Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40

• Published in: Blood 2005-10, Vol.106 (8), p.2806-2814
• Main Authors: de Goër de Herve, Marie-Ghislaine, Durali, Deniz, Tran, Tú-Anh, Maigné, Gwénola, Simonetta, Federico, Leclerc, Philippe, Delfraissy, Jean-François, Taoufik, Yassine
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Apoptosis - drug effects; Caspases - metabolism; CD40 Antigens - immunology; Cell Differentiation; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Enzyme Activation; Fas Ligand Protein; Humans; Membrane Glycoproteins - metabolism; T-Lymphocytes - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-12-4678

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 α (TNF-α)-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)