T AND B CELL STIMULATORY CYTOKINES AND SLE

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The long-term goal of this laboratory is to define the T cell mechanisms which initiate and perpetuate humoral autoimmunity in systemic lupus erythematosus (SLE). The hypothesis to be tested in this grant is that the onset of SLE is associated with activation of CD4+T cells resulting in spontaneous secretion of cytokines with both T cell and B cell stimulatory activity. In the absence of CD8+T cells, production of B cell stimulatory cytokines continues whereas T cell stimulatory cytokines, such as IL2, are down-regulated. The overall aims of this project are to define the T cell subsets whose activation leads to humoral autoimmunity as well as to determine the role of several cytokines and their production kinetics during the development of autoimmunity. To achieve this goal, we will use a well characterized, T cell driven murine model of SLE i.e., the parent-into-F1 model of graft-vs-host disease(GVHD) in which SLE-like disease is induced in normal, unirradiated F1 mice following the injection of donor strain T cells. This model lends itself well to a kinetic analysis of T cell subset activation, sequential cytokine production, and a study of immune intervention at different stages of disease activity. Furthermore, by comparing the results obtained in autoimmune GVHD to those occurring in acute, lethal GVHD, we will be able to distinguish those immunologic mechanisms that are specific for the development of autoimmunity from those that are common to both forms of GHVD. This proposal has the following specific aims: 1) Define the respective roles of CD4+ and CD8+T cells in the development of autoimmunity. 2) To define the kinetics of T cell and B cell stimulatory cytokines as measured by increased cytokine gene expression [for IL2, IL4,IL5,IL10 and gamma interferon (IFNg) and by assays of spontaneous cytokine production (IL2,IL5 and IFNg). Increased cytokine production or gene expression will be studied further in order to determine the lymphocyte subset responsible as well as whether it is donor or host in origin. Additional measures of in vivo B cell activation will be tested. 3) To block or change manifestations of SLE GVHD by in vivo treatment with monoclonal antibodies (mAb) which block the function of cytokines (IL2,IL4,IFNg and IL5) or T cell subsets (CD4+ or CD8+). In vivo mAb will be given at the onset of GVHD to determine if mAb treatment can block disease development. In later studies, mAb will be delayed until 2 weeks after SLE GVHD induction to determine if established disease can be reversed.