REGULATION OF AUTOIMMUNITY WITH T CELL RECEPTOR PEPTIDES

T 细胞受体肽调节自身免疫

• 批准号: 6709344
• 负责人: ARTHUR A. VANDENBARK
• 金额: $ 37.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709344
• 关键词: T cell receptor; active immunization; antireceptor antibody; autoimmunity; clinical research; clone cells; helper T lymphocyte; human subject; human therapy evaluation; immunoregulation; interferon gamma; interleukin 10; interleukin 4; leukocyte activation /transformation; monoclonal antibody; multiple sclerosis; polymerase chain reaction; recombinant proteins

DESCRIPTION (Adapted from the Investigator's Abstract): T cell recognition of naturally expressed TCR V gene determinants represents an important regulatory mechanism for inhibiting T cell-mediated inflammatory responses and autoimmune diseases. In theory, anti-TCR response occurs during the formation of the T cell repertoire and involves T cell display of MHC-associated V gene epitopes. Thereafter, expansion of inflammatory T cells would lead to a coordinate activation of TCR-reactive Th2 cells that would eventually limit the Thl cell response and return the system to equilibrium. Our studies have demonstrated that vaccination of multiple sclerosis (MS) patients with TCR CDR2 peptides expressed by neuroantigen-specific Thl cells can rapidly boost anti-TCR Th2 responses in about half of the injected patients, with an associated decrease in response to the neuroantigen and a possible clinical benefit. However, a basic understanding of T-T network interactions is still lacking. In preliminary studies using the ELISPOT assay, the investigators observed that healthy donors had a substantial frequency (200-500 cells/million blood cells) of IL 10 producing Th2 cells specific for CDR2 peptides. In contrast, half of the MS patients had decreased responses (0-31 cells/million blood cells). Taken together, these data suggest that MS patients have a selective regulatory defect that might allow expansion of pathogenic T cells. The investigators' general hypothesis is that human anti-TCR reactive Th2 cells can regulate both target and bystander Thl cells by recognition of TCR determinants of the cognate V gene and release of inhibitory cytokines. The lack of TCR-specific Th2 cells in some MS patients could explain observed V gene bias by allowing selective expansion of Thl cells expressing unregulated V genes, including potentially pathogenic myelin-reactive T cells. The specific aims of this proposal will 1) define naturally processed and expressed TCR determinants recognized by regulatory Th2 cells, 2) investigate the mechanism by which TCR reactive T cells regulate target and bystander Thl cells, and 3) evaluate the degree and extent of the defective Th2 response to recombinant TCR proteins and peptides in MS patients and controls, and relate decreased anti-TCR response to oligoclonal expansions of activated Thl cells. This proposal represents an important first step to define the molecular basis for natural T-T network interactions, and the information obtained will be crucial for understanding how TCR peptide vaccination affects this basic regulatory mechanism in the context of a putative Thl-mediated inflammatory disease. Conceivably, successful vaccination with TCR peptides affects mainly those MS patients with defective anti-TCR T cell frequencies by boosting regulatory Th2 responses. The approach outlined in this proposal thus has the potential to define the set of TCR determinants needed to restore deficient regulatory responses in each patient.

描述（改编自研究者摘要）：T细胞识别 天然表达的TCR V基因决定簇代表了一种重要的调节因子， 抑制T细胞介导的炎症反应和自身免疫的机制 疾病理论上，抗TCR反应发生在T细胞形成过程中， 细胞库，并涉及MHC相关V基因表位的T细胞展示。 此后，炎性T细胞的扩增将导致一个协调的免疫反应。 TCR反应性Th2细胞的活化，其最终将限制Th1细胞 使系统恢复平衡。我们的研究表明 用TCR CDR 2肽接种多发性硬化症（MS）患者 由神经抗原特异性Th1细胞表达的抗TCR-Th2抗体可快速增强抗TCR-Th2抗体 大约一半的注射患者有反应， 对神经抗原的反应和可能的临床益处。但 对T-T网络交互作用的基本理解仍然缺乏。在 在使用ELISPOT分析的初步研究中，研究人员观察到， 健康献血者有相当高的频率（200 - 500个细胞/百万血细胞） IL 10产生的Th2细胞特异性的CDR2肽。相比之下， MS患者的反应降低（0 - 31个细胞/百万血细胞）。采取 总之，这些数据表明，MS患者有选择性的调节， 可能允许致病性T细胞扩增的缺陷。调查人员的 一般假设是人抗TCR反应性Th2细胞可以调节 靶向和旁观者Thl细胞通过识别靶向和旁观者Thl细胞的TCR决定簇， 同源V基因和抑制性细胞因子的释放。缺乏TCR特异性 一些MS患者中的Th2细胞可以解释观察到的V基因偏倚， 选择性扩增表达未调节的V基因的Thl细胞，包括 潜在致病性髓鞘反应性T细胞。具体目标是 建议将1）定义自然加工和表达的TCR决定因素 2）研究TCR与调节性Th2细胞的相互作用机制， 反应性T细胞调节靶细胞和旁观者Thl细胞，和3）评估反应性T细胞对Thl细胞的影响。 缺陷性Th2对重组TCR蛋白的应答的程度和范围， 在MS患者和对照组中的抗TCR肽，并将降低的抗TCR应答与 活化的Thl细胞的寡克隆扩增。该提案代表了 确定天然T-T网络分子基础的重要第一步 相互作用，获得的信息将是至关重要的理解 TCR肽疫苗接种如何影响这种基本的调节机制， 在假定的Th 1介导的炎性疾病的背景下。可以想象， TCR肽的成功疫苗接种主要影响那些MS患者， 通过加强调节性Th2应答来降低有缺陷的抗TCR T细胞频率。的 因此，本提案中概述的方法有可能确定一套 TCR决定因素需要恢复缺陷的调节反应， 病人