Key result
Alloantibody and complement deposition drives cardiac allograft vasculopathy via noncanonical NF-κB signaling.
Why the study?
Pathological interactions between cellular and humoral immunity in cardiac allograft vasculopathy remain largely unexplored.
Does alloantibody and complement deposition promote T cell-mediated cardiac allograft vasculopathy through noncanonical NF-κB signaling in endothelial cells?
Does alloantibody and complement deposition promote T cell-mediated cardiac allograft vasculopathy through noncanonical NF-κB signaling in endothelial cells?
Alloantibody and complement deposition on graft endothelial cells activates noncanonical NF-κB signaling, promoting T cell-mediated cardiac allograft vasculopathy, suggesting a novel therapeutic target.
Supports mechanistic synergy between DSA and alloreactive T cells in CAV; hypothesis-generating for NF-κB–targeted interventions, should not yet change practice.
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. 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-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.
No takes yet. Share an insight, caveat, or question.
Jane‐wit et al. (2013) studied Cardiac allograft vasculopathy. Alloantibody and complement (panel reactive antibody) was evaluated on Noncanonical nuclear factor-κB signaling activation and T cell recruitment. Alloantibody and complement deposition on graft endothelial cells activates noncanonical NF-κB signaling, enhancing alloreactive T cell activation and cardiac allograft vasculopathy development.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: