Longterm protection of mice against collagen-induced arthritis after short-term LF 15-0195 treatment: modulation of B and T lymphocyte activation.

OBJECTIVES

LF 15-0195 is an immunosuppressive agent obtained by organic synthesis, currently under clinical development for the treatment of vasculitis. We define the effects of LF 15-0195 in the murine collagen-induced arthritis (CIA) model, an experimental model of human rheumatoid arthritis.

METHODS

In our model, CIA was elicited in DBA/1 mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant, followed by a repeat injection 21 days later. Disease onset was observed 6 days after booster injection. In these experiments, mice were treated with 5 daily LF 15-0195 injections starting after the booster injection (days 21-25). The mice were observed for 40 days after the start of treatment, during which time arthritis was scored using clinical score and paw swelling assessment. Modulation of humoral immunity was documented by measuring the serum level of anti-CII IgG1 and IgG2a and cellular immunity by cytokines production by lymph node cells (LNC) and their proliferation in vitro.

RESULTS

Short-term treatment of LF 15-0195 after booster injection prevented longterm development of CIA. LF 15-0195 inhibited B cell differentiation with a marked suppression of anti-CII IgG1 and IgG2a synthesis. Functional analyses of T lymphocytes showed that LF 15-0195 treatment reduces cytokine production by LNC after CII, anti-CD3, lipopolysaccharide stimulation.

CONCLUSION

LF 15-0195 treatment during a short time period prevented development of arthritis, inhibited humoral-specific response longterm, induced a decrease in the number of LNC, and decreased cytokine production of T LNC after ex vivo stimulation.