Project 3 - Modulation of Autoimmune Arthritis by Chinese Herbs

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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.