title: Intimate cell conjugate formation and exchange of membrane lipids precede apoptosis induction in target cells during antibody-dependent, granulocyte-mediated cytotoxicity.
abstract: Ab-dependent polymorphonuclear granulocyte (PMN)-mediated cytotoxicity may play an important role in the control of malignant diseases. However, little is known as to which particular pathways are used for the killing of malignant cells by PMN. The production of reactive oxygen intermediates (ROI) has been observed to occur during Ab-dependent, cell-mediated cytotoxicity (ADCC). However, PMN from a patient with chronic granulomatous disease demonstrated strong ADCC against malignant lymphoma cells. Furthermore, the inhibition of ROI production in PMN from healthy donors had no significant effect on ADCC. Therefore, ROI production by the NADPH oxidase of PMN does not appear to be mandatory for PMN-mediated ADCC. Recent data suggest a role for perforins in PMN-mediated cytotoxicity. However, in our assays concanamycin A, an inhibitor of perforin-mediated ADCC by mononuclear cells, had no inhibitory effect on PMN-mediated ADCC. Using electron microscopy we observed that PMN and their target cells intimately interact with the formation of interdigitating membrane protrusions. During PMN and target cell contact there was a mutual exchange of fluorescent membrane lipid dyes that was strongly increased in the presence of tumor-targeting Abs. This observation may be closely related to the recently described process of trogocytosis by lymphocytes. The presence of transient PMN-tumor cell aggregates and the accumulation of PMN with tumor cell-derived membrane lipids and vice versa were associated with effective ADCC as measured by chromium-release or apoptosis induction.
authors.affiliation: Institute for Clinical Immunology, Division of Hematology/Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Horner
authors.forename: Carola
authors.initials: C
authors.lastname: Frank
authors.forename: Claudia
authors.initials: C
authors.lastname: Dechant
authors.forename: Roland
authors.initials: R
authors.lastname: Repp
authors.forename: Martin
authors.initials: M
authors.lastname: Glennie
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Stockmeyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology*; D018941:Antigens, CD19 / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002449:Cell Aggregation / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D006681:HLA-D Antigens; D018942:Macrolides; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C036978:concanamycin A; C508053:ERBB2 protein, human