PPAR-γ signaling and IL-5 inhibition together prevent chronic rejection of MHC Class IImismatched cardiac grafts

Abstract

Background: Chronic rejection can prevent long-term survival of organ transplants. Although the beneficial effects of peroxisome proliferator- activated receptor-gamma (PPAR-γ) in reducing graft rejection have been reported, the details of the underlying mechanisms remain unclear, especially in the context of modulating cellular infiltration and preventing vasculopathy and interstitial fibrosis. Methods: The therapeutic effects of the PPAR-γ agonist, rosiglitazone, combined with antiinterleukin-5 are explored in a mouse model of MHC Class IIhistoincompatible cardiac transplantation. Results: Rosiglitazone treatment alone marginally increased long-term survival and reduced CD8 T-cell infiltration and vasculopathy in the grafts. However, there was no reduction in collagen deposition and interleukin (IL)-4, IL-5 and eosinophil infiltration were increased. AntiIL-5 antibody treatment alone reduced eosinophil infiltration and collagen deposition, but had no effect on CD8 T-cell infiltration or vasculopathy. Combined treatment with antiIL-5 antibody and rosiglitazone prevented graft rejection. Furthermore, rosiglitazone treatment increased adiponectin receptor II expression in grafts and on dendritic cells and T cells in vitro. Graft survival correlated with increased expression in grafts of the inhibitory molecule PD-L1. Conclusions: The findings obtained increase the knowledge on the mode of action of rosiglitazone in promoting the survival of MHC Class IImismatched cardiac transplants in which the CD8 T cells and eosinophils play key roles. PPAR-γ signaling combined with IL-5 blockade prevents graft rejection. © 2011 International Society for Heart and Lung Transplantation. All rights reserved.