Peroxisome Proliferator-Activated Receptor-gamma Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells

Article

关键词: INTIMA-MEDIA THICKNESS;    EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS;    TYPE-2 DIABETES-MELLITUS;    SMOOTH-MUSCLE-CELLS;    INTERFERON-GAMMA;    TRANSPLANT ARTERIOSCLEROSIS;    TRANSENDOTHELIAL MIGRATION;    ENDOTHELIAL-CELLS;    PPAR-GAMMA;    INDEPENDENT MECHANISMS;   

DOI  :  10.1161/CIRCULATIONAHA.110.015396

来源: SCIE

【 摘 要 】

Background-Ligands activating the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR gamma) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPAR gamma agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPAR gamma in human transplantation are unknown. Methods and Results-We tested the effects of PPAR gamma 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-gamma -dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPAR gamma 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 PPAR gamma antagonist GW9662 reversed the protective effects of PPAR gamma agonists, confirming the involvement of PPAR gamma -mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPAR gamma effects. Conclusion-Our results suggest that PPAR gamma agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection. (Circulation. 2011;124:196-205.)

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