Therapeutic effects of antibodies to tumor necrosis factor-α, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis

Abstract

Introduction: Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis. Methods; Arthritis was induced inDBA/1 mice with 300 μg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-α, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-α, IFN-γ, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-α and IFN-γ production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production. Results: Large amounts of TNF-α and IFN-γ and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-α mAbs and CTLA-4Ig suppressed TNF-α production, whereas anti-IFN-γ mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-γ production. A single injection of anti-TNF-α and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-γ and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies. Conclusion: TNF-α and IL-6 play an important role in GPI-induced arthritis, whereas IFN-γ appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis. © 2008 Matsumoto et al.; licensee BioMed Central Ltd.