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* Institute for Clinical Immunology, Division of Hematology/Oncology and
Institute for Clinical Immunology, Division of Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany;
University Hospital, Section for Stem Cell and Immune Therapy, Campus Kiel, University of Schleswig-Holstein, Kiel, Germany; and
Tenovus Research Laboratory, Southampton General Hospital, Southampton, United Kingdom
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.
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1 This work was supported by the Wilhelm Sander-Stiftung (Grant 2000.032.2), the Interdisciplinary Center for Clinical Research (Projects A3 and A4), the ELAN-Fond (06.05.24.1) at the University Hospital of the University of Erlangen-Nuremberg, Deutsche Forschungsgemeinschaft Sonderforschungsbereich 643 (project B5), and the Lupus Erythematodes Selbsthilfegemeinschaft, eingetragener Verein.
2 M.H. and B.S. contributed equally to the senior authorship.
3 Address correspondence to Dr. Martin Herrmann, Institute for Clinical Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: Martin.Herrmann{at}med3.imed.uni-erlangen.de
4 Abbreviations used in this paper: ADCC, Ab-dependent cell-mediated cytotoxicity; bsAb, bispecific Ab; CGD, chronic granulomatous disease; CMA, concanamycin A; DiI, 2-[3-(1,3-dihydro-3,3-dimethyl-1-octadecyl-2H-indol-2-ylidene)-1-propenyl]-3,3- dimethyl-1-octadecyl-perchlorate; DiO, 3-octadecyl-2-[3-(3-octadecyl-2(3H)-benzoxazolylidine)-1-propenyl]-perchlorate; DPI, diphenyleneiodonium chloride; FSC, forward scatter; hIgG1, humanized IgG1; mIgG1, mouse IgG1; MNC, mononuclear cell; NHD, normal healthy donor; PI, propidium iodide; PMN, polymorphonuclear granulocyte; RajiH, HER-2/neu transfected Raji cell; ROI, reactive oxygen intermediate; SSC, side scatter; z-VAD-fmk, benzyloxycarbonlyl-Val-Ala-DL-Asp-fluoromethylketone.
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