title: Targeting the intragraft microenvironment and the development of chronic allograft rejection.
abstract: In this review, we discuss a paradigm whereby changes in the intragraft microenvironment promote or sustain the development of chronic allograft rejection. A key feature of this model involves the microvasculature including (a) endothelial cell (EC) destruction, and (b) EC proliferation, both of which result from alloimmune leukocyte- and/or alloantibody-induced responses. These changes in the microvasculature likely create abnormal blood flow patterns and thus promote local tissue hypoxia. Another feature of the chronic rejection microenvironment involves the overexpression of vascular endothelial growth factor (VEGF). VEGF stimulates EC activation and proliferation and it has potential to sustain inflammation via direct interactions with leukocytes. In this manner, VEGF may promote ongoing tissue injury. Finally, we review how these events can be targeted therapeutically using mTOR inhibitors. EC activation and proliferation as well as VEGF-VEGFR interactions require PI-3K/Akt/mTOR intracellular signaling. Thus, agents that inhibit this signaling pathway within the graft may also target the progression of chronic rejection and thus promote long-term graft survival.
authors.affiliation: The Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
authors.forename: Marc
authors.initials: M
authors.lastname: Dufour
authors.forename: Tatsuichiro
authors.initials: T
authors.lastname: Seto
authors.forename: Sarah
authors.initials: S
authors.lastname: Bruneau
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014184:Transplantation, Homologous; D019737:Transplants; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases