MODE OF ACTION OF H-LINKED IMMUNE RESPONSE (IR) GENES

该项目的长期目标是通过以下方式确定机制 哪些H-2连锁免疫反应(Ir)基因调节T细胞的免疫反应 细胞依赖抗原。尽管Ia抗原是 Ir基因产物被广泛接受，它不能解释Ia是如何 抗原介导具有高度特异性的ir基因功能。我们以前的 研究支持这一假设，即ir基因控制是 刺激各种调节辅助性和抑制性T细胞亚群。 因此，这项建议的具体目标集中在详细的 不同人群调节性T细胞亚群差异的特征 有反应的和无反应的小鼠。 近交系小鼠对日本血吸虫的抗体反应 合成多肽：L-谷氨酸60-L-丙氨酸30-L-酪氨酸10 和L-谷氨酸-50-L-酪氨酸(GT)和一组由 从不同物种获得的几种胰岛素变异体作为模型 系统。特异性辅助性T细胞克隆和抑制性T细胞的研究进展 细胞杂交瘤作为同质调节性T细胞的来源 继续。抑制性T细胞抑制反应的机制 将使用可溶性的、抗原特异性的抑制因子和 抑制者-诱导者因素。 准确了解ir基因功能的临床重要性 支持IR基因也调节免疫反应的证据 人类。几种器官特异性自身免疫性疾病与 人类白细胞抗原复合体D/DR区的某些单倍型提示 该基因座类似于小鼠的I区。因此，ir基因的作用 在小鼠实验性自身免疫性疾病的发展过程中 作为一个模型系统进行了研究。 一旦抑制性T细胞的生物学被很好地理解，它应该是 可能产生抑制因子来调节不可改变的免疫 具体回应。因为设计一种新的 对于每一种疾病和每一个人，我们都会决定 特定的因子可以通过一种新的抗原决定簇来靶向 抗原桥。如果大量的回应可以用一个单一的 因子，抑制因子的治疗潜力将非常大 很有希望。最终，这些研究可能会为预防 胰岛素依赖型糖尿病患者抗胰岛素抗体的诱导 使用特定的抑制性T细胞因子逆转自身免疫性疾病。

The long term objectives of this project are to determine the mechanisms by which H-2-linked immune response (Ir) genes regulate immune responses to T cell dependent antigens. Although the hypothesis that the Ia antigens are the Ir gene products is widely accepted, it does not explain how Ia antigens mediate the highly specific Ir gene functions. Our previous studies support the postulate that Ir gene control is the net result of the stimulation of various regulatory helper and suppressor T cell subsets. Thus, the specific aims of this proposal focus on the detailed characterization of differences in regulatory T cell subsets between responder and nonresponder mice. Development of antibody responses by inbred strains of mice to the synthetic polypeptides: L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) and L-glutamic acid50-L-tyrosine (GT) and a panel of proteins comprised of several insulin variants obtained from different species serve as model systems. Development of specific helper T cell clones and suppressor T cell hybridomas as sources of homogeneous regulatory T cells will be continued. The mechanisms by which suppressor T cells inhibit responses will be analyzed using soluble, antigen-specific suppressor factors and suppressor-inducer factors. The clinical importance of understanding precisely how Ir genes function is supported by evidence that Ir genes also regulate immune responses in humans. Several organ-specific autoimmune diseases are associated with certain haplotypes of the D/DR region of the HLA-complex suggesting that this locus is analogous to the murine I region. Thus, the role of Ir genes in development of experimental autoimmune diseases in mice will be investigated as a model system. Once the biology of suppressor T cells is well understood, it should be possible to produce suppressor factors to modulate indesirable immune responses specifically. Because it would not be feasible to design a new factor for every disease and every individual, we will determine whether specific factors can be targeted to neoantigenic determinants via an antigen bridge. If numerous responses can be suppressed with a single factor, the therapeutic potential of suppressor factors would be very promising. Ultimately these studies might provide the basis to prevent induction of anti-insulin antibodies in insulin-dependent diabetics and to reverse autoimmune diseases with specific suppressor T cell factors.