Alloantibody and Complement Promote T Cell-Mediated Cardiac Allograft Vasculopathy Through Noncanonical Nuclear Factor-[kappa]B Signaling in Endothelial Cells.
Jane-wit, Dan MD, PhD; Manes, Thomas D. PhD; Yi, Tai MD; Qin, Lingfeng MD, PhD; Clark, Pamela BS; Kirkiles-Smith, Nancy C. PhD; Abrahimi, Parwiz BA; Devalliere, Julie PhD; Moeckel, Gilbert MD; Kulkarni, Sanjay MD; Tellides, George MD, PhD; Pober, Jordan S. MD, PhD
128(23):2504-2516, December 3/10, 2013.
(Format: HTML, PDF)
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-[gamma], 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.
Methods and 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-[gamma]--producing CD4 T cells in a manner dependent on the activation of noncanonical nuclear factor-[kappa]B signaling. Noncanonical nuclear factor-[kappa]B 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-[gamma]--producing T cells and enhanced cardiac allograft vasculopathy lesion formation.
Conclusions-: Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-[kappa]B signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-[kappa]B 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.
(C) 2013 by the American College of Cardiology Foundation and the American Heart Association, Inc.