title: Enhancement of Rituximab-induced cell death by the physical association of CD20 with CD40 molecules on the cell surface.
abstract: CD20 is an attractive therapeutic target given the success of its monoclonal antibody, Rituximab, in the treatment of B-cell malignancies and B-cell-mediated autoimmune diseases. Treatment with Rituximab causes a rapid depletion of B cells and a decrease in disease symptoms. Despite the clinical efficiency of Rituximab, its mechanism of action is not completely understood. In this study, we aimed at further investigating the Rituximab-induced cell death and the factors affecting such responses. Our results indicate that Rituximab-induced cell death depends on the nature of the cells and levels of CD20 expression on the cell surface. Coexpression of CD20 with CD40, a member of the TNF receptor family that is known to be physically associated with CD20 on the cell surface, enhances the apoptotic response induced by Rituximab. Inhibiting the formation of CD40 disulfide-bound-homodimers, a process required for some CD40 signaling, further enhances Rituximab-induced cell death. Cell death induced by anti-CD40 mAb is also upregulated by the presence of CD20, suggesting a bidirectional influence of the CD20/CD40 association. Moreover, treating cells with both anti-CD20 and anti-CD40 antibodies improves the cell death response induced by a single-agent treatment. These results highlight the role of the CD20/CD40 association in triggering B-cell depletion and may pave the way for an alternative more efficient therapeutic strategy in treating B-cell-mediated disorders.
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Loubna
authors.initials: L
authors.lastname: Al-Zoobi
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Salti
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Colavecchio
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Malek
authors.initials: M
authors.lastname: Jundi
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Nadiri
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.affiliation: Arthritis Centre, University of Manitoba Arthritis Centre, RR149-800 Sherbrooke Street, Winnipeg, Manitoba R3A 1M4, Canada.
authors.forename: Hani
authors.initials: H
authors.lastname: El-Gabalawy
authors.affiliation: Laboratoire d'immunologie cellulaire et moléculaire, Centre de Recherche-Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 0A9, Canada mw.mourad@umontreal.ca.
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000378:metabolism* / Q000494:pharmacology; D018951:Antigens, CD20 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D011961:Receptors, Fc / Q000378:metabolism; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D011961:Receptors, Fc; D000069283:Rituximab
keywords: CD20; CD40; Rituximab; association; cell death