Title: T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase
Authors: Koh, Kian
Wang, YN
Yi, T
Shiao, SL
Lorber, MI
Sessa, WC
Tellides, G
Pober, JS # ×
Issue Date: 15-Sep-2004
Publisher: American Society for Clinical Investigation
Series Title: Journal of Clinical Investigation vol:114 issue:6 pages:846-856
Abstract: Allograft vascular dysfunction predisposes to arteriosclerosis and graft loss. We examined how dysfunction develops in transplanted human arteries in response to circulating allogeneic T cells in vivo using immuno-deficient murine hosts. Within 7-9 days, transplanted arteries developed endothelial cell (EC) dysfunction but remained sensitive to exogenous NO. By 2 weeks, the grafts developed impaired contractility and desensitization to NO, both signs of VSMC dysfunction. These T cell-dependent changes correlated with loss of eNOS and expression of iNOS - the latter predominantly within infiltrating T cells. Neutralizing IFN-gamma completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-gamma production and partially prevented dysfunction. Inhibiting iNOS partially preserved responses to NO at 2 weeks and reduced graft intimal expansion after 4 weeks in vivo. In vitro, memory CD4(+) T cells acted on allogeneic cultured ECs to reduce eNOS activity and expression of protein and mRNA. These effects required T cell activation by class II MHC antigens and costimulators (principally lymphocyte function-associated antigen-3, or LFA-3) on the ECs and were mediated by production of soluble mediators including IFN-gamma and TNF. We conclude that IFN-gamma is a central mediator of vascular dysfunction and, through dysregulation of NOS expression, links early dysfunction with late arteriosclerosis.
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Embryo and Stemcells (-)
× corresponding author
# (joint) last author

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