PROFILING SYNOVIAL VASCULATURE IN ARTHRITIS-PRONE RATS

描述(由申请人提供)： S.C.可诱导Lewis大鼠佐剂性关节炎(AA)。注射热灭活结核分枝杆菌H37Ra(Mtb)，是人类类风湿性关节炎(RA)的优秀模型。关节炎Lewis大鼠对65kD分枝杆菌热休克蛋白(Bhsp65)的T细胞反应增强，Bhsp65的180-188/177-191区域被认为含有Lewis大鼠的致病表位。据认为，在再生障碍性关节炎中，由Bhsp65启动的T细胞(在Mtb内)迁移到关节的滑膜，并可能通过识别一种交叉反应的自身抗原(尚未完全定义)而引起组织损伤。在这一点上，一种主张是Bhsp65诱导的T细胞的抗原靶标可能是同源自身热休克蛋白(HSP)。考虑到HSP是普遍表达的蛋白质，并且它们在本质上是高度保守的，有趣的是发现用Mtb免疫Lewis大鼠主要导致关节炎的诱导，而没有涉及其他器官的显著临床特征。我们认为滑膜血管内皮细胞显示独特的分子标志物，包括促进Mtb启动的潜在致关节炎T细胞有效运输到Lewis大鼠关节的归巢分子，这一属性可能是关节的重要决定因素之一，成为AA中Bhsp65特异性T细胞的主要靶点。此外，与Lewis大鼠不同，WKY大鼠[具有相同的MHC单倍型(RT.11)因为Lewis大鼠]对AA的诱导具有抗性。然而，结核分枝杆菌攻击的WKY大鼠并不缺乏对Bhsp65或其潜在的致关节炎表位180-188/177-191的强大T细胞反应。我们认为，这两个品系的靶器官差异可能是导致它们对AA易感性不同的原因之一。因此，为了全面了解关节炎靶器官损害的发病机制，检测关节血管内皮细胞的生理和功能属性至关重要。本研究的目的是：(1)确定靶器官(关节)滑膜血管内皮细胞的“地址分子”，以确定关节的血管内皮细胞是否与其他器官的滑膜血管内皮有显著差异；(2)比较Lewis大鼠和WKY大鼠的滑膜血管系统特征。我们相信，关节滑膜血管归巢标志物的识别将大大促进我们对AA和RA发病机制的理解，并为自身免疫性关节炎的治疗提供有希望的新靶点。

DESCRIPTION (provided by applicant): Adjuvant arthritis (AA) is inducible in the Lewis rat (RT.11) by s.c. injection of heat-killed M. tuberculosis H37Ra (Mtb), and it serves as an excellent model for human rheumatoid arthritis (RA). Arthritic Lewis rats raise T cell response to the 65 kD mycobacterial heat-shock protein (Bhsp65), and the region 180-188/177-191 of Bhsp65 is believed to harbor the pathogenic epitope for the Lewis rat. It is believed that in AA, the T cells primed by Bhsp65 (within Mtb) migrate into the synovium of joints and cause tissue damage presumably by recognizing a crossreactive self antigen (that has not yet been fully defined). In this regard, one proposition is that the antigenic targets of Bhsp65- primed T cells might be homologous self heat-shock proteins (Hsp). Considering that Hsp are ubiquitously expressed proteins and that they are highly conserved in nature, it is intriguing to find that immunization of Lewis rats with Mtb primarily leads to induction of arthritis without significant clinical features involving other organs. We propose that the synovial vascular endothelium displays unique molecular markers, including homing molecules that facilitate efficient trafficking of potentially arthritogenic T cells primed by Mtb into the joints of the Lewis rat, and that this attribute could be one of the important determinants of joints as the primary target (organ-specificity) of the Bhsp65- specific T cells in AA. Furthermore, unlike the Lewis rat, the WKY rat [which is of the same MHC haplotype (RT. 11) as the Lewis rat] is resistant to induction of AA. However, Mtb-challenged WKY rats are not deficient in raising potent T cell response to Bhsp65 or its potentially arthritogenic epitope 180-188/177-191. We suggest that the target organ differences between these two rat strains might contribute to their differential susceptibility to AA. Therefore, to fully understand the pathogenic mechanisms of target organ damage in arthritis, it is critical to examine the physiological and functional attributes of the vascular endothelium within the joints. This study is aimed at - (Aim 1) identification of'address molecules' for the synovial vascular endothelium of the target organ (joints) in the to determine whether vascular endothelium of the joints differs significantly from that of other organs, and (Aim 2) comparing the characteristics of synovial vasculature of Lewis and WKY rats. We believe that identification of the synovium vascular-homing markers for the joint would significantly advance our understanding of the pathogenesis of AA and RA, and also provide promising novel targets for the treatment of autoimmune arthritis.