EXPERIMENTAL INDUCTION OF SLE BY ALTERED IA

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The objective of the current proposal is to investigate mechanisms of autoantibody production in an experimentally induced model of systemic lupus erythematosus. Most of the experiments will utilize a chronic graft-versus-host reaction between Ia/b congenic mice, C57BL/6 and bm12. In this model, abnormal T-cell help is supplied by alloreactive T cells. The specific aims of the current proposal are aimed at elucidating generally applicable immunoregulatory pathways that are essential for the production or control of autoantibodies. One set of experiments will deal with the specificity of T cell/B cell collaboration required for autoantibody production. Induction of chronic GVH in double congenic chimeras (Ia and Igh allotype) will determine whether the precursors of autoantibody forming cells must be specifically recognized by alloreactive T cells. In a related set of experiments, the basic alloreactive graft-versus- host model will be expanded with T cells reactive to immunoglobulin allotype (IgG2a/a) and with nonspecific T cells specifically targeted by monoclonal immunoglobulin heterodimers which can cross link the T-cell receptor and B-cell surface markers. The possibility that alloreactive T cells also recognize self-antigen in conjunction with foreign Ia will be tested by selecting T-cell clones in vitro. The allotype marker experiments will be performed for both anti-chromatin and Coombs specificity. A further set of experiments will investigate the special role of the IgG2A isotype in autoantibody production. Several protocols will be attempted for suppression of this isotype, and the subsequent effect on autoantibody production will be ascertained. Finally, a series of experiments will deal with mechanisms of down regulation of autoantibody production in the graft-versus-host model. Prospective recipient animals will be pre-immunized with alloreactive T-cell lines. The transferred T cells that persist in recipients will be quantitated and described using monoclonal antibody markers. The possibility of anti- idiotype control will be investigated. C57BL/6-nu/nu mice will permit the testing of the role of host T cells. All these studies will increase our understanding of potential mechanisms that can lead to generalized autoantibody production in human collagen vascular disease, such as systemic lupus erythematosus.