Functional Attributes of Antibodies, Effector Cells, and Target Cells Affecting NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity
| Autor: | Gillian Dekkers, Sietse Q. Nagelkerke, James C. Zimring, Peter C. Ligthart, Louise A. de Neef, Manfred Wuhrer, Jana Koers, Christine W. Bruggeman, Erik L. de Graaf, Theo Rispens, Taco W. Kuijpers, Gestur Vidarsson, A. Robin Temming, Steven W. de Taeye |
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| Přispěvatelé: | Graduate School, AII - Infectious diseases, General Paediatrics, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, ARD - Amsterdam Reproduction and Development |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Erythrocytes
Glycosylation Immunology Cell chemical and pharmacologic phenomena Models Biological Immunophenotyping Cell membrane 03 medical and health sciences 0302 clinical medicine Antibody Specificity immune system diseases medicine Humans Immunology and Allergy Antigens Receptor skin and connective tissue diseases Fucosylation Antibody-dependent cell-mediated cytotoxicity biology Chemistry Effector Receptors IgG Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal hemic and immune systems In vitro Cell biology Killer Cells Natural medicine.anatomical_structure Immunoglobulin G biology.protein Antibody Biomarkers Protein Binding 030215 immunology |
| Zdroj: | Journal of Immunology, 203(12), 3126-3135 Journal of immunology (Baltimore, Md., 203(12), 3126-3135. American Association of Immunologists |
| ISSN: | 3126-3135 0022-1767 |
| Popis: | Ab-dependent cellular cytotoxicity (ADCC) is one of the most important effector mechanisms of tumor-targeting Abs in current immunotherapies. In ADCC and other Ab-dependent activation of myeloid effector cells, close cell–cell contact (between effector and target cell) and formation of immunological synapses are required. However, we still lack basic knowledge on the principal factors influencing ADCC potential by therapeutic Abs. In this study we investigated the combined roles of five factors affecting human NK cell–mediated ADCC, namely: 1) Ag density, 2) target cell membrane composition, 3) IgG FcγR polymorphism, 4) FcγR-blocking cytophilic Abs, and 5) Ab fucosylation. We demonstrate that the magnitude of NK cell–mediated ADCC responses is predominantly influenced by Ag density and Ab fucosylation. Afucosylation consistently induced efficient ADCC, even at very low Ag density, where fucosylated target Abs did not elicit ADCC. On the side of the effector cell, the FcγRIIIa–Val/Phe158 polymorphism influenced ADCC potency, with NK cells expressing the Val158 variant showing more potent ADCC. In addition, we identified the sialic acid content of the target cell membrane as an important inhibitory factor for ADCC. Furthermore, we found that the presence and glycosylation status of aspecific endogenous Abs bound to NK cell FcγRIIIa (cytophilic Abs) determine the blocking effect on ADCC. These five parameters affect the potency of Abs in vitro and should be further tested as predictors of in vivo capacity. |
| Databáze: | OpenAIRE |
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