In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis

Recombinant interferon beta (IFN beta) benefits patients with relapsing remitting multiple sclerosis (MS), but the mechanisms of action are unknown. We studied in vivo immunologic effects of IFN beta treatment and their relationship to clinical efficacy. Cytokines were measured in blood and CSF from MS patients participating in a placebo-controlled phase III clinical trial and an open-label phase intravenous (IV) tolerability study of IFN beta-1a. Additionally, immunologic studies were conducted in animals with proteolipid protein (PLP)-induced chronic relapsing experimental autoimmune encephalomyelitis. Single intramuscular (IM) injections of IFN beta-1a (6 MIU, 30 mu g) were associated with significant in vivo upregulation of interleukin-10 (IL-10) and IL-4 but not IFN gamma mRNA in peripheral blood mononuclear cells. Forty-eight hours after each IFN beta-1a injection, serum IL-10 levels increased and remained elevated for 1 week. IFN beta-1a recipients in the placebo-controlled phase III clinical trial showed significantly increased concentrations of CSF IL-10 after 2 years of treatment. This response correlated with a favorable therapeutic response. Exposure of PLP-reactive murine T-cell lines to IFN beta resulted in increased antigen-driven expression of IL-4 and IL-10 and reduced encephalitogenicity. IFN beta-1a injections induce systemic and intrathecal immunosuppressive cytokines. Myelin-specific T cells treated with IFN beta-1a demonstrate increased immunosuppressive cytokine expression and reduced encephalitogenicity. The relationship between increased CSF IL-10 and response to therapy suggests that induction of IL-10 is a mechanism underlying IFN beta-1a effects in MS patients.