title: Peroxisome proliferator-activated receptor-γ agonists prevent in vivo remodeling of human artery induced by alloreactive T cells.
abstract: BACKGROUND
  Ligands activating the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown.
  
  
  RESULTS
  We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ-dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J(2), ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO(+) memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects.
  
  
  CONCLUSIONS
  Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tobiasova
authors.forename: Lufeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Linfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Manes
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Marc I
authors.initials: MI
authors.lastname: Lorber
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Rodriguez
authors.forename: Je-Min
authors.initials: JM
authors.lastname: Choi
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Ivana
authors.initials: I
authors.lastname: Kawikova
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
mesh_terms: D019264:Adoptive Transfer; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000276:immunology; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018089:Superantigens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D045162:Thiazolidinediones / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: C477819:15-deoxyprostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D007004:Hypoglycemic Agents; D007519:Isoantigens; D047495:PPAR gamma; D018089:Superantigens; D045162:Thiazolidinediones; D015230:Prostaglandin D2; C039671:ciglitazone; D000077205:Pioglitazone