RESEARCH - T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

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T-614, a Novel Immunomodulator, Attenuates Joint Inflammation and

Articular Damage in Collagen-induced Arthritis

Posted 11 Mar 2009

Fang Du; Liang-jing Lü; Qiong Fu; Min Dai; Jia-lin Teng; Wei Fan;

Shun-le Chen; Ping Ye; Nan Shen; Xin-fang Huang; Jie Qian; Chun-de Bao

Abstract

Introduction: T-614 is a novel oral antirheumatic agent for the

treatment of rheumatoid arthritis. Whether it has immunomodulatory or

disease-modifying properties and its mechanism of action are largely

undetermined.

Methods: Rats with collagen-induced arthritis (CIA) were treated with

T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg

every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide

(10 mg/kg per day) were used as controls. A combination therapy group

was treated with both T-614(10 mg/kg per day) and methotrexate (1

mg/kg every 3 days). Hind paw swelling was evaluated and radiographic

scores calculated. Serum cytokine levels were assessed by Bio-plex

analysis. Quantitative PCR was used to evaluate expression of mRNA for

interferon-γ, IL-4 and IL-17. Serum IL-17 and anti-type II collagen

antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using

ELISA.

Results: Oral T-614 inhibited paw swelling and offered significant

protection against arthritis-induced cartilage and bone erosion,

comparable to the effects of methotrexate. CIA rats treated with T-614

exhibited decreases in both mRNA expression of IL-17 in peripheral

blood mononuclear cells and lymph node cells, and circulating IL-17 in

a dose-dependent manner. T-614 also reduced serum levels of tumor

necrosis factor-α, IL-1β and IL-6. A synergistic effect was observed

for the combination of methotrexate and T-614. In addition, T-614 (20

mg/kg per day) depressed production of anti-type II collagen

antibodies and differentially affected levels of IgG2a subclasses in

vivo, whereas IgM level was decreased without any change in the IgG1

level. Together, the findings presented here indicate that the novel

agent T-614 has disease-modifying effects against experimental

arthritis, as opposed to nimesulide.

Conclusions: Our data suggested that T-614 is an effective

disease-modifying agent that can prevent bone/cartilage destruction

and inflammation in in CIA rats. Combination with methotrexate

markedly enhances the therapeutic effect of T-614.

http://www.medscape.com/viewarticle/587580

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