Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy.
Triantaphyllopoulos KA., Williams RO., Tailor H., Chernajovsky Y.
OBJECTIVE: To investigate the therapeutic effects and possible mechanisms of action of constitutive expression of interferon-beta (IFNbeta) by syngeneic fibroblasts from DBA/1 mice in the collagen-induced arthritis (CIA) model. METHODS: Immortalized embryonic DBA/1 fibroblasts were infected with a retrovirus expressing murine IFNbeta. IFNbeta-expressing fibroblasts were then implanted intraperitoneally into mice immunized with bovine type II collagen. The effect of IFNbeta on paw swelling, anticollagen antibody levels, IgG1/IgG2a isotype profiles, arthritis score, histologic joint damage, and cytokine secretion from lymph node cells and from bone marrow-derived macrophages was assessed. RESULTS: A single injection of IFNbeta-secreting fibroblasts was sufficient to prevent arthritis or to ameliorate existing disease. Thus, IFNbeta reduced the clinical score and paw swelling irrespective of whether the injection was administered before or after disease onset in treated mice, compared with that in the untreated control group (P < 0.05). Histologic findings in the IFNbeta-treated mice were markedly less severe than in the control group (P < 0.001). This effect was accompanied by a decrease in total anticollagen IgG levels, a decrease in anticollagen IgG2a, and an increase in IgG1. In vitro, supernatants from these engineered fibroblasts inhibited collagen-induced interferon-gamma secretion from lymph node cells, and reduced the levels of tumor necrosis factor alpha and interleukin-12 produced by lipopolysaccharide/IFNgamma-treated bone marrow-derived macrophages. This effect was specific, since it was reversed with anti-IFNbeta polyclonal antibodies. CONCLUSION: These results indicate that IFNbeta, which is currently used as a treatment for relapsing, remitting multiple sclerosis, is a potent immunomodulatory and antiinflammatory cytokine in CIA and should be considered for the treatment of rheumatoid arthritis.