Amelioration of collagen-induced arthritis and suppression of interferon-?, interleukin-12, and tumor necrosis factor ? production by interferon-? gene therapy

Abstract

Objective. To investigate the therapeutic effects and possible mechanisms of action of constitutive expression of interferon-␤ (IFN␤) 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 IFN␤. IFN␤-expressing fibroblasts were then implanted intraperitoneally into mice immunized with bovine type II collagen. The effect of IFN␤ 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 marrowderived macrophages was assessed.Results. A single injection of IFN␤-secreting fibroblasts was sufficient to prevent arthritis or to ameliorate existing disease. Thus, IFN␤ 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 IFN␤-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-␥ secretion from lymph node cells, and reduced the levels of tumor necrosis factor ␣ and interleukin-12 produced by lipopolysaccharide/IFN␥-treated bone marrow-derived macrophages. This effect was specific, since it was reversed with anti-IFN␤ polyclonal antibodies.Conclusion. These results indicate that IFN␤, 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.Interferons are known predominantly for their inhibitory effects on viral replication and cellular proliferation, as well as for their capacity to modulate immune responsiveness. Interferon-␥ (IFN␥), for example, plays an important role in promoting immune and inflammatory responses, partly by up-regulating the antigenpresenting capacity of different cell types and partly by priming macrophages for proinflammatory cytokine production. In contrast, there is evidence of a predominantly antiinflammatory role for interferon-␤ (IFN␤), a type I interferon. This evidence is based principally on the beneficial therapeutic effect of IFN␤ in patients with multiple sclerosis (MS) (1) as well as in chronic, relapsing experimental allergic encephalomyelitis (an animal model of MS) (2,3). Specifically, administration of IFN␤ to MS patients in clinical trials has been shown to reduce the level of disease activity and the frequency of attacks (4). Conversely, the administration of IFN␥ is associated with exacerbation of preexisting autoimmune diseases such as systemic lupus erythematosus and MS (5,6). These findings support the concept that IFN␤ and IFN␥ have opposing e...

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

“…The conditionally immortalized fibroblasts were derived from embryonic fibroblasts of the DBA/1 mouse by infection with a retrovirus expressing a temperaturesensitive SV40 large T antigen (52). They possess high mitotic activity when cultured in vitro at 37°C, thus enabling their propagation and transduction with genes in retroviral vectors.…”

“…To generate immortalized DBA/1 fibroblasts, 10-12-day-old mouse DBA/1 embryos were treated with collagenase and pronase and fibroblast cell lines were grown in culture in DMEM with 10% FBS. The cells were transduced with the ecotropic retrovirus containing the large T antigen gene of SV40 tsTA58 and selected in 1 mg/ml G418 at 33°C (52).…”

A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats

“…[49][50][51] The continuous production of IFN-b by injection of IFN-b-expressing fibroblast or daily subcutaneous treatment with recombinant IFN-b inhibited inflammation as well as bone destruction in a system of collagen-induced arthritis in mice. 52,53 In addition, the expression of IFN-b was increased in synovial tissue of patients with RA. Its increased production in RA may be a reactive attempt to inhibit inflammation and bone destruction.…”

Electro-gene therapy of collagen-induced arthritis by using an expression plasmid for the soluble p75 tumor necrosis factor receptor-Fc fusion protein

“…The inhibitory effect of sTNFR:Fc on the level of IL-12 also suggests that sTNFR:Fc may downregulate Th1 activity, since IL-12 is known to play a pivotal role in promoting the differentiation of Th1 responses and inducing IFNg production. 37 Randomized, double-blind, placebo-controlled trials showed that human p75 sTNFR:Fc fusion protein treatment yielded significant clinical benefits, with minimal toxicity, in patients with RA who had inadequate responses to other disease-modifying drugs. 17 Soluble cytokine receptors may have a distinct advantage over other TNF-neutralizing agents, such as monoclonal antibodies, in terms of immunogenicity.…”