Longterm Protection of Mice Against Collagen-Induced Arthritis After Short-Term LF 15-0195 Treatment: Modulation of B and T Lymphocyte Activation

PATRICK DUCOROY, DANIEL de FORNEL, LAURENCE DUBREZ-DALOZ, ERIC SOLARY, and PATRICK DUTARTRE

ABSTRACT.

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. (J Rheumatol 2003;30:918-25)

Key Indexing Terms:

AUTOIMMUNITY
IMMUNOSUPPRESSIVE AGENT
TH1/TH2
ARTHRITIS
IMMUNOGLOBULIN
MOUSE MODEL

From Fournier SA Laboratories, Immunology, Daix; and INSERM U517, IFR 100, Faculty of Medicine, Dijon, France.

P. Ducoroy is supported by a CIFRE grant from Fournier SA Laboratories, the ANRT (Association Nationale de la Recherche Technique) and the Ministère de l'Education Nationale, de la Recherche et de la Technologie. L. Dubrez-Daloz is supported by a Post-Doctoral fellowship from the Conseil Regional de Bourgogne. E. Solary and group are supported by a special grant from the Ligue Nationale Contre le Cancer.

P. Ducoroy, PhD, Associate Researcher; D. de Fornel, PhD, Research Manager; L. Dubrez-Daloz, PhD; E. Solary, MD; D.P. Dutartre, MD, Head, Immunology Department.

Address reprint requests to Dr. P. Ducoroy, Laboratoires Fournier SA, Groupe Immunologie, 50 route de Dijon, 21121 Daix, France. E-mail: p.ducoroy@fournier.fr

Submitted February 27, 2002; revision accepted November 4, 2002.

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