Alloantibody and complement promote T cell–mediated cardiac allograft vasculopathy through noncanonical nuclear factor-κB signaling in endothelial cells
Open accessAbstract
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.
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MAC recruits and activates leukocytes by coordinating inflammasome activation and endothelial cytokine signalling.
“It has also been shown that MAC recruits and activates leukocytes by coordinating inflammasome activation and endothelial cytokine signalling [196,197,198,199,200]”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [196]
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- Authors
- Jane-wit, D., Manes, T. D., Yi, T., Qin, L., Clark, P., Kirkiles-Smith, N. C., Abrahimi, P., Devalliere, J., Moeckel, G., Kulkarni, S., Tellides, G., & Pober, J. S.
- Affiliations
- From the 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.
- Yale University (US)
- Venue
- Circulation
- Published
- 2013-12
- Volume
- 128
- Issue
- 23
- Pages
- 2504-2516
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3885874
- OpenAlex
- W2132809216
- Cited by
- 144
- References
- 36
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 6 · 2023: 11 · 2022: 8 · 2021: 14 · 2020: 11 · 2019: 17 · 2018: 10 · 2017: 14 · 2016: 10 · 2015: 14 · 2014: 8
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL109455, R01HL109455, R01HL051014, T32HL007974)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Allergy and Infectious Diseases (T32AI089704)
- Topics
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Keywords
- cardiac allograft vasculopathy, alloantibodies, complement system, non-canonical NF-κB signaling, endothelial cells, interferon-gamma, CD4+ T cells, donor-specific antibodies, antibody-mediated rejection, heart transplantation, membrane attack complex, chronic rejection
- MeSH terms
- Animals, Cells, Cultured, Complement System Proteins, Coronary Vessels, Female, Humans, Isoantibodies, Signal Transduction, T-Lymphocyte Subsets, NF-kappa B, Mice, SCID, Endothelial Cells, Mice, Human Umbilical Vein Endothelial Cells, Allografts, Heterografts
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