CD80 binding peptides as therapeutic agents in arthritis

CD80结合肽作为关节炎的治疗剂

• 批准号: 7046777
• 负责人: MYTHILY SRINIVASAN
• 金额: $ 6.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-03 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046777
• 关键词: CD28 molecule; antirheumatic agents; apoptosis; binding proteins; bioinformatics; biotechnology; biotherapeutic agent; chemical kinetics; collagen; computer program /software; gene rearrangement; helper T lymphocyte; immune response; immunoglobulin genes; immunoregulation; inflammation; laboratory mouse; leukocyte activation /transformation; ligands; passive immunization; pharmacokinetics; protein protein interaction; rheumatoid arthritis; synthetic peptide; terminal nick end labeling; tissue /cell culture

DESCRIPTION (provided by applicant): Rheumatoid arthritis (IRA) is a T cell mediated autoimmune disease that affects nearly 1% of the population worldwide. Collagen-induced arthritis (CIA) is an animal model for RA that can be induced in susceptible strains of mice by immunizing with type II collagen (CII). Susceptibility to CIA is associated with specific MHC class II molecules on the antigen presenting cells (APC) that present arthritogenic peptides from CII and acitvate CII specfic T cells. Complete activation of T cells requires additional signals delivered via CD28 interacting with the b7 ligands on the APC. Activated T cells subsequently express CTLA-4, which also binds the b7 ligands and terminate the immune response. Thus the b7:CD28/CTLA4 molecules serve as attractive targets for immunomodulation. Costimulatory blockade by CTLA4-1g suppresses multiple autoimmune diseases such as psoriasis and systemic lupus erythematosus (SLE). Studies in animal models suggest that the beneficial effect of CTLA4-1g many be compromised by the adverse effects of concomitant blockade of downregulatory b7:CTLA-4 interaction. Theoretically, a selective blockade of CD28 leaving the b7:CTLA4-1g interaction intact should preferentially suppress activated T cells. Recently, a peptide mimic of the ligand binding epitope of CD28 was shown to inhibit T cell responses. Structurally, the CD28 peptide adopted a polyproline type II (PPII) helical conformation found in regions of transient protein-protein interactions. In the present proposal knowledge derived from the interresidue interatomic distances in the human b7-1: CD152 complex, the residue-residue contact preferences and the propensity for residues in PP II helical conformation are integrated in the design of b7-competitive antagonist peptides (b7-CAP) such that the new peptides lower molecular mass, optimum PP II helical content in the context of ligand binding.The specific aims are to determine the binding kinetics of the b7-CAPs to b7-1 and b7-2 and evaluate the preventive and therapeutic efficacy of the b7-CAPs and CD28 peptide mimics in DBA/1 Lac J mice induced CIA.

描述（由申请人提供）：风湿性关节炎（伊拉）是一种T细胞介导的自身免疫性疾病，影响全球近1%的人口。胶原诱导的关节炎（CIA）是RA的动物模型，其可以通过用II型胶原（CII）免疫在易感品系的小鼠中诱导。对CIA的易感性与抗原呈递细胞（APC）上的特异性MHC II类分子相关，所述抗原呈递细胞（APC）呈递来自CII的致关节炎肽并活化CII特异性T细胞。T细胞的完全活化需要通过与APC上的b7配体相互作用的CD 28递送的额外信号。活化的T细胞随后表达CTLA-4，其也结合b7配体并终止免疫应答。因此，b7：CD 28/CTLA 4分子作为免疫调节的有吸引力的靶点。CTLA 4 -1g的共刺激阻断抑制多种自身免疫性疾病，如银屑病和系统性红斑狼疮（SLE）。在动物模型中的研究表明，CTLA 4 -1g的有益作用可能会受到同时阻断下调b7：CTLA-4相互作用的副作用的损害。从理论上讲，选择性阻断CD 28而保持b7：CTLA 4 -1g相互作用完整，应优先抑制活化的T细胞。最近，CD 28的配体结合表位的肽模拟物显示出抑制T细胞应答。在结构上，CD 28肽采用了在瞬时蛋白质-蛋白质相互作用区域中发现的聚脯氨酸II型（PPII）螺旋构象。在本提议中，从人b7-1中的残基间原子间距离导出的知识：CD 152复合物、残基-残基接触偏好和残基在PP II螺旋构象中的倾向被整合到b7竞争性拮抗肽（b7-CAP）的设计中，使得新肽具有较低的分子量，具体目的是确定b7-CAP与b7-1和b7-2的结合动力学，并评估b7-CAP的预防和治疗功效。DBA/1 Lac J小鼠诱导的CIA中的CAP和CD 28肽模拟物。