PROFILING SYNOVIAL VASCULATURE IN ARTHRITIS-PRONE RATS

描述（由申请人提供）： 佐剂性关节炎（AA）在刘易斯大鼠（RT. 11）中可通过皮下注射诱导。注射热灭活M.结核病H37 Ra（Mtb），并且其用作人类风湿性关节炎（RA）的优良模型。关节炎刘易斯大鼠提高了T细胞对65 kD分枝杆菌热休克蛋白（Bhsp 65）的应答，并且Bhsp 65的180-188/177-191区域被认为具有刘易斯大鼠的致病性表位。据信，在AA中，由Bhsp 65（在Mtb内）引发的T细胞迁移到关节的滑膜中，并可能通过识别交叉反应性自身抗原（尚未完全定义）引起组织损伤。在这方面，一个命题是，Bhsp 65引发的T细胞的抗原靶可能是同源的自身热休克蛋白（HSP）。考虑到Hsp是普遍表达的蛋白质并且它们在自然界中高度保守，有趣的是发现用Mtb免疫刘易斯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。我们提出，滑膜血管内皮细胞显示独特的分子标记，包括归巢分子，促进潜在的致关节炎的T细胞的有效运输到刘易斯大鼠的关节，结核分枝杆菌引发，这一属性可能是关节的主要目标（器官特异性）的Bhsp 65特异性T细胞在AA的重要决定因素之一。此外，与刘易斯大鼠不同，WKY大鼠[与刘易斯大鼠具有相同的MHC单倍型（RT.11）]对AA的诱导具有抗性。然而，Mtb攻击的WKY大鼠在提高对Bhsp 65或其潜在的致关节炎表位180-188/177-191的有效T细胞应答方面并不缺乏。我们认为，这两种大鼠品系之间的靶器官的差异可能有助于他们的差异敏感性AA。因此，为了充分了解关节炎中靶器官损伤的致病机制，检查关节内血管内皮的生理和功能属性至关重要。本研究的目的是-（目的1）鉴定靶器官（关节）滑膜血管内皮的“地址分子”，以确定关节的血管内皮是否与其他器官的血管内皮显著不同，以及（目的2）比较刘易斯和WKY大鼠滑膜血管系统的特征。我们相信，关节滑膜血管归巢标志物的鉴定将显着推进我们对AA和RA发病机制的理解，也为治疗自身免疫性关节炎提供了有前途的新靶点。

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.