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Open Access Research article

Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-κB binding activity and TNF-α secretion of T cells

Dirk Pohlers1, Carsten B Schmidt-Weber2, Angels Franch3, Jürgen Kuhlmann4, Rolf Bräuer5, Frank Emmrich6 and Raimund W Kinne1*

Author Affiliations

1 Experimental Rheumatology Unit, Friedrich Schiller University, Jena, Germany

2 Swiss Institute of Asthma and Allergy Research (SIAF), Davos, Switzerland

3 Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

4 Max Planck Institute of Molecular Physiology, Dortmund, Germany

5 Institute of Pathology, Friedrich Schiller University, Jena, Germany

6 Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany

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Arthritis Res 2002, 4:184-189  doi:10.1186/ar404

Published: 8 January 2002

Abstract

The aim of this study was to analyze the differential effects of three anti-CD4 monoclonal antibodies (mAbs) (with distinct epitope specifities) in the treatment of rat adjuvant arthritis (AA) and on T-cell function and signal transduction. Rat AA was preventively treated by intraperitoneal injection of the anti-CD4 mAbs W3/25, OX35, and RIB5/2 (on days -1, 0, 3, and 6, i.e. 1 day before AA induction, on the day of induction [day 0], and thereafter). The effects on T-cell reactivity in vivo (delayed-type hypersensitivity), ex vivo (ConA-induced proliferation), and in vitro (mixed lymphocyte culture) were assessed. The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed. While preventive treatment with OX35 and W3/25 significantly ameliorated AA from the onset, treatment with RIB5/2 even accelerated the onset of AA by approximately 2 days (day 10), and ameliorated the arthritis only in the late phase (day 27). Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-α secretion, and more strongly induced NF-κB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation. Depending on their epitope specificity, different anti-CD4 mAbs differentially influence individual proinflammatory functions of T cells. This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies.

Keywords:
adjuvant arthritis; anti-CD4 monoclonal antibody; TNF-alpha; NF-kappaB