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

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.)This work was supported by a pilot grant from Pfizer to Dr Kawikova, RO1 HL088258 to Dr Bothwell, and PO1-HL070295 to Drs Pober, Tellides, and Bothwell, as well as by Takeda Pharmaceuticals North America, Inc., to Drs Bothwell and Kawikova. Dr Tobiasova was partially supported by MSM 00211620812 by the Czech Ministry of Education. Dr Choi was partially supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0012859)