ELEVATED INTERLEUKIN-12 IN PROGRESSIVE MULTIPLE-SCLEROSIS CORRELATES WITH DISEASE-ACTIVITY AND IS NORMALIZED BY PULSE CYCLOPHOSPHAMIDE THERAPY

Multiple sclerosis is postulated to be a Th1-type cell-mediated autoim mune disease. We investigated cytokine profiles in patients with progr essive multiple sclerosis by using intracytoplasmic staining. We found increased IL-12 production by monocytes and increased IFN-gamma produ ction by T cells in untreated patients as compared with controls;In pa tients treated with methotrexate, methylprednisolone, or cyclophospham ide/methylprednisolone (CY/MP), only CY/MP treatment normalized the el evated IL-12 production. Furthermore, CY/MP-treated patients had decre ased IFN-gamma and increased IL-4, IL-5, and TGF-beta expression. Pati ents followed prospectively before and after starting CY/MP treatment showed a gradual decrease in IL-12 and IFN-gamma production and an inc rease in IL-4 and IL-5. In vitro, addition of 4-hydroperoxycyclophosph amide, a metabolite of cyclophosphamide decreased IL-12 production in mononuclear cell cultures. When patients were classified as having act ive or stable disease, IL-12 production correlated with disease activi ty. In summary, our results demonstrate a Th1-type cytokine bias in pe ripheral blood mononuclear cells of untreated progressive MS patients that is reversed by CY/MP treatment and is associated with Th2 and TGF -beta (Th3) type responses. These findings provide a basis for immune monitoring of patients with MS and suggest that treatments that downre gulate IL-12 may prove to be beneficial in progressive MS.