MOLECULAR EVENTS IN ANTIGEN RECOGNITION

在上一个资助期内，详细分析了相互作用 多肽与MHC分子之间的相互作用。在这个过程中 研究，多肽抗原类似物的一种新机制 抑制T细胞对这些抗原的识别。确实是 发现某些抗原类似物不仅与抗原竞争 结合MHC，但抗原类似物/MHC复合体也可以竞争 与T细胞受体结合的抗原/MHC复合体。这 应用将“T细胞受体拮抗”的观察扩展到 探讨以下问题：第一，考察一系列实验 可能使用抗原类似物来干预AFP的过程 将进行自身免疫性疾病。要做到这一点，一个人或一个人的能力 一些抑制多克隆抗原特异性反应的类似物需要 已经成立了。接下来，这类类似物在体内抑制 将使用实验性过敏来评估疾病过程 以脑炎为模型。由于类似物的潜在医学用途是 依赖于所涉及的特定自身抗原的性质的知识 在自身免疫性疾病的发病机制方面，将努力 确定NOD小鼠糖尿病模型中涉及的自身抗原。这个 抗原诱导T细胞受体拮抗作用的关系 类似物及其诱导T细胞不完全刺激的能力 保罗·艾伦所描述的细胞(部分无能)也将被评估。 具体地说，关于类比的结构关系的问题 它们是TCR拮抗剂，而那些是部分激动剂 定义，以及这些不同的类比的能力将引发早期 信号事件，如酪氨酸磷酸化。最后，分析了 抗原类似物的生物学效应也将在TCR中进行评估 转基因系统。刺激类似物的结构关系 外周T细胞及诱导阳性和阴性选择的细胞 将在胸腺中进行分析。这将允许对 解释胸腺分化事件的亲和力假说。

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.