The administration of HgCl2 to Brown Norway (BN) rats produces an excellent animal model for studying xenobiotic-induced autoimmunity. Studies from our laboratory have shown that mercury-treated BN rats experience a decrease in peripheral RT6+ T lymphocytes, a change that precedes the appearance of circulating autoantibodies to renal antigens (e.g., laminin) and membranous glomerulonephritis. In contrast, Lewis (LEW) as well as congenic rats (between LEW and BN) are resistant to these effects of HgCl2, even when experimentally depleted of RT6+ T cells. Recently, we have observed that chimeric rats obtained by adoptive transfer of BN lymphocytes into gamma-irradiated LEW.IN congenic rats (BN-> LEW.IN chimeras) are susceptible to the autoimmune effects of mercury and experience a significant decrease in peripheral RT6.2+ T lymphocytes. On the basis of these observations we have suggested the hypothesis that mercury alters the delicate balance between T cells with suppressor (RT6.2+) and helper activities. that normally exists within the cellular (possibly cytokine-mediated) immunoregulatory network. This hypothesis postulates that the immunotoxic effects of HgCl2 in BN rats comprise a decrease of immunoregulatory activities of RT6.2+ T lymphocytes (resulting in a deficiency of """"""""suppressor"""""""" cytokines, possibly IFN-gamma and/or TGF-beta), stimulation of T helper activities (possibly Th2 lymphocytes, secreting IL-4, IL-6, etc.) and stimulation of B cells (both directly and indirectly, i.e., through stimulation of T helper cells). Thus, the combination of deficient immunoregulatory restraints from RT6+ T lymphocytes plus B cell activation, together with a possible mercury-induced release of autoantigens from target tissues (e.g., laminin from renal basement membranes), results in the production of autoantibodies against laminin. These autoimmune responses lead to membranous glomerulonephritis. We now propose to continue the study of this hypothesis with the following Specific Aims: 1. Dissect the role of RT6.2+ T lymphocytes (and their subsets) In BN-> LEW.1N chimeras treated with HgCI2. We propose to perform adoptive transfers of purified RT6.2+T cells (or their fractionated subsets) to functionally identify their immunoregulatory activities. 2. Confirm the immunoregulatory properties of RT6.2+ T lymphocytes by their adoptive transfer Into BN rats prior to or during HgCl2 treatment. We will determine whether adoptive transfer of RT6.2+ T lymphocytes from normal, untreated BN rats inhibits the induction or the continuation of autoimmune disease in mercury-treated BN rats. We will also determine whether RT6.2+ T lymphocytes from rats that have recovered from mercury-induced autoimmune disease have any immunoregulatory effects in BN rats. 3. Perform mechanistic and phenotypic studies of the cytokine network in HgCl2-induced autoimmune disease of BN rats. We will investigate whether IFN-gamma modulates Th2- like and Th1-like autoimmune responses to laminin induced by mercury in BN rats. We will also determine the cytokine profile of RT6.2+ and RT6.2- T cells from normal and mercury-treated BN rats. Finally, we will examine the role of IL-I0 (alone and in combination with IFN-gamma) in the modulation of mercury-induced Th2-like and Th1-like autoimmune responses to laminin.
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