CONTROL OF ALLOIMMUNITY BY IMMUNIZATION WITH TCR PEPTIDE

通过 TCR 肽免疫控制同种免疫

• 批准号: 3146456
• 负责人: Daniel P. Gold
• 金额: $ 27.13万
• 依托单位: SIDNEY KIMMEL CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3146456
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; T lymphocyte; antireceptor antibody; cell population study; disease /disorder model; experimental allergic encephalomyelitis; graft versus host disease; histocompatibility; immunization; immunoregulation; laboratory rat; monoclonal antibody; nucleic acid sequence; peptide chemical synthesis; polymerase chain reaction; tissue /cell culture

T cells respond to environmental or experimentally introduced foreign antigens by recognizing degraded peptides associated with molecules of the major histocompatibility complex (MHC. Recognition of self antigen molecules in autoimmunity involves a similar process. Recent studies with two different model systems in rats - one involving T cells which cause graft-versus-host (GVH) disease, and the second involving T cells reactive to myelin basic protein that cause experimental allergic encephalomyelitis (EAE) - have demonstrated that disease causing T cell populations are themselves very effective vaccines for inducing immune resistance in these two disease models. In both cases, the immune resistance mechanism depends on regulatory T cells reactive to antigen specific receptors on disease causing T cells. There are two questions that arise from these experimental findings: (i) are T cell antigen receptors (TCR) themselves processed and recognized as self-peptides associated with MHC? and (ii) is recognition of processed TCR part of a fundamental mechanism of immune regulation? Recent demonstrations that synthetic peptides corresponding to the variable elements of T cell receptors on EAE causing clones are effective vaccines against active disease support the notion that receptors on disease-causing T cells are processed and can stimulate an immunoregulatory response. If the EAE and GVH resistance models operate by similar mechanisms, then it should be possible to identify TCR peptides which are effective vaccines against active GVH disease. Accordingly, we outline here a series of studies designed to: (i) identify, by PCR and direct sequencing procedures, the variable gene segments of T cell receptors employed in alloreactive T cell subpopulations including "mono-Vbeta" T cell populations selected with appropriate monoclonal antibodies (ii) prepare synthetic peptides presumed to correspond to natural TCR peptides and test their efficacy as vaccines in producing specific resistance to GVH disease; and (iii) explore the immune status of animals immunized with selected TCR peptides or "mono-Vbeta" T cell populations, and the fate of T cells bearing the corresponding native TCR molecules.

T细胞对环境或实验引入的外源性 抗原通过识别降解的肽与分子 主要组织相容性复合体（MHC. 自身抗原识别 自身免疫中的分子也涉及类似的过程。 最近在大鼠中使用两种不同模型系统的研究-一种涉及 引起移植物抗宿主（GVH）疾病的T细胞，以及 涉及T细胞对髓鞘碱性蛋白的反应， 实验性过敏性脑脊髓炎（EAE）-已经证明， T细胞群本身就是非常有效的疫苗 在这两种疾病模型中诱导免疫抵抗。 无论是 免疫抵抗机制依赖于调节性T细胞 对引起疾病的T细胞上的抗原特异性受体具有反应性。 从这些实验结果中产生了两个问题：（一） 是T细胞抗原受体（TCR）本身处理和识别 作为与MHC相关的自身肽？ 及（ii）承认 处理TCR的免疫调节的基本机制的一部分？ 最近的研究表明， 引起EAE的克隆上的T细胞受体的可变元件是有效的 针对活动性疾病的疫苗支持这样的观点， 致病的T细胞被加工，可以刺激 免疫调节反应。 如果EAE和GVH抗性模型运行 通过类似的机制，那么应该可以识别TCR 这些肽是针对活动性GVH疾病的有效疫苗。 因此，我们在此概述了一系列研究，旨在：（一） 通过PCR和直接测序程序鉴定可变基因 同种异体反应性T细胞中使用的T细胞受体片段 亚群，包括“单-V β”T细胞群，其用 适当的单克隆抗体（ii）制备合成肽 假定其对应于天然TCR肽并测试其功效 作为疫苗产生对GVH疾病的特异性抗性;和（iii） 探索用所选TCR肽免疫的动物的免疫状态 或“单-V β”T细胞群，以及携带该T细胞的T细胞的命运。 相应的天然TCR分子。