INDUCTION OF IMMUNE TOLERANCE TO DNA: THERAPY FOR SLE

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This proposal concerns the development of an immunologically specific therapy of Systemic Lupus Erythematosus (SLE). Since this autoimmune disease may stem from a failure of self tolerance, we propose induction of tolerance to autoantigens as a treatment. In view of the importance of immune complexes containing antibodies to nucleic acid antigens in SLE, the induction of tolerance to those antigens might provide a specific therapy for the disease. This idea is supported by evidence that tolerance to autoantigens can be induced by tolerogen (i.e., autoantigens covalently linked to isologous IgG). In addition, we have been able to link fragments of DNA long enough to accommodate the combining size of anti DNA antibodies made either by mice or humans with SLE to isologous IgG. Preliminary findings suggest that these tolerogens a) influence murine lupus, and b) diminish anti DNA antibodies in peripheral blood lymphocytes from SLE patients in vitro. This renewal seeks to confirm and extend these preliminary observations. We will determine if murine lupus in females of both BFW1 and MRL +/+ strain mice can be prevented or treated. We will also determine which DNA fragments conjugated to human gamma globulin are the best tolerogens to suppress either spontaneous or antigen induced antibodies to nucleic acid antigens in vitro. The goal is to develop the data bases for the induction of unresponsiveness to DNA in SLE patient. In addition, DNA digest linked to either KLH or tetanus toxoid will be used to develop an antigen specific model using normal lymphoid cells from various sources or SLE patient's PBL to study some aspects of the cellular mechanisms of both immunity and tolerance in humans in vitro.