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：
8441582
负责人：
ALISON FINNEGAN
金额：
$ 30.47万
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8441582
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 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 Health 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 Cell Lymphoid Tissue Mediating Modeling Mus Pattern Phenotype Population Process Production Proteoglycan Regulation Reporting Rheumatoid Arthritis Route Signal Transduction Site System T cell differentiation T cell response 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.

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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis.

DOI：
10.1586/14760584.2015.1026330
发表时间：
2015-06
期刊：
Expert review of vaccines
影响因子：
6.2
作者：
Rosenthal KS;Mikecz K;Steiner HL 3rd;Glant TT;Finnegan A;Carambula RE;Zimmerman DH
通讯作者：
Zimmerman DH

Location of CD4+ T cell priming regulates the differentiation of Th1 and Th17 cells and their contribution to arthritis.