The effect of an interleukin‐1 receptor antagonist protein on type ii collagen–induced arthritis and antigen‐induced arthritis in mice

Abstract

Objective. To investigate the anti-arthritic effect of recombinant human interleukin-1 receptor antagonist protein (IRAP) in two experimental models of arthritis.Methods. Recombinant IRAP was administered daily to mice with type I1 collagen-induced arthritis (CIA) or with antigen-induced arthritis (AIA) provoked by methylated bovine serum albumin (mBSA). Disease incidence and severity were assessed by a clinical index and histologic features. Serum antibody to type I1 collagen, spleen cell proliferation to mBSA, and anti-IRAP antibodies were measured as indices of immune function.Results. IRAP reduced the incidence and delayed the onset of CIA and suppressed the antibody response to type I1 collagen. In contrast, IRAP did not affect the pathogenesis of AIA and had no effect on either humoral or cellular immune responses to mBSA in arthritic mice.Conclusion. These observations suggest that interleukin-1 may play a prominent role in the development of some, but not all, forms of arthritis.Interleukin-1 (IL-1) is present in the synovial fluid of rheumatoid arthritis (RA) patients (1-3). In approximately 40% of joint fluids from patients with RA, osteoarthritis, and miscellaneous connective tis-

Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist

“…Administration of human IL1Ra has been shown to inhibit the development of CIA. Although a relatively low dose of recombinant IL-1Ra (3-30 mg/day) was effective in the preventive model of murine CIA, 14 sustained high blood levels of IL-1Ra, such as by continuous administration or osmotic pumping system, were required to obtain a complete suppression of all aspects of the disease. 15,17 The efficacy of recombinant human IL-1Ra in the treatment of active RA was confirmed in long-term placebo-controlled clinical studies.…”

“…Indeed, it was already reported that repeated injections of the human IL-1Ra (hIL-1Ra) protein could induce the antibody response to hIL-1Ra in CIA mice, although the antibody response to hIL-1Ra did not inhibit the therapeutic effects of the injected protein. 14 Further investigation into the mechanism involved in the decrease in the level of transgene expression will help to develop a new strategy for long-term gene expression by naked DNA.…”

“…However, owing to its short half-life in vivo, the recombinant protein has to be administrated continously. [14][15][16][17] Effective control of autoimmune arthritis requires prolonged neutralization of proinflammatory mediators, and gene therapy offers several potentially unique advantages over previous protein therapies. With the recent advances in gene therapy, the IL-1Ra gene has been delivered by retrovirus-based, adenovirusbased and adeno-associated virus (AAV)-based vectors into synoviocytes to achieve anti-inflammatory effects both in vivo and in vitro with a varying degree of success.…”

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

“…In patients with rheumatoid arthritis (RA), 2 critical proinflammatory cytokines are interleukin-1 (IL-1) and tumor necrosis factor ␣ (TNF␣) (3). Inhibition of IL-1 and/or TNF␣ reduces the extent of inflammation in RA (4,5) and lessens inflammation and bone destruction in various experimental models of arthritis (6)(7)(8)(9)(10)(11)(12). Therefore, therapeutic agents that inhibit the action of these 2 cytokines are gaining rapid acceptance as early, aggressive treatments for RA.…”

Biologic agents for treating rheumatoid arthritis. Concepts and progress

“…Animal models of arthritis have provided considerable insight into possible roles of cytokines in perpetuating and modulating arthritis. IL-1 and TNF inhibitors have been shown to ameliorate established collageninduced arthritis (49)(50)(51)(52)(53). Mice transgenic for the human TNFa gene develop chronic inflammatory arthritis, and treatment of these mice with anti-TNF MAb or rTNFR:Fc fusion protein abrogates the arthritis (5435).…”