The effects of in vivo inhibition of the biosynthesis of polyamines on the clinical and immunopathological manifestations of murine lupus will be studied using difluoromethylornithine (DFMO) in three strains of autoimmune mice, male BXSB, female MRL- 1pr/1pr and female NZB/W. DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme involved in polyamine biosynthesis. The concentration of polyamines is increased in systemic lupus erythematosus (SLE). Preliminary work suggests that polyamines may enhance the antigenicity of DNA or increase the production of autoantibodies of both. DFMO treatment of a small group of MRL-lpr/lpr mice resulted in a lowering of anti-DNA antibody levels and prolongation of life. The possibility of a pathogenic role for polyamines in SLE will be examined by: (1) depleting the polyamine levels using DFMO and studying the lifespan, clinical manifestations, and serum levels of anti-DNA antibodies in DFMO-treated and untreated mice, and (ii) immunizing normal mice, BALB/c with polyamines complexed with polynucleotides and measuring the concentration of anti- DNA antibodies in their serum. The efficacy of DFMO in combination with three drugs of known efficacy in murine lupus, cyclosporin, corticosteroids and cyclophosphamide will be determined. To understand the effect of DFMO on tissue damage characteristic of SLE, sections of kidneys, spleens, lymph nodes and arteries of DFMO-treated and untreated mice will be examined by light, immunofluorescent and electron microscopy. The mechanism of action of DFMO will be studied by determining changes in ODC activity and polyamine concentration in the kidney and liver homogenates and plasma of DFMO-treated and untreated mice and the functional status of spleen cells in these animals. The proposal represents a novel approach to understand the pathogenesis of lupus and its treatment. DFMO is a relatively non-toxic drug. If DFMO proves to be an efficient drug to treat murine lupus, or combinations of DFMO and other drugs show additive or synergistic effects, clinical studies to treat SLE patients will be possible since considerable information on the pharmacology and toxicity of DFMO is available from its use in Phase I and Phase II studies on cancer patients.
NIH ExPorter
NIH ExPorter