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Alloantibody and Complement Promote T Cell-Mediated Cardiac Allograft Vasculopathy through Non-Canonical NF-κB Signaling in Endothelial Cells
- Publication Year :
- 2013
-
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. 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.
- Subjects :
- Endothelium
medicine.medical_treatment
T cell
Mice, SCID
Article
Mice
Isoantibodies
T-Lymphocyte Subsets
Physiology (medical)
medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
Secretion
Cells, Cultured
Heart transplantation
business.industry
NF-kappa B
Endothelial Cells
Arteriosclerosis
Complement System Proteins
medicine.disease
NFKB1
Allografts
Coronary Vessels
Transplantation
medicine.anatomical_structure
Immunology
Heterografts
Female
Signal transduction
Cardiology and Cardiovascular Medicine
business
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....e10a6bc245196abb010253537a971a23