Activation of natural killer cells by rituximab in granulomatosis with polyangiitis
Abstract Objective In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA. Methods B cell depletion,...
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-019-2054-0 |
| _version_ | 1819058603113316352 |
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| author | Doris Urlaub Shuyang Zhao Norbert Blank Raoul Bergner Maren Claus Theresa Tretter Hanns-Martin Lorenz Carsten Watzl Wolfgang Merkt |
| author_facet | Doris Urlaub Shuyang Zhao Norbert Blank Raoul Bergner Maren Claus Theresa Tretter Hanns-Martin Lorenz Carsten Watzl Wolfgang Merkt |
| author_sort | Doris Urlaub |
| collection | DOAJ |
| description | Abstract Objective In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA. Methods B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. Results NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. Conclusion B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies. |
| first_indexed | 2024-12-21T13:57:49Z |
| format | Article |
| id | doaj.art-cecf829c83b049bcb9ae221678273532 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-21T13:57:49Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-cecf829c83b049bcb9ae2216782735322022-12-21T19:01:29ZengBMCArthritis Research & Therapy1478-63622019-12-0121111110.1186/s13075-019-2054-0Activation of natural killer cells by rituximab in granulomatosis with polyangiitisDoris Urlaub0Shuyang Zhao1Norbert Blank2Raoul Bergner3Maren Claus4Theresa Tretter5Hanns-Martin Lorenz6Carsten Watzl7Wolfgang Merkt8Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo)Department of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of HeidelbergDepartment of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of HeidelbergDepartment of Rheumatology, Nephrology, Oncology, Klinikum LudwigshafenLeibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo)Department of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of HeidelbergDepartment of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of HeidelbergLeibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo)Department of Hematology, Oncology and Rheumatology, Internal Medicine V, University Hospital of HeidelbergAbstract Objective In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA. Methods B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. Results NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. Conclusion B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.https://doi.org/10.1186/s13075-019-2054-0Natural killer cellsRituximabB cell depletionRheumatic diseasesANCA-associated vasculitisGranulomatosis with polyangiitis |
| spellingShingle | Doris Urlaub Shuyang Zhao Norbert Blank Raoul Bergner Maren Claus Theresa Tretter Hanns-Martin Lorenz Carsten Watzl Wolfgang Merkt Activation of natural killer cells by rituximab in granulomatosis with polyangiitis Arthritis Research & Therapy Natural killer cells Rituximab B cell depletion Rheumatic diseases ANCA-associated vasculitis Granulomatosis with polyangiitis |
| title | Activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| title_full | Activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| title_fullStr | Activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| title_full_unstemmed | Activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| title_short | Activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| title_sort | activation of natural killer cells by rituximab in granulomatosis with polyangiitis |
| topic | Natural killer cells Rituximab B cell depletion Rheumatic diseases ANCA-associated vasculitis Granulomatosis with polyangiitis |
| url | https://doi.org/10.1186/s13075-019-2054-0 |
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