Perforin mediates endothelial cell death and resultant transplant vascular disease in cardiac allografts.
T cell-induced endothelial injury is an important event in the development of transplant vascular disease (TVD), the leading expression of chronic rejection of vascularized organ transplants. However, the precise contribution of perforin to vascular damage in allografts and resultant TVD has not been addressed in vivo. Minor histocompatability antigen mismatched mouse heterotopic cardiac transplants were performed from 129J donors into C57Bl/6 (wild-type (WT)) or perforin knockout (PKO) recipients. Perforin was abundant in immune infiltrates in the myocardium and vasculature of transplanted hearts in WT mice. Allograft coronary arteries in both WT and PKO mice had considerable vasculitis. There was also marked endothelial disruption, as well as TUNEL-positivity in the endothelial region, in coronary arteries of hearts transplanted into WT mice that was not evident in PKO recipients (P = 0.05). At 30 days post-transplantation, intimal thickening was assessed on elastic Van Gieson-stained ventricular sections. There was an average of 54.2 +/- 6.7% luminal narrowing of coronary arteries in allografts from WT mice as compared to 13.4 +/- 5.1% luminal narrowing in PKO counterparts (P < 0.00002). In summary, perforin plays a primary role in endothelial damage and the resultant onset and progression of TVD.
Choy
Jonathan C
JC
James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital/University of British Columbia, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Kerjner
Alexandra
A
Wong
Brian W
BW
McManus
Bruce M
BM
Granville
David J
DJ
D000818:Animals; D017209:Apoptosis; D001158:Arteries / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D006084:Graft Rejection / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology*; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000473:pathology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin