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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02279

Natural Killer Cells Promote Kidney Graft Rejection Independently of Cyclosporine A Therapy

Muhammad I. Ashraf1,  Attia Sarwar2,  Anja A. Kühl3,  Elena Hunger2,  Arne Sattler2,  Felix Aigner1, Heinz Regele4, Martina Sauter5, Karin Klingel5,  Stefan Schneeberger6,  Thomas Resch7 and  Katja Kotsch2*
  • 1Department of Surgery, Charité University Medicine Berlin, Germany
  • 2Department of General, Visceral and Vascular Surgery, Charité Medical University of Berlin, Germany
  • 3Core Unit Immunopathology for Experimental Models (iPATH), Germany
  • 4Clinical Institute for Pathology, Medical University of Vienna, Austria
  • 5Tübingen University Hospital, Germany
  • 6Department of Surgery, Innsbruck Medical University, Austria
  • 7Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Austria

Natural Killer (NK) cells have recently been recognized as key players in antibody-mediated chronic allograft failure, thus requiring a comprehensive understanding whether NK cells can escape conventional immunosuppressive regimens. Influence of cyclosporine A (CyA) on NK cell function was studied in a mouse model of allogeneic kidney transplantation (KTX, BALB/c to C57BL/6). Recipients were treated daily with CyA (10 mg/kg) for seven or 14 days for long term survival (day 56). Administration of CyA in recipients resulted in significantly reduced frequencies of intragraft CD4+ and CD8+ T cells, illustrating reduced IFNγ production. In contrast, NK cell frequencies remained unaffected in CyA recipients and IFNg production and degranulation of NK cells were not reduced as compared with controls. Depletion of NK cells in combination with CyA resulted in a further improvement in kidney function until day 7 and prolonged graft survival until day 56 as compared to untreated controls. Surviving animals demonstrated higher intragraft frequencies of proliferating CD4+FoxP3+Ki67+ regulatory T (TREG) cells as well as higher frequencies of CD8+CD122+ TREG. We here demonstrate that NK cell depletion combined with CyA synergistically improves graft function and prolongs graft survival, suggesting that NK cell targeting constitutes a novel approach for improving KTX outcomes.

Keywords: Kidney Transplantation, Natural Killer cells, Cyclosporine A, Graft Rejection, Immunosuppression

Received: 04 Jun 2019; Accepted: 09 Sep 2019.

Copyright: © 2019 Ashraf, Sarwar, Kühl, Hunger, Sattler, Aigner, Regele, Sauter, Klingel, Schneeberger, Resch and Kotsch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Katja Kotsch, Department of General, Visceral and Vascular Surgery, Charité Medical University of Berlin, Berlin, Baden-Württemberg, Germany, katja.kotsch@charite.de