ReviewsNatural Killer Cells: Critical Effectors During Antibody-mediated Rejection of Solid Organ AllograftsMiyairi, Satoshi MD, PhD1; Baldwin, William M. III MD, PhD1; Valujskikh, Anna PhD1; Fairchild, Robert L. PhD1Author Information 1 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. Received 8 October 2019. Revision received 9 March 2020. Accepted 30 March 2020. All of the authors participated in the organization and preparation of this review. The authors declare no funding or conflicts of interest. S.M. participated in organizing and writing the article. W.M.B. participated in organizing and writing the article. A.V. participated in organizing and writing the article. R.L.F. participated in organizing and writing the article. Correspondence: Robert L. Fairchild, PhD, Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, NB3-51, 9500 Euclid Ave, Cleveland, OH 44195. ([email protected]). Transplantation: February 2021 - Volume 105 - Issue 2 - p 284-290 doi: 10.1097/TP.0000000000003298 Buy Metrics Abstract Antibody-mediated rejection (AMR) is an important cause of graft loss and continues to present a formidable obstacle to successful transplantation. Unresolved problems continue to be the absence of effective strategies to ablate the donor-specific antibody (DSA) response as well as to attenuate the antibody-mediated graft tissue injury. While the properties of DSA that cause greater graft tissue injury and the characteristic microvascular pathology of the graft injury are well documented, the mechanisms underlying the injury mediated by the antibodies remains unclear. Recent transcriptome interrogation of kidney and heart biopsies procured during ongoing AMR has indicated the expression of genes associated with natural killer (NK) cell activation that is absent during T cell–mediated rejection. The expression of NK cell transcripts during AMR correlates with the presence of CD56+ cells in the microcirculation inflammation observed during AMR. Several mouse models have recently demonstrated the role of NK cells in antibody-mediated chronic vasculopathy in heart allografts and the requirement for NK cell activation during acute AMR of kidney allografts. In the latter model, NK cell activation within kidney allografts is regulated by the activation of myeloid cells producing myeloperoxidase. Overall, the studies to date indicate that AMR constitutes a complex series of DSA-induced interactions with components of the innate immune response. The innate immune participants and their expressed effector functions resulting in the rejection are beginning to be identified. The identification of these components should uncover novel targets that can be used to attenuate acute graft tissue injury in the presence of DSA. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.