title: Platelets in early antibody-mediated rejection of renal transplants.
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.
authors.affiliation: Departments of Immunology and Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio.
authors.forename: Hsiao-Hsuan
authors.initials: HH
authors.lastname: Kuo
authors.affiliation: Departments of Immunology and.
authors.forename: Ran
authors.initials: R
authors.lastname: Fan
authors.affiliation: Departments of Immunology and.
authors.forename: Nina
authors.initials: N
authors.lastname: Dvorina
authors.affiliation: Pathology, Cleveland Clinic, Cleveland, Ohio; and.
authors.forename: Andres
authors.initials: A
authors.lastname: Chiesa-Vottero
authors.affiliation: Departments of Immunology and baldwiw@ccf.org.
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D006084:Graft Rejection / Q000276:immunology*; D007518:Isoantibodies / Q000502:physiology; D016030:Kidney Transplantation; D008297:Male; D016513:Mice, SCID; D015539:Platelet Activation
chemical_list: D007518:Isoantibodies
keywords: acute rejection; electron microscopy; endothelial cells; immunology and pathology; platelets; transplant pathology