IMMUNOLOGIC BASIS ENIVR MODULATION OF AUTOIM ARTHRITIS

描述(摘自调查人员摘要) 易感大鼠皮下注射可诱发佐剂性关节炎(AA) 注射热灭活结核分枝杆菌H37Ra，作为一种 人类类风湿性关节炎(RA)的极佳模型。关节炎大鼠和 RA患者对65千道尔顿(KDa)分枝杆菌产生T细胞反应 热休克蛋白(Bhsp65)。Bhsp65同时含有致关节炎和 保护性/调节性T细胞决定因素。热休克蛋白(HSPs)是 在原核生物和真核生物中都高度保守的蛋白质。这个 调查人员做了一项有趣的观察，发现 Fisher大鼠的AA非常直接地受到环境因素的调节 在屏障设施(BB-Fisher)饲养和饲养的F344大鼠易患 AA，而Fisher大鼠在传统的(CV)设施中饲养和维护 (CVFisher)对AA具有抗性。此外，BB-Fisher大鼠在转移时 进入一个CV设施并在那里呆了几周，获得了对AA的抵抗力。 然而，这种由BB-Fisher大鼠获得的AA抗性可以是 如果给大鼠喂食新霉素或酸化水(以防止或 减少环境因素对肠道的侵占)从#日开始 他们被转移到简历中心。令人惊讶的是，天真的简历-费舍尔，而不是BB- Fisher大鼠自发提高T细胞对Bhsp65的反应，包括Bhsp65 C-末端决定因素(BCTD)[研究人员先前已表明 BCTD参与了Lewis大鼠急性AA的调节]。此外， CV-Fisher大鼠的AA抗性可过继转移到幼稚的BB- 未分离的CV-Fisher大鼠脾细胞移植 在体外用BCTD重新刺激。这些初步发现提供了一种新的 微生物在自身免疫中的作用：保护自身免疫免受 自身免疫性疾病而不是疾病诱导(后者的影响已经 在其他几种自身免疫的动物模型中观察到)。调查人员 在这项探索性研究中，我将检验以下命题： A)环境因素直接参与赋予对 AA至CV-Fisher大鼠。实验性重建BB-Fisher大鼠的实验研究 来自CV-Fisher大鼠的微生物菌群(为简单起见，这些 重组大鼠被称为BBCV-Fisher大鼠)应呈现这些 对AA耐药的大鼠。B)微生物菌群(包含Bhsp65的hsp6O同系物 结核分枝杆菌)诱导CV-和BBCV-Fisher大鼠抗AA 通过一种免疫机制。这一假设将通过启动来检验。 与结核分枝杆菌Bhsp65交叉反应的T细胞(分子 模仿)。这些T细胞的子集通过以下方式提供对再生障碍性贫血的保护 机制(S)将在本研究中定义。或者，微生物菌群可以 诱导潜在的致关节炎T细胞的免疫偏离。C) CV-或BBCV-Fisher大鼠的“获得性”AA抵抗应采取过继措施 可通过定义的T细胞亚群(CD4/CD81)转移到幼年BB-Fisher大鼠。 这项研究的结果应该对以下两个方面具有重要意义 认识环境因素对类风湿关节炎发病的影响 在生活在不同地理条件下的人类人口中， 开发新的类风湿关节炎预防/治疗方法。

DESCRIPTION (Taken from the Investigator's Abstract) Adjuvant arthritis (AA), inducible in susceptible rat strains by subcutaneous injection of heat-killed Mycobacterium tuberculosis H37Ra, serves as an excellent model for human rheumatoid arthritis (RA). Both arthritic rats and RA patients develop T cell responses to the 65-kilodalton (kDa) mycobacterial heat-shock protein (Bhsp65). Bhsp65 contains both arthritogenic and protective/regulatory T cell determinants. Heat-shock proteins (hsps) are highly conserved proteins both in prokaryotes and eukaryotes. The investigators have made an interesting observation that the susceptibility to AA of Fisher rats is very directly modulated by environmental agents: Fisher F344 rats bred and raised in a barrier facility (BB-Fisher) are susceptible to AA, whereas Fisher rats bred and maintained in a conventional (CV) facility (CVFisher) are resistant to AA. Furthermore, BB-Fisher rats, when transferred into a CV facility and kept there for several weeks, acquire resistance to AA. However, this acquisition of AA-resistance by BB-Fisher rats can be circumvented if rats are fed neomycin or acidified water (to prevent or diminish colonization of gut by environmental agents) beginning on the day of their transfer into the CV facility. Strikingly, naive CV-Fisher, and not BB- Fisher rats, spontaneously raised T cell responses to Bhsp65, including Bhsp65 C-terminal determinants (BCTD) [the investigators have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat]. Furthermore, AA-resistance of CV-Fisher rats can be adoptively transferred to naive BB- Fisher rats by unfractionated splenic cells of naive CV-Fisher rats restimulated in vitro with BCTD. These preliminary findings provide a novel perspective on the role of microbes in autoimmunity: protection from an autoimmune disease instead of disease induction (the latter effect has been observed in several other animal models of autoimmunity). The investigators will test the following propositions in this exploratory study: A) Environmental agents are directly involved in conferring resistance against AA to CV-Fisher rats. Experimental reconstitution of BB-Fisher rats with microbial flora derived from CV-Fisher rats (for simplicity, these reconstituted rats are referred to as BBCV-Fisher rats) should render these rats resistant to AA. B) Microbial flora (containing hsp6O homologs of Bhsp65 of M. tuberculosis) induce protection from AA in CV- and BBCV-Fisher rats through an immunological mechanism. This hypothesis will be tested by priming T cells that are cross-reactive with Bhsp65 of M. tuberculosis (molecular mimicry). A subset of these T cells serves to afford protection from AA by mechanism(s) to be defined in this study. Alternatively, microbial flora may induce immune deviation of potentially arthritogenic T cells. C) The "acquired" AA-resistance of CV- or BBCV-Fisher rats should be adoptively transferable to naive BB-Fisher rats by a defined T cell subset (CD4/CD81). The results of this study should have important implications both for understanding the influence of environmental factors on the pathogenesis of RA in human populations living under different geographical conditions, and in developing new preventive/therapeutic approaches for RA.