REGULATION OF AUTOIMMUNITY WITH T CELL RECEPTOR PEPTIDES

抗原性自身TCR序列的T细胞识别构成了一种独特的外周自我调节 Th1细胞针对组织特异性抗原抑制炎症反应的机制 比如髓鞘蛋白。从我们使用TCR多肽接种患者的临床试验中获得的数据 多发性硬化症(MS)对TCR的起源和作用机制提出了关键的问题。 需要回到动物模型中的特定T细胞。具体地说，我们观察到TCR反应 T细胞可能获得与CD4+CD25+调节性T细胞(Treg)相关的特性，除了它们的 先前已证实的通过释放IL-10来调节Th1细胞的能力，其特性类似于 Th2或Tr1细胞。这些观察提出了一个根本的问题，即TCR反应细胞 代表单一的不同的调节谱系，或者T细胞是否携带自身TCR特异性的T细胞受体 决定因素可以分化为不同类型的调节性或效应性T细胞，根据其微观 环境。这个问题具有重要的意义，因为在后一种情况下，自身免疫性疾病 过程本身可能会导致与健康期间不同的TCR反应性T细胞亚型的分布， 对调节功能的影响未知。因此，我们提出了TCR特异性T细胞的假设 代表了一种独特的自身反应细胞谱系，这些细胞介导了一系列调控效应，这些调控效应 依赖于胸腺和外周分化途径。为了解决这一假设，我们建议 目的：1)确定CD4+TCR特异性T细胞的发育途径；2)确定哪些是 TCR反应性T细胞抑制致病T细胞和旁观者T细胞的调控机制 预防实验性自身免疫性脑脊髓炎(EAE)；以及3)评估TCR反应性T细胞的频谱 免疫前后HC和MS患者的细胞类型及其对免疫功能的影响我们 将利用人源化的TG小鼠，这些小鼠表达人类白细胞抗原-DR2，这是一种已知的多发性硬化症的危险因素，是高度敏感的 抗髓鞘少突胶质细胞糖蛋白(MOG)-35-55多肽诱导的EAE。而且，为了更多地 有效地跟踪致病T细胞并评估集中的抗TCR反应的诱导，我们将利用 也表达髓鞘碱性蛋白(MBP)-85-99肽的人TCR的DR2小鼠。这些 DR2/TCR+小鼠对MBP-85-99多肽诱导的EAE高度易感，我们进一步提出 通过产生DR2/CIITA-TG小鼠来模拟人类T细胞提呈自身TCR决定簇，其中T细胞 细胞被编程为过度表达II类分子。在这些小鼠和小鼠身上进行的研究 Treg相关的Foxp3基因对于明确确定保护功能的差异至关重要 各种TCR反应亚型。动物模型的结果将被翻译回人类身上 供者评估未免疫的HC和TCR疫苗接种的MS中存在的TCR亚型的分布 患者需要建立与临床利益相关的主导模式。

T cell recognition of antigenic self-TCR sequences constitutes a distinct peripheral autoregulatory mechanism for limiting inflammatory reactions mediated by Th1 cells directed at tissue-specific antigens such as myelin proteins. Data obtained from our clinical trials using TCR peptides to vaccinate patients with multiple sclerosis (MS) have raised crucial questions regarding the origin and mechanism of action of TCR- specific T cells that will require a return to animal models. Specifically, we have observed that TCR-reactive T cells may acquire properties associated with CD4+CD25+ regulatory T cells (Treg), in addition to their previously documented ability to regulate Th1 cells through the release of IL-10, with properties similar to Th2 or Tr1 cells. These observations raise the fundamental question of whether the TCR-reactive cells represent a single distinct regulatory lineage or whether T cells bearing T cell receptors specific for self TCR determinants can differentiate into different types of regulatory or effector T cells according to their micro- environment. This question has important implications because in the latter case, the autoimmune disease process itself might direct a different distribution of TCR-reactive T cell subtypes than occurs during health, with unknown effects on regulatory function. We thus propose the hypothesis that TCR-specific T cells represent a unique lineage of autoreactive cells that mediate a spectrum of regulatory effects that are dependent on both thymic and peripheral differentiation pathways. To address this hypothesis, we propose to: 1) Determine what are the developmental pathways for CD4+ TCR-specific T cells; 2) Determine what are the governing mechanisms by which TCR-reactive T cells inhibit pathogenic and bystander T cells and prevent experimental autoimmune encephalomyelitis (EAE); and 3) Evaluate the spectrum of TCR-reactive T cell types in HC and in MS patients before and after vaccination and their effects on immune function. We will utilize humanized Tg mice that express HLA-DR2, a known risk factor for MS, that are highly susceptible to EAE induced with myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide. Moreover, in order to more effectively follow pathogenic T cells and evaluate induction of a focused anti-TCR response, we will utilize DR2 mice that also express a human TCR specific for myelin basic protein (MBP)-85-99 peptide. These DR2/TCR+ mice are highly susceptible to EAE induced with the MBP-85-99 peptide, and we further propose to mimic human T cell presentation of self-TCR determinants by producing DR2/CIITA-Tg mice, in which T cells are programmed to over-express class II molecules. Studies in these mice and in mice deficient in the Treg associated Foxp3 gene are crucial for a definitive determination of differences in the protective function of various TCR-reactive subtypes. Results from the animal models will then be translated back to human donors to evaluate the distribution of TCR subtypes present in un-immunized HC and TCR vaccinated MS patients to establish predominant patterns that are associated with clinical benefit.