MOLECULAR EVENTS IN ANTIGEN RECOGNITION

在上一个供资期间，详细分析了 肽和MHC分子之间的联系。在这些过程中， 研究，一种新的机制，肽抗原的类似物 抑制T细胞对这些抗原的识别。这是 发现某些抗原类似物不仅与抗原竞争， 抗原类似物/MHC复合物也可以与MHC竞争结合， 用抗原/MHC复合物与T细胞受体结合。这 本申请将对“T细胞受体拮抗作用”的观察扩展到 探讨以下问题：一是通过一系列实验考察 抗原类似物干预免疫反应过程的潜在用途 将进行自身免疫性疾病。要做到这一点，一个或 抑制多克隆抗原特异性应答的一些类似物需要 确立了习 接下来，研究了此类类似物抑制体内肿瘤生长的能力。 疾病过程将进行评估，使用实验过敏 脑炎为模型。由于类似物的潜在医学用途是 这取决于对所涉及的特异性自身抗原的性质的了解 在自身免疫性疾病的发病机理中，将努力 确定参与NOD小鼠糖尿病模型的自身抗原。的 抗原诱导的T细胞受体拮抗作用 类似物和类似物诱导T细胞不完全刺激的能力 如Paul艾伦所述，也将评估细胞（部分无反应性）。 具体而言，关于类似物的结构关系的问题 TCR拮抗剂和部分激动剂将 定义，因为这些不同的类似物的能力，以引起早期 信号传导事件如酪氨酸磷酸化。最后，分析 抗原类似物的生物学效应的评估也将在TCR中进行。 转基因系统 类似物的结构关系， 外周T细胞和那些诱导阳性和阴性选择的T细胞 将分析胸腺中的细胞。这将允许对 亲和力假说来解释胸腺分化事件。

Over the previous funding period, a detailed analysis of the interaction between peptide and MHC molecules was made. During the course of those investigations, a novel mechanism by which analogs of peptide antigens inhibit the recognition of those antigens by T cells was made. It was found that certain antigen analogs not only competed with antigen for binding to MHC, but the antigen analog/MHC complexes could also compete with antigen/MHC complexes for binding to the T cell receptor. This application extends the observations on "T-cell receptor antagonism" to explore the following issues: First, a series of experiments to examine the potential use of antigen analogs to intervene in the course of an autoimmune disease will be performed. To do this, the capacity of one or a few analogs to inhibit polyclonal antigen-specific responses needs to be established. Next, the capacity of such analogs to inhibit an in vivo disease process will be evaluated, using experimental allergic encephalitis as the model. Since the potential medical use of analogs is dependent upon knowledge of the nature of specific autoantigens involved in the pathogenesis of autoimmune disease, an effort will be made to identify the autoantigens involved in the NOD mouse model of diabetes. The relationship between T cell receptor antagonism elicited by antigen analogs and the capacity of analogs to induce incomplete stimulation of T cells (partial anergy), as described by Paul Allen, will also be assessed. Specifically, questions concerning the structural relationship of analogs that are TCR antagonists and those that are partial agonists will be defined, as will the capacity of these different analogs to elicit early signaling events such as tyrosine phosphorylation. Finally, the analysis of the biologic effects of antigen analogs will also be evaluated in a TCR transgenic system. The structural relationship of analogs that stimulate peripheral T cells and those that induce positive and negative selection in the thymus will be analyzed. This will allow an evaluation of an affinity hypothesis to explain thymic -differentiation events.