title: Granzyme B induces endothelial cell apoptosis and contributes to the development of transplant vascular disease.
abstract: Endothelial cell death induced by cytotoxic T cells is a key initiating event in the development of transplant vascular disease (TVD), the leading cause of late solid organ transplant failure. We studied the role of the granzyme B (GrB) pathwaye, which is one of the main mechanisms by which T cells induce apoptosis of allogeneic targets, in the pathogenesis of TVD. Granzyme B, in combination with perforin (pfn), induced apoptosis of cultured endothelial cells. In hearts transplanted into GrB knockout (GrB-KO) mice, there was a similar level of vasculitis as compared to WT mice, indicating that GrB does not affect immune infiltration into allograft arteries. However, there was a significant reduction in luminal narrowing of allograft arteries from GrB-KO mice as compared to WT recipients. These results indicate that GrB plays a role in endothelial cell death in allograft arteries and in the resultant development of TVD.
authors.affiliation: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Choy
authors.forename: Rani P
authors.initials: RP
authors.lastname: Cruz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kerjner
authors.forename: Jennette
authors.initials: J
authors.lastname: Geisbrecht
authors.forename: Tracy
authors.initials: T
authors.lastname: Sawchuk
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Fraser
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hudig
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001158:Arteries / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology*; D053804:Granzymes; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases