Systemic high-dose recombinant-alpha-2a-interferon therapy modulates lymphokine production in multiple sclerosis.

Chronic systemic high-dose recombinant alpha 2a-interferon (rIFNA) therapy reduces exacerbation rate and MRI signs of disease activity in relapsing/remitting multiple sclerosis (RR MS) patients. In order to clarify the possible mechanisms underlying the clinical efficacy of rIFNA in MS, several immunologic studies were performed as a part of a pilot clinical trial. Twenty RR MS patients were treated with 9 x 10(6) IU of rIFNA (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Cytokine production by cultured lymphocytes, major histocompatibility complex class II (MHC-II) antigen expression on cultured macrophages, peripheral blood (PB) and cerebrospinal fluid (CSF) lymphocyte phenotype, and IgG and beta 2 microglobulin levels were studied before therapy, after 6 months of therapy, and 6 months after stopping therapy. rIFNA therapy was associated with reduction of interferon-gamma and tumor necrosis factor-alpha production by PB lymphocytes (p < 0.04), and with slight, not significant, increase of transforming growth factor-beta 2 or interleukin (IL)-10 production. IL-4 was undetectable in the culture supernatants both before and after therapy. rIFNA therapy had no effect on macrophage MHC-II molecule expression. An increased percentage of CD8+, CD8+ high CD11b+ low, and CD3- CD16+ CD56+ cells, and of CD4+ absolute cell number was observed in CSF after rIFNA therapy. After rIFNA administration, IgG level significantly increased both systemically (p < 0.02) and intrathecally (p < 0.001). Serum beta 2 microglobulin level increased (p < 0.01), as well. Only 1 out of the 12 rIFNA treated patients developed neutralizing antibodies 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 probably 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 temporary and restricted to the period of drug administration.