Effective Treatment of Adjuvant Arthritis with a Stimulatory CD28-specific Monoclonal Antibody

MARTA RODRÍGUEZ-PALMERO, ÀNGELS FRANCH, MARGARIDA CASTELL, CARME PELEGRÍ, FRANCISCO J. PÉREZ-CANO, CHRISTOPH KLEINSCHNITZ, GUIDO STOLL, THOMAS HÜNIG, and CRISTINA CASTELLOTE

ABSTRACT.

Objective. To determine the immunomodulatory effects of the anti-rat CD28 monoclonal antibody (Mab) JJ316 on the onset of rat adjuvant arthritis (AA). JJ316 is a superagonistic Mab that induces polyclonal T cell proliferation in the absence of T cell receptor (TCR) ligation and promotes the expansion of regulatory T cells.

Methods. Female Wistar rats in which AA was induced were treated with JJ316 on Day 0 and Day 9 postinduction. A parallel treatment with JJ319, a "conventional" CD28-specific Mab that costimulates anti-TCR triggered proliferation, was performed. Severity of arthritis was monitored by means of an arthritic score, and by recording hindpaw volume and body weight increases. Serum antibodies against the AA-inducing mycobacteria were also determined by ELISA. To ascertain the effect of JJ316 on T lymphocytes in vivo, blood CD4+CD45RC^high (Th1-like) and CD4+CD45RC^low (Th2-like) cells were analyzed by flow cytometry, and the relative levels of interleukin 2 (IL-2), IL-10, and interferon-g (IFN–g) mRNA in synovial tissue were measured by real-time reverse transcription-polymerase chain reaction.

Results. JJ316 efficiently prevented the inflammatory process of AA. This effect was associated with a specific decrease in the blood CD4+CD45RC^high/CD4+CD45RC^low T cell ratio and high IL-10 mRNA expression in the synovia. In addition, anti-mycobacteria antibody levels decreased in JJ316 treated animals. In contrast, administration of the conventional anti-CD28 Mab JJ319 did not improve inflammation.

Conclusion. JJ316, a stimulatory CD28-specific Mab known to promote Th2 function and the expansion of regulatory T cells, provides effective protection from AA. (J Rheumatol 2006;33:110-8)

Key Indexing Terms:

EXPERIMENTAL ARTHRITIS
IMMUNOTHERAPY
LYMPHOCYTE
INFLAMMATION
CYTOKINES
ANTIBODIES

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From the Department of Physiology, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; and the Institute for Virology and Immunobiology and the Neurological Clinic, University of Würzburg, Würzburg, Germany.

Supported by the Generalitat de Catalunya (2001SGR-000141), by the Deutsche Forschungsgemeinschaft through SFB 479, and by Fonds der Chemischen Industrie e.V.

M. Rodríguez-Palmero, PhD; T. Hünig, PhD, Professor of Immunology, Department of Immunology; C. Kleinschnitz, MD, Professor of Neurology; G. Stoll, MD, Professor of Neurology, Department of Neurology, University of Würzburg; A. Franch, PhD, Professor of Physiology; M. Castell, PhD, Professor of Physiology; C. Pelegrí, PhD, Professor of Physiology; F.J. Pérez-Cano, PhD, Assistant Professor of Physiology; C. Castellote, PhD, Professor of Physiology, Department of Physiology, Faculty of Pharmacy, University of Barcelona.

M. Rodríguez-Palmero and A. Franch contributed equally to this study.

Address reprint requests to Prof. C. Castellote, Departament de Fisiologia, Facultat de Farmàcia, Av. Joan XXIII s/n, edifici B, 3a planta, E-08028 Barcelona, Spain. E-mail: cristinacastellote@ub.edu

Accepted for publication August 2, 2005.

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