T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase.
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-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.
Koh
Kian Peng
KP
Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Wang
Yinong
Y
Yi
Tai
T
Shiao
Stephen L
SL
Lorber
Marc I
MI
Sessa
William C
WC
Tellides
George
G
Pober
Jordan S
JS
D000818:Animals; D001158:Arteries / Q000276:immunology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology / Q000502:physiology*
D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse