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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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Submitted December 8, 2004
Accepted June 16, 2005
Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells. The Janus face of anti-CD40
Marie-Ghislaine de GOER de HERVE, Deniz DURALI, Tu-Anh TRAN, Gwenola MAIGNE, Federico SIMONETTA, Philippe LECLERC, Jean-Francois DELFRAISSY, and Yassine TAOUFIK*
INSERM E-109, Faculty of Medicine, University Paris XI, Bicetre, France
Laboratory of Immunology, Bicetre Hospital, Bicetre, France
Confocal Microscopy Station, Bicetre Hospital, Bicetre, France
INSERM E-109, Faculty of Medicine, University Paris XI, Bicetre, France; Laboratory of Immunology, Bicetre Hospital, Bicetre, France
* Corresponding author; email: yassine.taoufik{at}kb.u-psud.fr.
Agonistic monoclonal antibodies to CD40 (CD40 mAbs) have a puzzling dual therapeutic effect in experimental animal models. CD40 mAbs induce tumor regression by potentiating anti-tumoral T cell responses, while 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, in a human system, we found that while anti-CD40 led immature DCs to mature and become immunogenic, it also reduced the capacity of LPS and 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 FADD and caspase 8 activation. On human cells, CD40 activation by such agonists could therefore, by inducing maturation, trigger immune responses to antigens presented by immature DCs, which are otherwise non immunogenic. 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.
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