title: Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy.
abstract: Cardiac allograft vasculopathy is the major cause of late graft loss in heart transplant recipients. Histological studies of characteristic end-stage lesions reveal arterial changes consisting of a diffuse, confluent, and concentric intimal expansion containing graft-derived cells expressing smooth muscle markers, extracellular matrix, penetrating microvessels, and a host mononuclear cell infiltrate concentrated subjacent to an intact graft-derived luminal endothelial cell lining with little evidence of acute injury. This intimal expansion combined with inadequate compensatory outward remodeling produces severe generalized stenosis extending throughout the epicardial and intramyocardial arterial tree that causes ischemic graft failure. Cardiac allograft vasculopathy lesions affect ≥50% of transplant recipients and are both progressive and refractory to treatment, resulting in ≈5% graft loss per year through the first 10 years after transplant. Lesions typically stop at the suture line, implicating alloimmunity as the primary driver, but pathogenesis may be multifactorial. Here, we will discuss 6 potential contributors to lesion formation (1) conventional risk factors of atherosclerosis; (2) pre- or peritransplant injuries; (3) infection; (4) innate immunity; (5) T-cell-mediated immunity; and (6) B-cell-mediated immunity through production of donor-specific antibody. Finally, we will consider how these various mechanisms may interact with each other.
authors.affiliation: From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT. jordan.pober@yale.edu.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.affiliation: From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT.
authors.forename: Dan
authors.initials: D
authors.lastname: Jane-wit
authors.affiliation: From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: From the Departments of Immunobiology (J.S.P.), Internal Medicine (D.J.-w.), and Surgery (L.Q. and G.T.), Yale University School of Medicine, New Haven, CT.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D064591:Allografts; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003141:Communicable Diseases / Q000276:immunology / Q000473:pathology; D003324:Coronary Artery Disease / Q000097:blood / Q000276:immunology / Q000473:pathology*; D003331:Coronary Vessels / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007113:Immunity, Innate; D007518:Isoantibodies / Q000097:blood; D012307:Risk Factors; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D007518:Isoantibodies
keywords: T-lymphocytes; transplantation