CD200‐FC, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen‐induced arthritis

Abstract

Objective. The CD200 receptor (CD200R) is an inhibitory receptor expressed by myeloid cells that is postulated to play an important role in regulation of the immune system. The purpose of this study was to evaluate the efficacy of a soluble ligand of CD200R in established collagen-induced arthritis (CIA) in mice and to analyze changes in cytokine expression following therapy in order to understand its primary mechanism of action.Methods. Arthritis was induced in DBA/1 mice, and CD200-Fc fusion protein, an isotype control monoclonal antibody, or TNFR-Fc fusion protein was administered over a period of 10 days (total of 4 doses). Cytokine expression in the joint was assessed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction.Results. CD200-Fc significantly reduced the severity of established arthritis at the clinical and histologic levels. The therapeutic effect of CD200-Fc at 1 mg/kg was comparable with that of TNFR-Fc at 4 mg/kg. CD200R was found to be expressed in arthritic synovia and in lymph nodes, yet no changes in T cell cytokine levels (interferon-␥, interleukin-5 [IL-5], IL-10, IL-17) were detected after CD200-Fc therapy. There was no evidence of an expansion of forkhead box P3-positive regulatory T cells or a change in serum anticollagen IgG1 and IgG2a levels. However, administration of CD200-Fc markedly decreased the expression of messenger RNA for tumor necrosis factor ␣, IL-1␤, IL-10, and matrix metalloproteinase 13 in the joint to the same extent as administration of TNFR-Fc.Conclusion. CD200-Fc is an effective therapeutic agent in established CIA that targets proinflammatory cytokine expression in the joint without any obvious systemic immunosuppressive effects. Our findings indicate that CD200-Fc has considerable potential as a novel therapeutic agent in rheumatoid arthritis in humans.

What have we learnt from targeted anti-TNF therapy?

“…The results were highly encouraging. The potency of CD200Fc in CIA is similar to etanercept, and the benefit is linked to reducing macrophage-derived proinflammatory cytokines such as TNF, IL1 and IL6 25. This confirms the concept that macrophages are a major source of these cytokines.…”

CD200:CD200R-Mediated Regulation of Immunity

“…These observations were confirmed in independent studies [124] which compared CD200Fc with TNF inhibition (the current method of choice for refractory RA patients in the clinic). Inhibition mediated by CD200Fc in this system was comparable to that achieved by TNFRFc [125]. Recently Chen et al (personal communication) have established the importance of the CD200:CD200R axis in regulation of intestinal inflammation in a model of dextran sulfate-induced colitis in mice.…”

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…For analysis of IDO expression by quantitative RT-PCR, tissue samples were collected from the mice, snap-frozen in liquid nitrogen, and pulverized. RNA isolation and RT were performed as previously described (18). RNA transcripts were quantified by quantitative real-time PCR in a Rotor-Gene 6000 Thermocycler (Corbett Life Science, Sydney, New South Wales, Australia), using Platinum SYBR Green SuperMix-UDG (Invitrogen, San Diego, CA) and the following primers (19): for control hypoxanthine guanine phosphoribosyltransferase (HPRT), forward 5Ј-GCTTTCCCTGGTTAAGCAGTACA-3Ј, reverse 5Ј-CAAACTTGTCTGGAATTTCAAAT-3Ј; for IDO, forward 5Ј-GGCTTCTTCCTCGTCTCTCTATTG-3Ј, reverse 5Ј-TGACGCTCTACTGCACTGGATAC-3Ј.…”