Abstract
IntroductionImmunization 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.MethodsArthritis was induced in DBA/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.ResultsLarge 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.ConclusionTNF-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.
Highlights
Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice
tumor necrosis factor (TNF)-α and IL-6 play an important role in GPIinduced 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
Summary
Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The effects of various anti-cytokine mAbs have been examined in this model, especially after the onset of AP = alkaline phosphatase; APC = antigen-presenting cell; CBA = cytometric bead array; CIA = collagen-induced arthritis; CTLA-4Ig = cytotoxic Tlymphocyte antigen 4 immunoglobulin; GPI = glucose-6-phosphate isomerase; GST = glutathione S-transferase; hGPI = recombinant GPI-GST fusion; ICOS = inducible co-stimulator; IFN = interferon; IL = interleukin; mAb = monoclonal antibody; PBS = phosphate-buffered saline; RA = rheumatoid arthritis; TNF = tumor necrosis factor. Previous studies reported that anti-IL-1 and anti-IL-12 mAbs significantly suppressed arthritis, whereas anti-TNF-α therapy had little effect in this model [2,3,4,5], and blockade of IL-6 had no effect in established CIA [6], indicating different therapeutic mechanisms in RA [7,8]
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