REGULATION OF AUTOIMMUNITY WITH T CELL RECEPTOR PEPTIDES

描述(改编自研究人员摘要)：T细胞识别 自然表达的TCR V基因决定簇代表了一种重要的调节 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细胞的形成过程中。 细胞库，包括MHC相关V基因表位的T细胞展示。 此后，炎性T细胞的扩张将导致协调 激活TCR反应性Th2细胞，最终限制Th1细胞 作出反应，并使系统恢复平衡。我们的研究表明 多发性硬化(MS)患者TCR CDR2多肽疫苗免疫效果观察 神经抗原特异性Th1细胞表达可迅速增强抗TCR Th2抗体 大约一半的注射患者的反应，伴随着相关的下降 以应对神经抗原和可能的临床益处。然而，a 对T-T网络相互作用的基本了解仍然缺乏。在……里面 使用ELISPOT分析的初步研究中，调查人员观察到 健康献血者有相当高的频率(200-500个细胞/百万血细胞) 产生CDR2多肽的IL-10特异性Th2细胞。相比之下，一半的人 MS患者的反应降低(0-31个细胞/百万血细胞)。已被占用 总而言之，这些数据表明多发性硬化症患者有选择性的调节 可能导致致病T细胞扩张的缺陷。调查人员的 一般假设是人类抗TCR反应性Th2细胞可以调节两者 靶向和旁观者THL细胞通过识别TCR决定簇 同源V基因与抑制性细胞因子的释放缺乏特定于TCR的 一些多发性硬化症患者的Th2细胞可以通过允许 表达非调控V基因的Th1细胞的选择性扩增 潜在致病的髓鞘反应性T细胞。这样做的具体目的是 建议书将1)定义自然加工和表达的TCR决定因素 被调节性Th2细胞识别，2)研究TCR的机制 反应性T细胞调节靶细胞和旁观者THL细胞，以及3)评估 缺陷Th2对重组TCR蛋白反应的程度和程度 多发性硬化症患者和对照组中的多肽，并与抗TCR反应降低有关 活化Th1细胞的寡克隆性扩增。这项提议代表了一个 确定天然T-T网络分子基础的重要第一步 相互作用，所获得的信息对于理解 TCR多肽疫苗如何影响这一基本调控机制 推测为Th1介导的炎症性疾病的背景。可想而知， 成功接种TCR多肽主要影响MS患者 通过增强调节性Th2反应而导致的抗TCRT细胞频率缺陷。这个 因此，本提案中概述的方法有可能定义一组 需要TCR决定因素来恢复每一个有缺陷的监管反应 有耐心的。

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.