Cytokine Regulation of Collagen-induced Arthritis

胶原诱导的关节炎的细胞因子调节

• 批准号: 7285668
• 负责人: ROBERT A ORTMANN
• 金额: $ 12.43万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7285668
• 关键词: Address; Adjuvant; Animal Model; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Binding; Biological Assay; Cells; Characteristics; Collagen; Collagen Arthritis; Collagen Type II; Complement; Condition; Cytokine Receptors; DBA/1J Mouse; Development; Disease; Disease Progression; Disease Resistance; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Freund' s Adjuvant; Genes; Genus Mycobacterium; Haplotypes; Histologic; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoblotting; Immunoglobulins; Immunotherapy; In Vitro; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Interleukin-18; Interleukin-4; Joints; Knockout Mice; Lead; Leukocytes; Ligands; Link; Mediating; Mediator of activation protein; Modeling; Modification; Monitor; Mouse Strains; Mus; Mycobacterium tuberculosis; Nature; Numbers; Oligopeptides; Pathologic; Pathologic Processes; Pathway interactions; Play; Polyarthritides; Polymerase Chain Reaction; Population; Powder dose form; Precipitation; Predisposition; Preparation; Procedures; Process; Production; Property; Protocols documentation; Publishing; Rattus; Regulation; Research; Research Personnel; Rheumatoid Arthritis; Role; Signal Transduction; Specificity; Standards of Weights and Measures; T-Cell Receptor; T-Lymphocyte; Testing; Thinking; Time; Toll-like receptors; Work; base; cell mediated immune response; chemokine; chemokine receptor; cytokine; design; improved; lymph nodes; monocyte; mutant; novel; programs; receptor; receptor expression; response

DESCRIPTION (provided by applicant): Collagen-induced arthritis is a well-studied animal model of human rheumatoid arthritis. An autoimmune process evolves after immunization with heterologous type II collagen in an adjuvant that induces an inflammatory response. The nature of the inflammatory response induced may be as critical as the antigen used, for mouse strains that have been previously believed to be resistant to disease can become susceptible when the immunization protocol is modified. The long-term objectives of this application are to develop an independent program of research that leads to an improved understanding of the etiopathogenesis of inflammatory arthritis based on a clearer characterization of the inflammatory responses necessary for an autoimmune disease to develop. Initially, characterization of immunomodulatory Th2 cytokines in disease progression will be performed. IL-4 and IL-10 deficient mice will be immunized with type II collagen, and the development of arthritis will be monitored. The immune response to collagen will be studied as determined by cytokine and chemokine expression in the absence of endogenous IL-4 or IL-10. The T cell response to antigen resulting from different immunization protocols will also be studied, as differences in the T cell repertoire may be responsible for the presence or absence of disease. T cell receptor V3 gene usage as well as epitope specificity of collagen-reactive T cells will be determined. Levels of collagen-reactive antibodies and binding specificities will be determined to assess the effect on B cell reactivity. Finally, innate immune responses to these immunization protocols will be ascertained. The expression and function of toll-like receptors will be studied by flow cytometry and immunoblotting, and the ability to produce cytokines such as IL-12 and IL-18 under different immunization conditions will be determined. By better understanding unique inflammatory pathways that are required for the development of disease, specific immunotherapy strategies for the treatment of autoimmune processes such as rheumatoid arthritis may be designed.

描述（由申请人提供）： 胶原诱导的关节炎是人类类风湿性关节炎的充分研究的动物模型。 在用佐剂中的异源II型胶原免疫后，自身免疫过程发展，其诱导炎症反应。诱导的炎症反应的性质可能与所使用的抗原一样重要，因为先前被认为对疾病具有抗性的小鼠品系在修改免疫方案时可能变得易感。本申请的长期目标是开发一个独立的研究项目，该项目基于对自身免疫性疾病发展所需的炎症反应的更清晰表征，提高对炎症性关节炎发病机制的理解。 首先，将进行疾病进展中免疫调节性Th 2细胞因子的表征。用II型胶原免疫IL-4和IL-10缺陷小鼠，并监测关节炎的发展。在不存在内源性IL-4或IL-10的情况下，通过细胞因子和趋化因子表达测定，研究对胶原蛋白的免疫应答。还将研究由不同免疫方案产生的对抗原的T细胞应答，因为T细胞库的差异可能是疾病存在或不存在的原因。将确定T细胞受体V3基因使用以及胶原反应性T细胞的表位特异性。将测定胶原蛋白反应性抗体水平和结合特异性，以评估对B细胞反应性的影响。最后，将确定对这些免疫方案的先天免疫应答。将通过流式细胞术和免疫印迹研究toll样受体的表达和功能，并确定在不同免疫条件下产生细胞因子如IL-12和IL-18的能力。通过更好地了解疾病发展所需的独特炎症途径，可以设计用于治疗自身免疫过程如类风湿性关节炎的特异性免疫治疗策略。