Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin-4 production and associated eosinophilia

Multiple sclerosis (MS) is postulated to be a Th1-type cell-mediated autoimmune disease. Thus therapies that decrease T cell interferon (IFN)-gamma production or increase interleukin (IL)-4 production would be expected to have an ameliorating effect on MS. Some progressive MS patients receiving pulse cyclophosphamide therapy developed peripheral blood eosinophilia. We investigated whether cyclophosphamide-treated patients had immune deviation toward Th2 responses. We measured cytokine production in patients receiving either monthly intravenous methylprednisolone (MP), intravenous cyclophosphamide plus methylprednisolone ((CY/MP), methotrexate, IFN-beta 1b, in untreated MS patients, and in healthy controls. Minimal IL-4 was secreted in untreated patients (129 +/- 62 pg/ml), methotrexate-treated patients (99 +/- 79 pg/ml), and healthy controls (50 +/- 13 pg/ml). A marked increase in IL-4 was observed in CY/MP patients (1,503 +/- 291 pg/ml). Patients treated with MP (418 +/- 160 pg/ml) or IFN-beta 1b (425 +/- 167 pg/ml) showed small increases. Eosinophilia in CY/MP-treated patients (6.0 +/- 0.7%) correlated with increased IL-4. IL-10 production was also increased in CY/MP-treated patients. Both CY/MP- and MP-treated groups had decreased production of IFN-gamma compared with untreated MS. These findings demonstrate pronounced immune deviation favoring Th2-type responses after pulse cyclophosphamide therapy.