ROLE OF MHC GENES IN IMMUNREGULATION

胸腺中的克隆缺失是T细胞 识别自体自体MHC II类抗原，Mls抗原， 和男性H-Y抗原的表达受到调节。然而，我们的研究 表达生理水平人胰岛素的转基因小鼠 表明耐受性不能通过克隆缺失来维持。 这些 观察结果支持这样一种观点，即， 外周免疫系统维持自身反应性T细胞的无反应性 胸腺中未被删除的细胞。 使用表达人胰岛素基因的转基因小鼠，我们将解剖 维持外周耐受性的机制 为此我们将 确定：1）胰岛素特异性Th细胞是否是无反应性的， 2）Ts细胞在表达耐受性中的作用， 转基因小鼠; 3）是否可以刺激人胰岛素特异性CTL 在非转基因T细胞的转基因接受者中;以及，4）如果存在 转基因小鼠中高亲和力T细胞克隆缺失的证据。 这个项目的第二个目标是确定为什么克隆缺失在 胸腺对循环自身抗原无效， 胰岛素 我们假设胸腺中T细胞的克隆性缺失 是抗原剂量依赖性的， 到达这些转基因小鼠的胸腺不足以引起 克隆缺失。 对这一假设的预测是， 循环中的胰岛素水平将导致 人胰岛素特异性T细胞。 这将使用转基因技术进行评估。 小鼠表达人胰岛素的调节下， 金属硫蛋白启动子或I-E α启动子。 从这些研究中吸取的经验教训可能为解决这些问题提供新的途径。 自身免疫性疾病的治疗。 因此，我们的研究将扩展到 实验性变态反应性免疫病模型 脑脊髓炎（EAE）。 该系统将用于解决 在这种情况下， 自我容忍失败，以及一旦自我容忍失败， 疾病发生。 这些模型系统对于理解 有证据表明，自身反应性免疫性疾病 存在于外周免疫系统中的T细胞可以从免疫系统中逃脱。 正常的监管机制。 越来越多的证据表明，自身免疫可能参与了 艾滋病的发病机制。 因此，我们的研究可能与 了解艾滋病中的免疫功能障碍， 设计治疗方法。

Clonal deletion in the thymus is the mechanism by which T cells recognizing autologous autologous MHC class II antigens, Mls antigens, and the male H-Y antigen are regulated. However, our studies of transgenic mice expressing physiological levels of human insulin indicate that tolerance is not maintained by clonal deletion. These observations support the idea that additional mechanisms operate in the peripheral immune system to maintain unresponsiveness of autoreactive T cells not deleted in the thymus. Using transgenic mice expressing the human insulin gene, we will dissect the mechanisms that maintain peripheral tolerance. To this end, we will determine: 1) whether insulin-specific Th cells are anergic in transgenic mice; 2) the role of Ts cells in tolerance expressed by transgenic mice; 3) whether human insulin-specific CTL can be stimulated in transgenic recipients of nontransgenic T cells; and, 4) if there is evidence for clonal deletion of high avidity T cells in transgenic mice. The second goal of this project is to determine why clonal deletion in the thymus is not effective for circulating autoantigens such as insulin. We hypothesize that clonal deletion of T cells in the thymus is antigen dose-dependent and that the concentration of insulin which reaches the thymus in these transgenic mice is insufficient to cause clonal deletion. A prediction of this hypothesis is that increasing the levels of insulin in the circulation will result in clonal deletion of human insulin-specific T cells. This will be assessed using transgenic mice expressing human insulin under the regulation of the metallothionein promoter or the I-E alpha promoter. The lessons learned from these studies may provide new approaches to the treatment of autoimmune diseases. Thus, our studies will be extended to an immunological disease model of Experimental Allergic Encephalomyelitis (EAE). This system will be used to address the circumstances in which peripheral mechanisms of maintaining self-tolerance fail and whether regulation can be re-instated once the disease occurs. These model systems are particularly relevant for the understanding of autoimune diseases in man in which there is evidence that auto-reactive T cells, present in the peripheral immune system, can escape from the normal regulatory mechanisms. Accumulating evidence suggests that autoimmunity may be involved in the pathogenesis of AIDS. Thus, our studies may be relevant toward understanding the immune dysfunction operating in AIDS and lead to the designing of therapeutic approaches for its treatment.