T CELL RESPONSE IN MHC CLASS II TRANSGENIC RATS AND MICE

类风湿性关节炎(RA)是一种常见的疾病，它会导致相当大的 发病率和超额死亡率。治疗目前是经验性的， 不够充分。人类白细胞抗原-DR分子，它是多态的II类 人类主要组织相容性复合体(MHC)编码的糖蛋白 表达在抗原提呈细胞表面，起着中心作用 在人类免疫反应中，通过结合多肽抗原的方式 可被胸腺细胞和T细胞识别。大多数DR基因的多态性 在人类群体中居住在DRB1基因座，特别是在 编码Beta1结构域的外显子中的三个高变区。 大约90%的类风湿性关节炎患者可以被证明是遗传性的 编码一组DRbeta链的HLA-DRB1基因座上的一个或多个等位基因 它们拥有非常密切相关的初级氨基酸序列 第三个高变区。这一发现表明DR分子 具有RA相关序列的基因直接参与发病过程 在RA中。对类风湿关节炎发病机制的理解很可能会 如果DR分子易患糖尿病的机制 Ra，阐明了这一点。然而，很难接近这一点。 由于研究MHC II类的局限性而导致的实验问题 在人类身上起作用。在这个项目中，转基因小鼠和大鼠品系 会产生表达两种不同的人类白细胞抗原-DR分子中的一种 这使人类易患类风湿性关节炎，并明显保护人类 对抗RA。将进行实验以测试转基因是否 产品是以生理方式表达的，以及它们是否存在 T细胞的抗原。如果是这样的话，将对这种可能性进行研究 DR转基因对两种实验性关节炎动物模型的影响 大鼠和小鼠，胶原性关节炎和佐剂性关节炎，以及 将研究与RA相关的DR分子可以 具体呈现与一个或两个相关的多肽 实验性关节炎对DR限制性、多肽特异性T细胞的作用。如果 这种DR限制性T细胞反应可以证明，其能力 反应性T细胞在转移到转基因后诱发疾病 将对受体动物进行调查，也将调查 多肽和DR分子的反应性T细胞。预期的结果是 该项目将生产转基因啮齿动物品系，将 对于RA的研究非常有用，以及改进的 了解类风湿关节炎相关DR分子结合和 目前已知参与免疫识别的多肽抗原 会导致炎症性关节炎。

Rheumatoid arthritis (RA) is a common disorder that causes considerable morbidity and excess mortality. Treatment is currently empirical and inadequate. The HLA-DR molecules, which are polymorphic class II glycoproteins encoded by the human major histocompatibility complex (MHC) expressed on the surfaces of antigen presenting cells, play a central role in the human immune response by binding peptide antigens in a manner that can be recognized by thymocytes and T cells. Most of the DR polymorphism within the human population resides in the DRB1 locus, specifically within three hypervariable regions in the exon encoding the beta1 domain. Approximately 90% of individuals with RA can be shown to have inherited one or more alleles at the HLA-DRB1 locus that encode a group of DRbeta chains that share very closely related primary amino acid sequences within the third hypervariable region. This finding suggests that DR molecules possessing RA-associated sequences participate directly in the pathogenesis of RA. It is likely that the understanding of the pathogenesis of RA would be aided considerably if the mechanism by which DR molecules predispose to RA were elucidated. However, it has been difficult to approach this problem experimentally because of the limitations in studying MHC class II function in humans. In this project, lines of transgenic mice and rats will be produced that express either of two different HLA-DR molecules, one that predisposes humans to RA and one that apparently protects humans against RA. Experiments will be done to test whether the transgene products are expressed in a physiologic manner and whether they present antigen to T cells. If so, studies will be carried out of the potential influence of the DR transgenes on two experimental models of arthritis in rats and mice, collagen-induced arthritis and adjuvant arthritis, and the possibility will be examined that the RA-associated DR molecule can specifically present peptides associated with one or both of the experimental arthritides to DR-restricted, peptide-specific T cells. If such a DR-restricted T cell response can be demonstrated, the capacity of the responding T cells to induce disease upon transfer to transgenic recipient animals will be investigated, as will the fine specificity of the responding T cells for peptide and DR molecule. The anticipated result of this project will be the production of transgenic rodent lines that will be exceedingly useful for the study of RA, as well as an improved understanding of the capacity of RA-associated DR molecules to bind and present peptide antigens known to be involved in immune recognition that leads to inflammatory arthritis.