CD80 binding peptides as therapeutic agents in arthritis

CD80结合肽作为关节炎的治疗剂

• 批准号: 6932334
• 负责人: MYTHILY SRINIVASAN
• 金额: $ 7.58万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932334
• 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(申请人提供)：类风湿性关节炎(IRA)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。胶原性关节炎(CIA)是一种类风湿性关节炎(RA)的动物模型，可以用II型胶原(CII)免疫敏感品系的小鼠。对CIA的易感性与抗原提呈细胞(APC)上的特异性MHC II类分子有关，APC呈递CII和激活CII特异性T细胞的致关节炎多肽。T细胞的完全激活需要通过CD28与APC上的b7配体相互作用传递额外的信号。激活的T细胞随后表达CTLA-4，CTLA-4也与b7配体结合并终止免疫反应。因此，b7：CD28/CTLA4分子是有吸引力的免疫调节靶点。CTLA4-1G共刺激阻断可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，CTLA4-1G的有益作用可能会被伴随着阻断下调b7：CTLA-4相互作用的不利影响所折衷。理论上，选择性地阻断CD28而保持b7：CTLA4-1g相互作用不变，应该优先抑制激活的T细胞。最近，一种模拟CD28配体结合表位的多肽被证明可以抑制T细胞反应。在结构上，CD28多肽采用了在瞬时蛋白质-蛋白质相互作用区域中发现的多脯氨酸II型(PPII)螺旋构象。在本提案中，根据人b7-1：CD152复合体中残基之间的原子间距离，将残基-残基接触偏好和PP II螺旋构象中残基的倾向整合到b7竞争拮抗肽(b7-CAP)的设计中，使新的多肽在配体结合的背景下具有较低的分子质量和最佳的PP II螺旋含量。具体目的是确定b7-caps与b7-1和b7-2的结合动力学，并评价b7-caps和CD28多肽模拟物对DBA/1Lac J小鼠诱导的CIA的预防和治疗效果。