The objectives of this project are to define the mechanisms of autoimmunity in MRL/lpr mice, an animal model of systemic lupus-like autoimmune disease, and to develop approaches for controlling autoimmunity in vivo. The underlying hypothesis is that lpr lymphocytes are resistant to tolerance (anergy or deletion)-inducing stimuli, leading to abnormal development of T cells and excessive cytokine production, and anomalous response patterns of B cells. In addition, these abnormalities may be associated with aberrant expression of surface molecules that are involved in lymphocyte interactions and that may serve as targets for specific antagonists. The following specific aims are proposed: 1. Immunohistologic analysis of lymphocyte development and activation: In order to define cellular abnormalities in vivo, immunohistochemistry will be used to examine cytokine-producing T cells in lymphoid tissues of lpr and control mice, their kinetics of appearance, and their relation to activated autoantibody-producing B cells. The lifespans of lymphocytes in lpr mice, and in lpr x normal chimeras, will be studied by in vivo BUDR labeling. 2. Role of cytokines in autoantibody production: Antagonists against defined cytokines (IL4, IFNgamma) will be administered to lpr mice, and effects on autoantibody titers, immune complex-mediated lesions and lymphoproliferation will be examined. To complement this approach, lpr and +/+ mice will be mated with IL4 transgenic mice, to examine the effects of IL4 over-expression on autoimmunity. 3. Anergy in lpr-derived lymphocytes: The susceptibility of lpr-derived resting T cells and neonatal B lymphocytes to tolerance will be examined. A class II-restricted cytochrome c-specific TCR transgene will be bred into lpr mice, and effects on autoimmunity as well as tolerance in these homogeneous T cells will be examined. 4. Lymphocyte surface markers in lpr mice: the expression of three surface proteins, B7, CD22 and CD40, that are known to be involved in T-B cell interactions, will be studied in resting and activated lpr lymphocytes of different ages. Attempts will be made to produce monoclonal antibodies specific for lpr B cells. the ability of antibodies or inhibitors against these surface proteins to block autoimmunity will be examined.
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