Impaired interleukin-12 production in multiple sclerosis patients

Multiple sclerosis (MS), a disease of the human central nervous system, is believed to be a T cell mediated autoimmune disorder with genetic and envir onmental influences. Interleukin-12 (IL-12), a proinflammatory cytokine pro duced primarily by antigen presenting cells is a potent inducer of interfer on-gamma (IFN-gamma) and other ThI cytokines that may ploy on important rol e in MS pathogenesis. We have investigated IL-12 production induced by the T cell independent pathway in untreated and IFN-beta treated MS patients, h ealthy individuals and other neurological disease (OND) patients in respons e to the human pathogen Staphylococcus aureus. We report that peripheral bl ood mononuclear cells (PBMC) from untreated MS patients produce normal amou nts of the biologically active IL-12 p70 heterodimer but significantly less free IL-12 p40 heavy chain than PBMC from both healthy and disease control s when challenged in vitro with Staphylococcus aureus. Both mRNA expression of the inducible IL-12 p40 chain and protein levels were found to be reduc ed in untreated MS Patients. No decrease in the production of the IL-12 p40 was seen in MS patients on IFN-beta therapy. The decreased production of I L-12 p40 heavy chain is not attributed to increased IL-10 secretion, a defe ct in the production of cytokines by macrophages or the number of cytokine producing cells. The factor(s) responsible for the decrease in p40 remain t o be determined. Since IL-12 p40 antagonizes the biological activity of IL- 12 in vitro and in vivo identification of a defect in the 'natural' antagon ist of IL-12, may Provide the basis for immune therapy.