CONTROL OF ALLOIMMUNITY BY IMMUNIZATION WITH TCR PEPTIDE

T细胞对环境或实验引入的外来物质有反应 通过识别与以下分子相关的降解肽来识别抗原 主要组织相容性复合体(MHC.对自身抗原的识别 自身免疫中的分子也涉及到类似的过程。 最近对大鼠两种不同模型系统的研究-其中一种涉及 导致移植物抗宿主(GVH)疾病的T细胞，以及第二种 涉及T细胞对髓鞘碱性蛋白的反应，导致 实验性变态反应性脑脊髓炎(EAE)-已经证明 引起疾病的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。在这两个地方 病例中，免疫耐受机制取决于调节性T细胞 对引起疾病的T细胞上的抗原特异性受体起反应。 这些实验结果引发了两个问题：(I) T细胞抗原受体(TCR)本身是否被处理和识别？ 作为与MHC相关的自体多肽？和(Ii)承认 加工过的TCR是免疫调节的基本机制吗？ 最近的研究表明，合成的多肽与 导致EAE克隆的T细胞受体可变元件是有效的 针对活动性疾病的疫苗支持这样一种观点，即 致病T细胞经过处理后可以刺激 免疫调节反应。如果EAE和GVH阻力模型运行 通过类似的机制，应该可以识别TCR 多肽是预防活动性GVH疾病的有效疫苗。 因此，我们在此概述了一系列旨在：(I) 通过聚合酶链式反应和直接测序程序鉴定可变区基因 T细胞受体片段在同种异体反应T细胞中的应用 包括通过以下方式选择的“单Vbeta”T细胞亚群 合适的单抗(II)制备合成肽 假定与天然TCR多肽相对应并测试其有效性 作为疫苗来产生对GVH疾病的特异性抵抗力；以及 精选TCR多肽免疫动物的免疫状态研究 或“单Vbeta”T细胞群，以及携带 相应的天然TCR分子。

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.