REGULATION OF AUTOIMMUNITY WITH T CELL RECEPTOR PEPTIDES

T 细胞受体肽调节自身免疫

• 批准号: 7099293
• 负责人: ARTHUR A. VANDENBARK
• 金额: $ 35.07万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099293
• 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 (provided by applicant): 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.

描述（由申请人提供）：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身调节机制，用于限制由针对组织特异性抗原（如髓磷脂蛋白）的Th 1细胞介导的炎症反应。从我们使用TCR肽对多发性硬化症（MS）患者进行疫苗接种的临床试验中获得的数据已经提出了关于TCR特异性T细胞的起源和作用机制的关键问题，这将需要返回动物模型。具体而言，我们已经观察到，TCR反应性T细胞可能获得与CD 4 + CD 25+调节性T细胞（Treg）相关的特性，除了它们先前记录的通过释放IL-10调节Th 1细胞的能力之外，还具有与Th 2或Tr 1细胞相似的特性。这些观察结果提出了以下基本问题：TCR反应性细胞是否代表单一独特的调节谱系，或者携带对自身TCR决定簇特异性的T细胞受体的T细胞是否可以根据其微环境分化成不同类型的调节或效应T细胞。这个问题具有重要意义，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TCR反应性T细胞亚型的分布与健康期间不同，对调节功能的影响未知。因此，我们提出的假设，TCR特异性T细胞代表一个独特的谱系的自身反应细胞介导的一系列的调节作用，这是依赖于胸腺和外周分化途径。为了验证这一假说，我们提出：1）确定CD 4 + TCR特异性T细胞的发育途径; 2）确定TCR反应性T细胞抑制致病性和旁观者T细胞并预防实验性自身免疫性脑脊髓炎（EAE）的调控机制;和3）评估疫苗接种前后HC和MS患者中TCR反应性T细胞类型的谱及其对免疫功能的影响。我们将利用表达HLA-DR 2的人源化Tg小鼠，HLA-DR 2是MS的已知风险因子，其对髓鞘少突胶质细胞糖蛋白（MOG）-35-55肽诱导的EAE高度敏感。此外，为了更有效地跟踪致病性T细胞并评估集中的抗TCR应答的诱导，我们将利用也表达对髓鞘碱性蛋白（MBP）-85-99肽特异性的人TCR的DR 2小鼠。这些DR 2/TCR+小鼠对用MBP-85-99肽诱导的EAE高度敏感，并且我们进一步提出通过产生DR 2/CIITA-Tg小鼠来模拟自身TCR决定簇的人T细胞呈递，其中T细胞被编程为过表达II类分子。在这些小鼠和Treg相关Foxp 3基因缺陷小鼠中的研究对于明确确定各种TCR反应性亚型的保护功能差异至关重要。然后将动物模型的结果转回到人类供体，以评价未免疫HC和TCR接种MS患者中存在的TCR亚型分布，以建立与临床获益相关的主要模式。