REGULATION OF AUTOIMMUNITY WITH T-CELL RECEPTOR PEPTIDES

T 细胞受体肽调节自身免疫

• 批准号: 2264750
• 负责人: ARTHUR A. VANDENBARK
• 金额: $ 25.82万
• 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 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2264750
• 关键词: SCID mouse; T cell receptor; T lymphocyte; antireceptor antibody; autoimmunity; clone cells; epitope mapping; experimental allergic encephalomyelitis; human subject; immunotherapy; monoclonal antibody; multiple sclerosis; myelin basic proteins; passive immunization; polymerase chain reaction; synthetic peptide; tissue /cell culture

The overall goal of this proposal is to test the hypothesis that induction of immunity against synthetic peptides that resemble natural human TCR V-beta-5.2 idiotopes can regulate potentially pathogenic T cells that preferentially express V-beta-5.2. Our prior studies in rats and mice demonstrated that TCR V-beta-8.2 CDR2 peptides can prevent and treat clinical signs of experimental encephalomyelitis by inducing T cells and antibodies that can inhibit the mono-V-beta-8.2 T cell response to myelin basic protein (BP). Recently, we found biased use of V-beta-5.2 and V-beta-6.1 by BP-specific T cells from multiple sclerosis (MS) patients, a result corroborated by others who found V-beta-5.2+ T cells with a BP-specific CDR3 motif in MS plaques. We have now shown that anti-TCR specific T cells and antibodies can be induced by injecting TCR V-beta-5.2 or V-beta-6.1 peptides into MS patients. Thus the stage is set to test whether these T cells and antibodies can regulate V-beta-5.2 + T cells, including those specific for BP. Successful regulation of BP reactivity would allow a critical evaluation of the role of BP in the MS disease process, and would establish a prototypic approach for the treatment of other autoimmune diseases characterized by limited V gene expression. AIM 1. To assess the frequency, specificity, TCR repertoire, and encephalitogenicity of human BP-specific T cells. In this aim, we will develop the ability to rapidly and repeatedly evaluate MS disease- associated changes in BP-specific T cell responses in blood and CSF. Moreover, we will assess the encephalitogenic activity of these T cells by passive transfer into MHC compatible, bone marrow reconstituted SCID-Hu mice. AIM 2. To establish the effects of TCR peptide injection on TCR and BP responses. With a focus on V-beta-5.2, we will inject overlapping peptides into MS patients with V-beta-5.2-biased responses to BP to determine which regions are immunodominant T and B cell idiotopes. In responders, we will monitor functional changes in V-beta-5.2+ T cells and in responses to BP. AIM 3. To evaluate potential regulatory mechanisms induced by TCR peptides. In this aim, we will isolate and characterize distinct anti-TCR peptide-specific T cell clonotypes and antibodies induced after TCR peptide boosting. We will evaluate each T cell clonotype and affinity purified antibodies for their ability to regulate autologous V-beta-5.2+ BP-reactive T cells in vitro and in the SCID-Hu mouse.

该提议的总体目标是检验以下假设。 诱导对类似于天然的合成肽的免疫力 人类TCR V-beta-5.2白痴可以调节潜在的致病性T 优先表达V-beta-5.2的细胞。我们先前在大鼠的研究 小鼠证明TCR V-Beta-8.2 CDR2肽可以预防和 通过诱导T来治疗实验性脑脊髓炎的临床体征 细胞和抗体可以抑制单v-beta-8.2 T细胞反应 髓磷脂碱性蛋白（BP）。 最近，我们发现了偏见的使用 V-Beta-5.2和V-Beta-6.1由BP特异性T细胞来自多发性硬化症 （MS）患者，结果由其他发现V-Beta-5.2+ T的结果证实 MS斑块中具有BP特异性CDR3基序的细胞。 我们现在显示了 可以通过注射来诱导抗TCR特异性T细胞和抗体 TCR V-BETA-5.2或V-BETA-6.1肽成MS患者。 因此，舞台 设置以测试这些T细胞和抗体是否可以调节 V-beta-5.2 + T细胞，包括特定于BP的细胞。 成功的 BP反应性的调节将允许对角色进行批判性评估 在MS疾病过程中的BP，将建立原型 治疗其他自身免疫性疾病的方法 有限的V基因表达。 目标1。评估频率，特异性，TCR曲目和 人BP特异性T细胞的脑作用。 在这个目标中，我们将 发展能够快速，反复评估MS疾病的能力 - 血液和CSF中BP特异性T细胞反应的相关变化。 此外，我们将评估这些T细胞的脑作用活性 通过被动转移到MHC兼容，骨髓重构 scid-hu小鼠。 目标2。建立TCR肽注射对TCR和BP的影响 回答。 重点是V-Beta-5.2，我们将注入重叠 肽进入对BP的V-Beta-5.2偏置反应的MS患者 确定哪些区域是免疫主导的T和B细胞杜鹃。 在 响应者，我们将监视V-Beta-5.2+ T细胞和 在对BP的回应中。 目标3。评估TCR诱导的潜在调节机制 肽。 在此目标中，我们将隔离和表征独特的 在 TCR肽的增强。 我们将评估每种T细胞的克隆型和 亲和力纯化的抗体具有调节自体的能力 V-Beta-5.2+ BP反应性T细胞在体外和SCID-HU小鼠中。