T CELL RESPONSE IN MHC CLASS II TRANSGENIC RATS AND MICE

风湿性关节炎（RA）是一种常见的疾病， 发病率和超额死亡率。 目前的治疗是经验性的， 不足 HLA-DR分子，具有多态性II类 由人主要组织相容性复合体（MHC）编码的糖蛋白 在抗原呈递细胞表面表达， 在人类免疫应答中通过结合肽抗原， 可以被胸腺细胞和T细胞识别。 大多数DR多态性 DRB 1基因座，特别是在 编码β 1结构域的外显子中的三个高变区。 大约90%的RA患者可以被证明是遗传性的 HLA-DRB 1基因座上编码一组DR β链的一个或多个等位基因 它们的一级氨基酸序列非常接近， 第三个高变区。 这一发现表明DR分子 具有RA相关序列直接参与发病机制 的RA。 这可能是了解类风湿关节炎的发病机制， 如果DR分子倾向于 RA被阐明。 然而，要做到这一点， 由于研究MHC II类的局限性， 在人类中的功能。 在这个项目中， 将产生表达两种不同HLA-DR分子中的任何一种， 使人类易患类风湿性关节炎， 对抗RA 将进行实验以测试转基因是否 产物以生理方式表达，以及它们是否存在 T细胞抗原。 如果是这样，将进行研究的潜力 DR转基因对两种实验性关节炎模型的影响 大鼠和小鼠，胶原诱导的关节炎和佐剂性关节炎，以及 将检查RA相关DR分子可以 特异性呈递与一种或两种多肽相关的肽， 实验性关节炎的DR限制性肽特异性T细胞。 如果 可以证明这种DR限制性T细胞应答， 应答T细胞在转移到转基因细胞后诱导疾病 将对受体动物进行研究，也将对受体的精细特异性进行研究。 对肽和DR分子的应答T细胞。 的预期结果 该项目将生产转基因啮齿动物品系， 对于RA的研究非常有用，以及改进的 了解RA相关DR分子结合的能力， 呈现已知参与免疫识别的肽抗原， 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.