title: Innate immune mechanisms in transplant allograft vasculopathy.
abstract: Allograft vasculopathy is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury and donor-specific antibody-induced complement activation confer heightened risk for allograft vasculopathy via numerous innate immune mechanisms, including MyD88, high-mobility group box 1 (HMGB1), and complement-induced noncanonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling.
  
  
  
  The role of MyD88, a signal adaptor downstream of the Toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced allograft vasculopathy. Importantly, triggering receptor on myeloid receptor 1, a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of allograft vasculopathy in mice. HMGB1, a nuclear protein that activates Toll-like receptors, also enhanced the development of allograft vasculopathy. Complement activation elicits assembly of membrane attack complexes on endothelial cells which activate noncanonical NF-κB signaling, a novel complement effector pathway that induces proinflammatory genes and potentiates endothelial cell-mediated alloimmune T-cell activation, processes which enhance allograft vasculopathy.
  
  
  
  Innate immune mediators, including HMGB1, MyD88, and noncanonical NF-κB signaling via complement activation contribute to allograft vasculopathy. These pathways represent potential therapeutic targets to reduce allograft vasculopathy after solid organ transplantation.
authors.affiliation: aDepartment of Cardiovascular Medicine bDepartment of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Jane-Wit
authors.forename: Caodi
authors.initials: C
authors.lastname: Fang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldstein
mesh_terms: D064591:Allografts / Q000637:transplantation*; D000818:Animals; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D016328:NF-kappa B; D051193:Toll-Like Receptors