REGULATION OF AUTOIMMUNITY WITH T CELL RECEPTOR PEPTIDES

T 细胞受体肽调节自身免疫

• 批准号: 7595878
• 负责人: ARTHUR A. VANDENBARK
• 金额: $ 36.12万
• 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/7595878
• 关键词: Address; Affect; Animal Model; Antigens; Autoimmune Diseases; Autoimmunity; Avidity; B-Lymphocytes; Back; Binding; Cells; Clinical; Clinical Trials; Data; Development; Encephalomyelitis; Environment; Experimental Autoimmune Encephalomyelitis; Genes; Green Fluorescent Proteins; HLA-DR2 Antigen; Health; Human; Immunization; In Vitro; Inflammatory; Interleukin-10; MHC Class II Genes; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin Associated Glycoprotein; Myelin Basic Proteins; Myelin Proteins; Pathway interactions; Patients; Pattern; Peptide Receptor; Peptides; Peripheral; Population; Process; Property; Proteins; Psoriasis; Reaction; Receptor Cell; Recombinants; Regulation; Research Personnel; Rheumatoid Arthritis; Risk Factors; Specificity; Surface; T-Cell Receptor; T-Lymphocyte; TCR Activation; Th1 Cells; Tissues; Translating; Vaccinated; Vaccination; cell type; cytokine; immune function; in vivo; migration; oligodendrocyte-myelin glycoprotein; prevent; programs; response

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.

抗原性自身TCR序列的T细胞识别构成了独特的外周自身调节免疫应答。 限制由针对组织特异性抗原的Th 1细胞介导的炎症反应的机制 例如髓磷脂蛋白。从我们的临床试验中获得的数据使用TCR肽对患有 多发性硬化（MS）提出了关于TCR的起源和作用机制的关键问题， 特异性T细胞，这将需要返回到动物模型。具体地说，我们已经观察到TCR反应性 T细胞可以获得与CD 4 + CD 25+调节性T细胞（Treg）相关的特性，除了它们的免疫调节功能之外。 先前记录的通过释放IL-10调节Th 1细胞的能力，具有类似于 Th 2或Tr 1细胞。这些观察结果提出了一个基本问题，即TCR反应性细胞是否 代表单一的不同调节谱系，或者是否T细胞携带对自身TCR特异的T细胞受体 决定子可以根据其微生物学特性分化成不同类型的调节性或效应性T细胞。 环境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 这一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，我们提出这样的假设，即TCR特异性T细胞 代表了自身反应细胞的独特谱系，其介导一系列调节作用， 依赖于胸腺和外周分化途径。为了解决这个问题，我们建议 目的：1）确定CD 4 + TCR特异性T细胞的发育途径; 2）确定CD 4 + TCR特异性T细胞的发育途径。 TCR反应性T细胞抑制致病性和旁观者T细胞的调控机制， 预防实验性自身免疫性脑脊髓炎（EAE）; 3）评估TCR反应性T细胞的谱 HC和MS患者接种疫苗前后的细胞类型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的已知危险因素， 髓鞘少突胶质细胞糖蛋白（MOG）-35-55肽诱导的EAE。此外，为了更 有效地跟踪病原性T细胞并评估集中抗TCR应答的诱导，我们将利用 DR 2小鼠还表达对髓鞘碱性蛋白（MBP）-85-99肽特异性的人TCR。这些 DR 2/TCR+小鼠对MBP-85-99肽诱导的EAE高度敏感，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 细胞被编程为过度表达II类分子。在这些小鼠和缺乏 Treg相关Foxp 3基因对于明确确定保护功能的差异至关重要 不同的TCR反应亚型然后将动物模型的结果翻译回人类 供体，以评价未免疫HC和TCR接种MS中存在的TCR亚型分布 患者建立与临床获益相关的主要模式。