ROLE OF MHC GENES IN IMMUNOREGULATION

胸腺中的克隆性删除是T细胞 识别自体MHC II类抗原，MLS抗原， 和男性H-Y抗原是受调控的。然而，我们的研究 表达生理水平人胰岛素的转基因小鼠 表明耐受性不是通过克隆删除来维持的。这些 观察结果支持这样的观点，即额外的机制在 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。 利用表达人类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细胞是否无能 转基因小鼠；2)ts细胞在耐受中的作用 转基因小鼠；3)能否刺激人胰岛素特异性CTL 在非转基因T细胞的转基因受体中；以及，4)如果有 转基因小鼠高亲和力T细胞克隆性缺失的证据 这个项目的第二个目标是确定为什么克隆删除在 胸腺对循环自身抗原是无效的，例如 胰岛素。我们假设胸腺中T细胞的克隆性删除 是抗原剂量依赖的，而胰岛素的浓度 在这些转基因小鼠中到达胸腺不足以导致 克隆性删除。这一假说的一个预测是，增加 循环中的胰岛素水平将导致克隆缺失 人类胰岛素特异性T细胞。这将使用转基因技术进行评估 在基因调控下表达人胰岛素的小鼠 金属硫蛋白启动子或I-Eα启动子。 从这些研究中吸取的经验教训可能会为 自身免疫性疾病的治疗。因此，我们的研究将扩展到 实验性变态反应免疫学疾病模型的建立 脑脊髓炎(EAE)。该系统将用于解决 在哪些情况下维持外围机制 自我容忍失败，以及一旦经济衰退，监管能否恢复 疾病就会发生。 这些模型系统对于理解 有证据表明自身反应性疾病的男性自身免疫病 存在于外周免疫系统中的T细胞可以逃脱 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，我们的研究可能与以下方面相关 了解免疫功能障碍在艾滋病中的作用并导致 为其治疗设计治疗方法。

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.