title: Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-κB signaling in endothelial cells.
abstract: BACKGROUND
  Cardiac allograft vasculopathy is the major cause of late allograft loss after heart transplantation. Cardiac allograft vasculopathy lesions contain alloreactive T cells that secrete interferon-γ, a vasculopathic cytokine, and occur more frequently in patients with donor-specific antibody. Pathological interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored.
  
  
  RESULTS
  We used human panel reactive antibody to form membrane attack complexes on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, membrane attack complexes upregulated inflammatory genes, enhancing the capacity of endothelial cells to recruit and activate allogeneic interferon-γ--producing CD4(+) T cells in a manner dependent on the activation of noncanonical nuclear factor-κB signaling. Noncanonical nuclear factor-κB signaling was detected in situ within endothelial cells both in renal biopsies from transplantation patients with chronic antibody-mediated rejection and in panel-reactive antibody--treated human coronary artery xenografts in immunodeficient mice. On retransplantation into immunodeficient hosts engrafted with human T cells, panel-reactive antibody--treated grafts recruited more interferon-γ--producing T cells and enhanced cardiac allograft vasculopathy lesion formation.
  
  
  CONCLUSIONS
  Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-κB signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-κB signaling in endothelial cells, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of cardiac allograft vasculopathy.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine (D.J.-w.), Department of Immunobiology (T.D.M., N.C.K.-S., P.A., J.D., J.S.P.), Department of Surgery (T.Y., L.W., S.K., G.T.), Department of Neurology (P.C.), and Department of Pathology (G.M., J.S.P.), Yale School of Medicine, New Haven, CT.
authors.forename: Dan
authors.initials: D
authors.lastname: Jane-Wit
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Manes
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Pamela
authors.initials: P
authors.lastname: Clark
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Kirkiles-Smith
authors.forename: Parwiz
authors.initials: P
authors.lastname: Abrahimi
authors.forename: Julie
authors.initials: J
authors.lastname: Devalliere
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
mesh_terms: D064591:Allografts / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology*; D003331:Coronary Vessels / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D064593:Heterografts / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007518:Isoantibodies / Q000097:blood / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D007518:Isoantibodies; D016328:NF-kappa B; D003165:Complement System Proteins
keywords: arteriosclerosis; endothelium; transplantation
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