Obstacles to Anti-CD4 Therapy in Rheumatoid Arthritis
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KeywordsPlacebo Rheumatoid Arthritis Clinical Benefit Clinical Efficacy Full Text
Monoclonal antibodies (mAbs) to CD4 have been employed in a variety of studies to patients with active rheumatoid arthritis (RA) in an attempt to control disease progression not only by preventing T cell activation but also by inducing tolerance to the putative autoantigen(s) [1,2,5]. Initial open labeled clinical trials have provided encouraging clinical results [1,2,4]. However, randomized controlled studies with chimeric immunoglobulins have largely failed to demonstrate a significant benefit of anti-CD4 mAbs over placebo [1,2,5]. Following those disappointing trials, favorable results of several dose-finding studies with high dosages of nondepleting CD4 mAbs were recently presented [1,2,6]. Whereas the mechanisms underlying the clinical benefit remain to be elucidated, it appears to be clear that depletion of CD4 T cells cannot explain clinical efficacy. Moreover, the data are consistent with the hypothesis that long lasting successful treatment of RA with mAb to CD4 might require long-term inhibition of peripheral T cell functions by non-depleting mAbs to CD4. Future studies are necessary to delineate precisely the dosing requirements for clinical benefit and to elucidate the mode of actions of anti-CD4 mAbs. Exciting new data that are indicative of a modulation of the detrimental Th1-dominated immune response in RA by anti-CD4 mAbs  warrant further investigation. Finally, data from animal studies suggest that new promising therapeutic perspectives in man might result from combining anti-CD4 mAbs with other biologic therapeutics [1,7,8].
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