title: Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism.
abstract: The presence of valine (V) at position 158 of FcgammaRllla (CD16) is known to improve clinical response to rituximab in indolent non-Hodgkin lymphoma (NHL). Little is known about the basic mechanisms for this observation. We examined natural killer (NK) cells from healthy donors representing the FcgammaRIIIa-158 polymorphic subgroups (V/V, V/F, and F/F) for gene transcript and cell surface CD16 expression, rituximab binding, and rituximab-dependent NK cell-mediated cytotoxicity. We observed higher levels of FcgammaRIIIa transcripts among individuals with the FcgammaRIIIa-158 V/V versus V/F or F/F genotype (P < .001); increased cell surface CD16 expression by quantitative flow cytometry on NK cells from individuals expressing at least one valine at FcgammaRIIIa-158 versus F/F (P = .029); as well as augmented rituximab binding and rituximab-mediated, antibody-dependent cellular cytotoxicity (ADCC). These results suggest that individuals expressing at least one valine at FcgammaRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC.
authors.affiliation: Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Evdoxia
authors.initials: E
authors.lastname: Hatjiharissi
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Daniel Ditzel
authors.initials: DD
authors.lastname: Santos
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Ciccarelli
authors.forename: Sigitas
authors.initials: S
authors.lastname: Verselis
authors.forename: Michael
authors.initials: M
authors.lastname: Modica
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Manning
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Dimmock
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kortsaris
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fox
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism*; D000069283:Rituximab; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab