RESUMEN
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. METHODS AND 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. CONCLUSION: Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.
Asunto(s)
Arterias/inmunología , Arterias/trasplante , Rechazo de Injerto/inmunología , Hipoglucemiantes/farmacología , PPAR gamma/agonistas , Prostaglandina D2/análogos & derivados , Linfocitos T/inmunología , Tiazolidinedionas/farmacología , Traslado Adoptivo , Anilidas/farmacología , Animales , Arterias/patología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Proliferación Celular/efectos de los fármacos , Citocinas/inmunología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/patología , Humanos , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/inmunología , Isoantígenos/inmunología , Ratones , Ratones SCID , PPAR gamma/antagonistas & inhibidores , PPAR gamma/inmunología , Pioglitazona , Prostaglandina D2/farmacología , Superantígenos/farmacología , Linfocitos T/patología , Linfocitos T/trasplante , Trasplante Heterólogo , Trasplante HomólogoRESUMEN
T helper 2 (Th2) cytokines are known to be important in protection against experimental autoimmune encephalomyelitis (EAE). To investigate the role of the signal transducer and activator of transcription factor 6 (STAT6) in EAE we used mice with two different targeted disruptions of the STAT6 gene. In this report, we show that mice with a targeted deletion of the first coding exon of the SH2 domain of STAT6 induce Th2 cell differentiation and are resistant to EAE induction. By contrast, STAT6(-/-) mice generated by deletion of amino acids 505 to 584 encoding the SH2 domain of STAT6 are defective in Th2 cell differentiation and develop very severe EAE. These results suggest that an altered STAT6 gene can be more efficient than wild type STAT6 in regulating the autoimmune response in EAE.