Peroxisome proliferator-activated receptor-? agonists prevent in vivo remodeling of human artery induced by alloreactive T cells.

ABSTRACT: Ligands activating the transcription factor peroxisome proliferator-activated receptor-? (PPAR?) 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? 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? in human transplantation are unknown.We tested the effects of PPAR? 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-?-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? 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? antagonist GW9662 reversed the protective effects of PPAR? agonists, confirming the involvement of PPAR?-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? effects.Our results suggest that PPAR? agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.

SUBMITTER: Tobiasova Z 

PROVIDER: S-EPMC3347886 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature