title: T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase.
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-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.
authors.affiliation: Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Kian Peng
authors.initials: KP
authors.lastname: Koh
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Shiao
authors.forename: Marc I
authors.initials: MI
authors.lastname: Lorber
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
mesh_terms: 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*
chemical_list: D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse