title: Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection.
abstract: Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor-specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody-mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN-γ) versus the contact-dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune-deficient C57BL/6 rag-/-γc-/-recipients, who also received monoclonal anti-major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild-type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN-γ-deficient NK cells or host IFN-γ neutralization led to amelioration of these lesions. Use of either perforin-deficient NK cells or CD95 (Fas)-deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell-derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN-γ production and contact-dependent cytotoxic activity are rate-limiting effector pathways that contribute to this form of antibody-induced chronic allograft vasculopathy.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO. christine.lin@ucdenver.edu.
authors.forename: C M
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO.
authors.forename: R J
authors.initials: RJ
authors.lastname: Plenter
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO.
authors.forename: M
authors.initials: M
authors.lastname: Coulombe
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO.
authors.forename: R G
authors.initials: RG
authors.lastname: Gill
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054353:Perforin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D015395:Histocompatibility Antigens Class I; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma
keywords: animal models: murine; basic (laboratory) research/science; cytokines/cytokine receptors; immunobiology; natural killer (NK) cells/NK receptors; rejection: antibody-mediated (ABMR); rejection: chronic