Project 3 - Modulation of Autoimmune Arthritis by Chinese Herbs

许多草药声称对各种疾病有益，并受到公众的欢迎。然而， 医学界对使用草药的科学原理持怀疑态度， 产品.这种怀疑的一个原因是，许多这些植物产品要么没有经过测试， 控制良好的实验系统或其作用机制尚未得到很好的定义。在本研究中， 本文拟对中药活络消灵的抗关节炎作用进行研究 丹，并确定这种作用的免疫学基础。我们的试点实验使用大鼠炎症 水肿和促炎剂诱导的关节炎（AA）模型表明，大鼠口服HLXL可 下调炎症/临床关节炎的严重程度。AA是诱导刘易斯大鼠皮下注射 （s.c.）注射热灭活M.结核病，它是一个很好的模型，为人类类风湿性关节炎， 关节炎（RA）。在AA中，65 kD的分枝杆菌热休克蛋白（Bhsp 65）是T细胞的焦点， 关节炎刘易斯大鼠的反应。特异性针对人白细胞介素1（IL-1）的决定簇（表位）区域180 - 188/177 - 191的T细胞被免疫组化。 Bhsp65是致病性的，而针对Bhsp65羧基末端决定簇（BCTD）的那些是致病性的。 调节疾病的能力这一信息使AA成为检测免疫学基础的理想模型。 HLXL的抗关节炎活性。我们假设HLXL的保护/有益作用， 关节炎（AA）涉及抗原特异性T细胞对致病性（180 - 180） 188/177 - 191区域）和/或调节（BCTD）决定簇。这可能是 通过HLXL对抗原呈递细胞（ARC）的功能或对免疫原性细胞的功能的作用来实现。 通过Bhsp 65特异性T细胞的细胞因子分泌（从Th1到Th2的免疫偏离，或TGF-β分泌），或 两者我们计划确定HLXL-（Aim 1）对T细胞增殖和细胞因子反应的影响， 细胞对Bhsp65的致病性与调节性决定簇的作用，以及通过测试 Bhsp65的加工和呈递（使用表位特异性T细胞系）在AA过程中在 刘易斯大鼠;（目的2）对特定炎症介质的影响：HLXL是否能显著下调 促炎/抗炎细胞因子、NF-κ B或一氧化氮和诱导型一氧化氮的水平/活性 （Aim 3）对关节炎刘易斯大鼠的天然Bhsp 65及其肽的抗体应答的影响，和 检测血清过继转移治疗AA的有效性;本研究的结果将有助于建立一个 为HLXL在自身免疫性关节炎中的应用提供了可靠的科学依据， 治疗RA患者的方法。

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.