INHERITED CONTROL MECHANISMS IN IG GENE EXPRESSION

这项研究的广泛目标是提供关于 LYL+T细胞对自身免疫球蛋白的耐受机制我们最近开发了一种 免疫球蛋白依赖性T细胞增殖法测定LYL+T细胞 细胞对自身和非我免疫球蛋白的反应性。使用同种异型同源基因小鼠，我们 证明应答的Lyl+T细胞识别异型决定因素 出现在外国免疫球蛋白上，这种反应对耐受性敏感 归纳法。事实上，这种抗原在结构上有很好的特征， 很容易通过标准技术进行定量，自然存在于血清和 在正常生理条件下，也以完整的膜形式存在 糖蛋白，以及明确定义的基因的可用性 多态和同种异型小鼠品系，为该系统提供了 在研究耐受的细胞基础方面具有独特的优势。少校 拟议调查的目标是确定哪些细胞类型 参与耐受性诱导。成年胸腺切除小鼠， 辐射诱导的骨髓嵌合体，实验上无丙种球蛋白血症， 同种异型抑制的小鼠将被用作工具来表征 目标人群，进一步明确B细胞所起的作用。这个 Ly2+抑制性T细胞可能参与了诱导 和/或维持LYL+T细胞耐受性将进行测试。特定的 诱导耐受所需的IgG2a分子的结构特征 将会被描述。此外，大量的骨髓瘤和杂交瘤 蛋白质，包括具有良好特性的突变型单抗 结构变化可用于分析可能的 免疫原性和耐受性决定因素之间的关系。总而言之， 这些研究有望使我们更清楚地了解细胞 免疫球蛋白动态平衡中的耐受事件和过程。

The broad objective of this research is to provide new information on the mechanism of Lyl+ T cell tolerance for self Ig. We recently developed an immunoglobulin-dependent T cell proliferation assay that measures Lyl+ T cell reactivity to self and nonself Ig. Using allotype congenic mice, we demonstrated that responding Lyl+ T cells recognize allotypic determinants present on the foreign Ig and that this response is sensitive to tolerance induction. The fact that the antigen is well characterized structurally, easily quantitated by standard techniques, naturally present in serum and under normal physiological conditions also exists as an integral membrane glycoprotein, as well as the availability of a well defined genetic polymorphism and allotype congenic mouse strains, provide this system with unique advantages for studying the cellular basis of tolerance. The major goal of the proposed investigation is to identify the types of cells that participate in tolerance induction. Adult thymectomized mice, radiation-induced bone marrow chimeras, experimentally agammaglobulinemic, and allotype-suppressed mice will be used as tools to characterize the target population and further define the role played by B cells. The possibility that Ly2+ suppressor T cells may be involved in the induction and/or maintenance of Lyl+ T cell tolerance will be tested. Specific structural features of the IgG2a molecule required for tolerance induction will be described. Moreover, a wide panel of myeloma and hybridoma proteins, including mutant monoclonal antibodies with well characterized structural alterations are available for analyzing the possible relationship between immunogenic and tolerogenic determinants. In sum, these studies will hopefully lead to a clearer understanding of cellular events in tolerance and processes involved in immunoglobulin homeostasis.