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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2806-2814.
Prepublished online as a Blood First Edition Paper on June 30, 2005; DOI 10.1182/blood-2004-12-4678.
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IMMUNOBIOLOGY
Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40
Marie-Ghislaine de Goër de Herve,
Deniz Durali,
Tú-Anh Tran,
Gwénola Maigné,
Federico Simonetta,
Philippe Leclerc,
Jean-François Delfraissy, and
Yassine Taoufik
From the INSERM E-109, Faculty of Medicine, University Paris XI, Bicêtre, France, and Laboratory of Immunology, Confocal Microscopy Station, Bicêtre Hospital, Bicêtre, France.
Agonistic monoclonal antibodies to CD40 (CD40 mAbs) have a puzzling dual therapeutic effect in experimental animal models. CD40 mAbs induce tumor regression by potentiating antitumoral T-cell responses, yet they also have immunosuppressive activity in chronic autoimmune inflammatory processes. CD40 mAbs are thought to act on antigen presentation by dendritic cells (DCs) to T cells. DCs can be distinguished as either immature or mature by their phenotype and their ability to generate an effective T-cell response. Here we found that, on human cells, although anti-CD40 led immature DCs to mature and became immunogenic, it also reduced the capacity of lipopolysaccharide (LPS) and tumor necrosis factor  (TNF-)-matured DCs to generate a specific CD4 T-cell response. This inhibitory effect was related to rapid and selective apoptosis of mature DCs. Anti-CD40-mediated apoptosis was due to an indirect mechanism involving cooperation with the death domain-associated receptor Fas, leading to activation of Fas-associated death domain protein (FADD) and caspase-8. On human cells, CD40 activation by such agonists could, therefore, trigger immune responses to antigens presented by immature DCs, which are otherwise nonimmunogenic, by inducing maturation. On the other hand, anti-CD40 mAbs, by rapidly inducing apoptosis, may reduce the capacity of inflammatory signal-matured immunogenic DCs to generate an effective T-cell response. These results call for caution in CD40 mAb-based immunotherapy strategies. (Blood. 2005;106:2806-2814)
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