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- Title
T cell-mediated vascular dysfunction of human allografts results from IFN-γ dysregulation of NO synthase.
- Authors
Koh, Kian Peng; Wang, Yinong; Yi, Tai; Shiao, Stephen L.; Lorber, Marc I.; Sessa, William C.; Tellides, George; Pober, Jordan S.
- 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 immunodeficient 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-y completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-y 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-γ and TNF. We conclude that IFN-γ is a central mediator of vascular dysfunction and, through dysregulation of NOS expression, links early dysfunction with late arteriosclerosis.
- Subjects
HOMOGRAFTS; ARTERIOSCLEROSIS; T cell differentiation; NITRIC oxide; MEDICAL experimentation on humans; ENDOTHELIUM
- Publication
Journal of Clinical Investigation, 2004, Vol 114, Issue 6, p846
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI200421767