title: Chronic allograft rejection: a fresh look.
abstract: OBJECTIVE
  New developments suggest that the graft itself and molecules expressed within the graft microenvironment dictate the phenotype and evolution of chronic rejection.
  
  
  RESULTS
  Once ischemia-reperfusion injury, cellular and humoral immune responses target the microvasculature, the associated local tissue hypoxia results in hypoxia-inducible factor 1α-dependent expression of pro-inflammatory and proangiogenic growth factors including vascular endothelial growth factor (VEGF) as a physiological response to injury. Local expression of VEGF can promote the recruitment of alloimune T cells into the graft. mTOR/Akt signaling within endothelial cells regulates cytokine- and alloantibody-induced activation and proliferation and their proinflammatory phenotype. Inhibition of mTOR and/or Akt results in an anti-inflammatory phenotype and enables the expression of coinhibitory molecules that limit local T cell reactivation and promotes immunoregulation. Semaphorin family molecules may bind to neuropilin-1 on regulatory T cell subsets to stabilize functional responses. Ligation of neuropilin-1 on Tregs also inhibits Akt-induced responses suggesting common theme for enhancing local immunoregulation and long-term graft survival.
  
  
  CONCLUSIONS
  Events within the graft initiated by mTOR/Akt-induced signaling promote the development of chronic rejection. Semaphorin-neuropilin biology represents a novel avenue for targeting this biology and warrants further investigation.
authors.affiliation: aTransplant Research Program, Pediatric Transplant Center bDepartment of Medicine, Division of Nephrology, Boston Children's Hospital cDepartment of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wedel
authors.forename: Sarah
authors.initials: S
authors.lastname: Bruneau
authors.forename: Nora
authors.initials: N
authors.lastname: Kochupurakkal
authors.forename: Leo
authors.initials: L
authors.lastname: Boneschansker
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
mesh_terms: D064591:Allografts; D000818:Animals; D002908:Chronic Disease; D006084:Graft Rejection; D006801:Humans; D016377:Organ Transplantation; D015398:Signal Transduction