Basic ResearchPlatelets in Early Antibody-Mediated Rejection of Renal TransplantsKuo, Hsiao-Hsuan*,†; Fan, Ran*; Dvorina, Nina*; Chiesa-Vottero, Andres‡; Baldwin, William M. III* Author Information Departments of *Immunology and ‡Pathology, Cleveland Clinic, Cleveland, Ohio; and †Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio Correspondence: Dr. William M. Baldwin III, Lerner Research Institute NB30, 9500 Euclid Avenue, Cleveland, OH 44195. Email: [email protected] Received December 10, 2013 Accepted June 22, 2014 Journal of the American Society of Nephrology 26(4):p 855-863, April 2015. | DOI: 10.1681/ASN.2013121289 Buy Metrics Abstract Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.