HUMAN CARTILAGE GP39 IN HLA-DR4 TRANSGENIC MURINE MODEL

风湿性关节炎（RA）被认为是一种自身免疫性疾病，其中T细胞错误地攻击透明软骨基质蛋白，例如II型胶原蛋白。 在与RA有关的自身抗原中，已经描述了一种新的候选靶抗原，人软骨gp-39（HC-gp-39）。 定义自身免疫反应的参数可能有助于诊断和制定新的治疗策略。 例如，如果已知HC gp-39或在人MHC等位基因背景下识别的其它软骨抗原的决定簇，则可以设计特异性干扰自身免疫应答的免疫干预的特异性策略。 在大多数情况下，T细胞介导的自身免疫性疾病，如RA和多发性硬化症（MS）的患者的决定簇作图研究未能提供明确的结果，对近交系小鼠品系的研究到目前为止通常集中在小鼠MHC单倍型的背景下的决定簇利用，因此可能不属于人类。 我提出通过使用已经被工程化以表达包括RA易感性等位基因HLA-DR 4（HLA-DRB 1 0401）和HLA-DRW 14（HLA-DRB 1 0404）的人MHC II类等位基因的小鼠来克服本申请中描述的实验的这种限制，这将因此产生具有人源化抗原呈递特性的鼠免疫系统。我们的实验将测试的假设，即人类II型胶原蛋白和HC gp-39表位的T细胞识别的重要性，在诱导和/或传播的多发性关节炎的HLA-DR 4和HLA-DR 14转基因小鼠，以及是否分子内和分子间传播的T细胞反应的多发性关节炎的传播是有意义的。 基于这些信息，我们将能够监测患者的反应并设计特异性免疫干预策略。 这一基本信息无法通过测试常规小鼠品系或通过人体研究获得，但可以通过使用本研究中提出的人源化小鼠容易地获得。

Rheumatoid arthritis (RA) is thought to be an autoimmune disease in which T cells erroneously attack hyaline cartilage matrix proteins like, for example type II collagen. Amongst the autoantigens implicated in RA, a novel candidate target antigen, human cartilage gp-39 (HC-gp-39) has been described. Defining the parameters of the autoimmune response may facilitate diagnosis and formulation of novel therapeutic strategies. For example, if the determinant(s) of HC gp-39 or other cartilage antigens recognized in the context of human MHC alleles were known, specific strategies for immune intervention could be designed which would interfere specifically with the autoimmune response. For the most part, determinant mapping studies of patients with T cell-mediated autoimmune diseases like RA and Multiple Sclerosis (MS) have failed to provide clear results and studies on inbred mouse strains have so far usually focused on determinant utilization in the context of murine MHC haplotypes and so may not pertain to humans. I propose to overcome this limitation for the experiments described in this application by using mice that have been engineered to express human MHC class II alleles including the RA susceptibility alleles HLA-DR4 (HLA-DRB1 0401) and HLA-DRW 14 (HLA-DRB1 0404), which will thus create a murine immune system with humanized antigen presentation properties. Our experiments will test the hypothesis that T cell recognition of human collagen type II and HC gp-39 epitopes are of importance in induction and/or propagation of polyarthritis in HLA-DR4 and HLA-DR14 transgenic mice, and whether intra-and intermolecular spreading of T cell responses are of significance in the propagation of polyarthritis. Based on this information, we will then be in a position to monitor responses in patients and design strategies for specific immune intervention. This essential information cannot be obtained by testing conventional mouse strains, nor through human studies, but it can readily be obtained through the use of humanized mice as proposed in this study.