Suppression of Collagen Induced Arthritis with Altered Peptide Ligands

用改变的肽配体抑制胶原诱导的关节炎

• 批准号: 7578745
• 负责人: ANDREW H KANG
• 金额: $ 37万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578745
• 关键词: Address; Affinity; Amino Acid Substitution; Amino Acids; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Arthritis; Attention; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Avidity; Binding; Biological Assay; CD4 Positive T Lymphocytes; CD44 gene; Cartilage; Cell Communication; Cells; Characteristics; Charge; Chronic; Collagen; Collagen Arthritis; Collagen Type I; Collagen Type II; Competitive Binding; Complex; DBA/1 Mouse; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; Experimental Models; Foxes; Funding; Harvest; Hybridomas; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunodominant Epitopes; Immunologics; Immunotherapy; Inflammatory; Interferons; Interleukin-17; Interleukin-4; Joints; Kinetics; Ligands; Limb structure; MHC Interaction; MHC binding peptide; Measures; Mediating; Microfluidics; Modeling; Mouse Strains; Mus; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Population; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Production; Proteins; Relative (related person); Rheumatoid Arthritis; Role; Severity of illness; Signal Transduction; Site; Spleen; Splenocyte; Staining method; Stains; Structure; Study of serum; Synapses; Synovitis; System; Systemic disease; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TCR Activation; TFRC gene; Testing; Time; Transgenic Mice; Treatment Protocols; ZAP-70 Gene; analog; autoimmune arthritis; base; cytokine; density; improved; in vitro testing; in vivo; insight; peptide analog

Rheumatoid arthritis is a chronic inflammatory disease of diarthrodial joints. This systemic disease is characterized by chronic synovitis, sustained by an antigen-driven immune process against one or more proteins found in cartilage. Although several antigens have been proposed to be involved in the autoimmune response in RA, type II collagen (CII) has received the most attention as a candidate autoantigen. Collageninduced arthritis (CIA) is an experimental model with several similarities to RA and is induced by immunization of susceptible strains of mice with CII. We have used the animal model of CIA to develop a specific immunotherapy capable of selectively blocking autoimmunity without interfering with the beneficial functions of the immune system. Previously we have identified and characterized the dominant determinant on CII recognized by T cells and have shown that arthritis can be suppressed by an analog peptide (A9), which differs from the wild-type determinant by three amino acids. We hypothesize that a major mechanism by which the A9 analog peptide functions is to drive uncommitted CD4+ T cells toward a unique inhibitory phenotype. Unlike the recently described Treg cells, the A9-induced inhibitory T cell subset is characterized by increased expression of FcRɣ, signaling through an alternate pathway (i.e. Syk rather than Zap-70), and secretion of predominantly IL-4. To further explore the hypothesis, we propose the following Specific Aims: 1) Identify the structural characteristics of A9 that are responsible for modulation of the immune response to CII and CIA. 2) Characterize the inhibitory T cells induced by A9 It is our belief that a definitive understanding of the mechanism(s) through which A9 suppresses arthritis will facilitate the development of improved treatments for RA.

类风湿性关节炎是一种关节慢性炎症性疾病。这 全身性疾病的特点是慢性滑膜炎，由抗原驱动的 针对软骨中发现的一种或多种蛋白质的免疫过程。虽然有几个 抗原被认为参与 II 型 RA 的自身免疫反应 胶原蛋白（CII）作为候选自身抗原最受关注。胶原蛋白诱导 关节炎 (CIA) 是一种与 RA 有许多相似之处的实验模型， 通过用 CII 免疫敏感品系小鼠来诱导。我们已经使用了 CIA动物模型开发一种能够选择性阻断的特异性免疫疗法 自身免疫而不干扰免疫系统的有益功能。 之前我们已经确定并描述了 CII 的主要决定因素 被 T 细胞识别并表明关节炎可以被类似物抑制 肽 (A9)，与野生型决定簇有 3 个氨基酸不同。我们 假设 A9 类似肽发挥作用的主要机制是 驱动未定型的 CD4+ T 细胞形成独特的抑制表型。与 最近描述的 Treg 细胞，A9 诱导的抑制性 T 细胞亚群的特点是 FcRɣ 表达增加，通过替代途径（即 Syk 而不是 比 Zap-70），并且主要分泌 IL-4。为了进一步探讨该假设， 我们提出以下具体目标：1）确定A9的结构特征 负责调节对 CII 和 CIA 的免疫反应。 2） 表征 A9 诱导的抑制性 T 细胞 我们相信，一个明确的 了解 A9 抑制关节炎的机制将有助于 开发改进的 RA 治疗方法。