Anti-DNA antibodies are diagnostic and prognostic markers for SLE, although mechanisms of their production are poorly understood. Attempts to stimulate anti-DNA by direct DNA immunization in normal animals have until recently been only minimally successful. Recent evidence from this laboratory indicates, however, that bacterial DNAs are more immunogenic than mammalian DNAs and are able to stimulate an effective anti-DNA response in normal mice that resembles the anti-DNA reactivity of lupus. I propose, therefore, to explore this new model of SLE anti-DNA production by utilizing hybridoma, T cell cloning, and molecular biologic techniques to elucidate further the immune response to nucleic acid antigens and the role of DNA in the induction of the anti-DNA of lupus. The following aims are proposed: 1) to compare immunochemical properties of monoclonal anti-DNA antibodies derived from immunized normal mice and autoimmune MRL-lpr/lpr mice and thereby assess similarities between induced and spontaneous anti- DNA antibodies; 2) to study the response of T cells to DNA immunization by proliferation assays and the ability of these T cells to provide help to anti-DNA producing B cells. DNA specific T cell clones will also be prepared as aberrant T cell helper function has been implicated in the pathogenesis of SLE; 3) to evaluate the renal disease induced by DNA immunization including the study of bound antibodies eluted from affected kidneys given the pathogenicity of anti-DNA antibodies in lupus nephritis. Dr. Gilkeson has worked in this line of research for two years developing the methods necessary to complete these studies. Funding of this grant will provide the time and salary support to continue an already productive line of research and to allow for the development of independence in the study of autoimmunity. Current expertise in this laboratory and Duke University Medical Center provides a supportive atmosphere for learning and growth as a clinical investigator. The Division of Rheumatology, with support provided by a program project grant for arthritis research, is actively involved in the study of autoimmune diseases. There is a commitment in the Division to develop young investigators, providing them with the support necessary to pursue a career in academic medicine. In this environment, studying the immunopathogenesis of induced anti-DNA responses will be a fruitful learning experience lending new insight into anti-DNA, the hallmark of lupus autoantibody production.
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