫生相关性声明类风湿关节炎（RA）是一种慢性炎症自身免疫性疾病，其特征是滑膜增生和白细胞浸润，导致软骨和骨骼的破坏。促炎效应的T辅助细胞已分为三个指定为T助手（Th）1，Th2和Th17的子集。基于其细胞因子分泌模式，趋化因子受体表达和传染性生物的清除，子集是不同的子集。自身免疫性疾病的模型可以分为Th1依赖性或Th17依赖性。目前尚不清楚是什么原因导致效应细胞分化的这种异质性。基于初步结果，我们假设在免疫系统中首先遇到抗原的上下文决定了T细胞效应子的选择。我们假设在不同组织部位与环境抗原或感染剂接触，使T辅助细胞倾向于分化为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性微环境，这些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。该建议将阐明抗原暴露途径影响/修改基本T细胞极化的机制。这些研究旨在发展对自身免疫性疾病过程的新见解，以促进RA的诊断和治疗。