Project 3 - Modulation of Autoimmune Arthritis by Chinese Herbs

许多草药声称对多种疾病有好处，很受公众欢迎。然而， 医学界对使用草药的科学依据持怀疑态度 产品。这种怀疑的一个原因是，这些植物产品中的许多要么没有在 控制良好的实验系统或它们的作用机制尚未得到很好的定义。在这项研究中， 我们拟详细阐述中药方剂活络消灵(HLXL)的抗关节炎作用。 并确定了这种作用的免疫学基础。我们的试点实验使用的是大鼠的炎性 水肿和佐剂性关节炎(AA)模型表明，大鼠口服HLXL可以 降低炎症/临床关节炎的严重程度。皮下注射诱导Lewis大鼠再生障碍性贫血 (S.C.)注射热致死的结核分枝杆菌，它是人类类风湿的极好模型 关节炎(RA)。在再障中，65kD分枝杆菌热休克蛋白(Bhsp65)是T细胞的焦点 关节炎Lewis大鼠的反应。猪瘟病毒决定簇(表位)区180-188/177-191的特异性T细胞 Bhsp65是致病的，而针对Bhsp65羧基末端决定簇(BCTD)的那些是致病的 本质上是控制疾病的。这一信息使再生障碍性贫血成为测试其免疫学基础的理想模型。 HLXL的抗炎作用。我们假设HLXL的保护/有益作用是针对 关节炎(AA)涉及抗原特异性T细胞对病原体的不同调节反应(180- Bhsp65内的188/177-191区域)和/或调控(BCTD)决定因素。这可能是 通过HLXL对抗原提呈细胞(ARC)的功能或对 Bhsp65特异性T细胞分泌细胞因子(Th1到Th2的免疫偏离，或转化生长因子-b的分泌)，或 两者都有。我们计划确定HLXL-(Aim 1)对T细胞增殖和细胞因子反应的影响。 细胞对抗Bhsp65的致病决定因素和调控决定因素，并通过测试ARC的有效性 Bhsp65(使用表位特异性T细胞系)在再生障碍性贫血过程中的处理和呈递 Lewis大鼠；(目标2)关于炎症的特定介质：HLXL是否显著下调 促炎/抗炎细胞因子、核因子-kB或一氧化氮和诱导型一氧化氮的水平/活性 合成酶；和(目标3)对关节炎Lewis大鼠天然Bhsp65及其多肽的抗体反应，以及 检测血清过继转移治疗再生障碍性贫血的疗效；本研究的结果将有助于建立 为HLXL在自身免疫性关节炎中的应用和开发更好的治疗方法提供可靠的科学依据 类风湿性关节炎患者的入路。

Many herbs claim to be beneficial against a variety of diseases and are quite popular with the public. Yet, there is some skepticism in the medical community about the scientific rationale for the use of herbal products. One reason for this skepticism is that many of these plant products have either not been tested in well-controlled experimental systems or their mechanisms of action have not been well defined. In this study, we propose to elaborate on the anti-arthritic activity of a Chinese herbal formula Huo-Luo-Xiao-Ling (HLXL) Dan, and determine the immunological basis of this effect. Our pilot experiments using the rat inflammatory edema and adjuvant-induced arthritis (AA) models have shown that oral feeding of HLXL to rats can downmodulate the severity of inflammation/clinical arthritis. AA is inducible in Lewis rats by subcutanenous (s.c.) injection of heat-killed M. tuberculosis, and it serves as an excellent model for human rheumatoid arthritis (RA). In AA, the 65 kD mycobacterial heat-shock p/otein (Bhsp65) is the focus of the T cell responses.of arthritic Lewis rats. The T cells specific for the determinant (epitope) region 180-188/177-191 of Bhsp65 are pathogenic, whereas those directed against Bhsp65 carboxy-terminal determinants (BCTD) are disease-regulating in nature. This information makes AA an ideal model for testing the immunologic basis of the anti-arthritic activity of HLXL. We hypothesize that the protective/beneficial effect of HLXL against arthritis (AA) involves differential modulation of the antigen-specific T cell responses to the pathogenic (180- 188/177-191 region) and/or regulatory (BCTD) determinants within Bhsp65 in Lewis rats. This could be achieved by the action of HLXL either on the function of the antigen presenting cells (ARC) or on the cytokine secretion (immune deviation from Th1 to Th2, or TGF-b secretion) by Bhsp65-specific T cells, or both. We plan to determine the effects of HLXL - (Aim 1)on the proliferative and cytokine response ofT cells against the pathogenic vs. regulatory determinants of Bhsp65, and on the ARC by testing the efficacy of processing and presentation of Bhsp65 (using epitope-specific T cell lines) during the course of AA in the Lewis rat; (Aim 2) on specific mediators of inflammation: whether HLXL significantly downmodulates the level/activity of pro-/anti-inflammatory cytokines, of NF-kB, or of nitric oxide and inducible nitric oxide synthase; and (Aim 3) on the antibody response to native Bhsp65 and its peptides of arthritic Lewis rats, and testing the efficacy of serum adoptive transfer on AA; The results of this study would help in establishing a reliable scientific basis for the use of HLXL in autoimmune arthritis, and in developing better therapeutic approaches for patients with RA.