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: 7914434
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914434
• 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; CD3 Antigens; 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; Cytolysis; DBA/1 Mouse; Data; Development; Disease; Down-Regulation; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Experimental Autoimmune Encephalomyelitis; Experimental Models; Exposure to; Flow Cytometry; Foxes; Funding; Harvest; Hen Egg Lysozyme; Hybridomas; Hydroxylation; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunodominant Epitopes; Immunologics; Immunoprecipitation; Immunotherapy; Incubated; Inflammatory; Inositol Metabolism Pathway; Interferons; Interleukin-17; Interleukin-4; JUN gene; Joints; Kinetics; Ligands; Limb structure; MAPK14 gene; MAPK8 gene; MHC Interaction; MHC binding peptide; Major Histocompatibility Complex; Measures; Mediating; Microfluidics; Mitogen-Activated Protein Kinases; Modeling; Mouse Strains; Mus; Nuclear; Outcome; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Phosphatidylinositols; Phospho-Specific Antibodies; Phosphorylation; Physiologic pulse; Piceatannol; Population; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Production; Protein Tyrosine Kinase; Proteins; Receptor-CD3 Complex, Antigen, T-Cell; Regulatory T-Lymphocyte; Relative (related person); Resources; Rheumatoid Arthritis; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Spleen; Splenocyte; Staining method; Stains; Structure; Study of serum; Sulfonamides; Synapses; Synovitis; System; Systemic disease; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TCR Activation; TFRC gene; Testing; Time; Transcription Factor AP-1; Transgenes; Transgenic Mice; Treatment Protocols; Variant; Western Blotting; ZAP-70 Gene; analog; autoimmune arthritis; base; c-myc Genes; cytokine; density; design; glycosylation; human SYK protein; improved; in vitro testing; in vivo; inhibitor/antagonist; insight; lymph nodes; novel; peptide analog; prevent; research study; response; transcription factor; tripolyphosphate

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.

风湿性关节炎是一种慢性关节炎性疾病。这 全身性疾病的特征在于慢性滑膜炎，其由抗原驱动的 免疫过程中对软骨中发现的一种或多种蛋白质。尽管几 已提出抗原参与II型RA的自身免疫应答 胶原（CII）作为候选自身抗原受到最多的关注。胶原诱导的 关节炎（CIA）是一种与RA有几个相似之处的实验模型， 通过用CII免疫易感小鼠品系诱导。我们已经使用了 CIA的动物模型，以开发能够选择性阻断 自身免疫而不干扰免疫系统的有益功能。 以前，我们已经确定并表征了CII上的主导决定簇 T细胞识别，并表明关节炎可以通过类似物抑制 肽（A9），其与野生型决定簇相差三个氨基酸。我们 假设A9类似肽发挥功能的主要机制是 驱动未定型的CD 4 + T细胞朝向独特的抑制性表型。不像 最近描述的Treg细胞，A9诱导的抑制性T细胞亚群的特征在于： FcR β的表达增加，通过替代途径（即Syk，而不是 比Zap-70），并且主要分泌IL-4。为了进一步探索这个假设， 我们提出了以下具体目标：1）确定A9的结构特征 负责调节对CII和CIA的免疫应答。（二） 表征A9诱导的抑制性T细胞我们相信， 了解A9抑制关节炎的机制将有助于 改善类风湿性关节炎的治疗方法。