SYSTEMIC HIGH-DOSE RECOMBINANT-ALPHA-2A-INTERFERON THERAPY MODULATES LYMPHOKINE PRODUCTION IN MULTIPLE-SCLEROSIS

Chronic systemic high-dose recombinant alpha(2a)-interferon (rIFNA) th erapy reduces exacerbation rate and MRI signs of disease activity in r elapsing/remitting multiple sclerosis (RR MS) patients. In order to cl arify the possible mechanisms underlying the clinical efficacy of rIFN A in MS, several immunologic studies were performed as a part of a pil ot clinical trial. Twenty RR MS patients were treated with 9 x 10(6) I U of rIFNA (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Cytokine production by cultured lymphocytes, major hist ocompatibility complex class IT (MHC-TI) antigen expression on culture d macrophages, peripheral blood (PB) and cerebrospinal fluid (CSF) lym phocyte phenotype, and IgG and beta, microglobulin levels were studied before therapy, after 6 months of therapy, and 6 months after stoppin g therapy. rIFNA therapy was associated with reduction of interferon-g amma and tumor necrosis factor-alpha production by PB lymphocytes (p < 0.04), and with slight, not significant, increase of transforming gro wth factor-beta(2) or interleukin (IL)-10 production. IL-4 was undetec table in the culture supernatants both before and after therapy. rIFNA therapy had no effect on macrophage MHC-II molecule expression. An in creased percentage of CD8 +, CD8 + high CD11b + low, and CD3 - CD16 CD56 + cells, and of CD4 + absolute cell number was observed in CSF af ter rIFNA therapy. After rIFNA administration, IgG level significantly increased both systemically (p < 0.02) and intrathecally (p < 0.001). Serum beta, microglobulin level increased (p < 0.01), as well. Only I out of the 12 rIFNA treated patients developed neutralizing antibodie s against rIFNA during therapy. Six months after stopping therapy all the immunologic changes returned to baseline. These data suggest that the beneficial effect of rIFNA therapy on MS disease activity is proba bly mediated by a downregulation of proinflammatory cytokine synthesis by PB lymphocytes rather than by macrophage MHC-II antigen expression . The immunologic effects of high-dose systemic rIFNA therapy are temp orary and restricted to the period of drug administration.