title: PPAR-γ signaling and IL-5 inhibition together prevent chronic rejection of MHC Class II-mismatched 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 anti-interleukin-5 are explored in a mouse model of MHC Class II-histoincompatible 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. Anti-IL-5 antibody treatment alone reduced eosinophil infiltration and collagen deposition, but had no effect on CD8 T-cell infiltration or vasculopathy. Combined treatment with anti-IL-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 II-mismatched cardiac transplants in which the CD8 T cells and eosinophils play key roles. PPAR-γ signaling combined with IL-5 blockade prevents graft rejection.
authors: Division of Pediatric Surgery, Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, SAR. ychenc@hku.hk
authors: Yan
authors: Y
authors: Chen
authors: Daxu
authors: D
authors: Li
authors: Julia Yuen Shan
authors: JY
authors: Tsang
authors: Na
authors: N
authors: Niu
authors: Jiao
authors: J
authors: Peng
authors: Jiang
authors: J
authors: Zhu
authors: Kenneth
authors: K
authors: Hui
authors: Aimin
authors: A
authors: Xu
authors: Vincent Chi Hang
authors: VC
authors: Lui
authors: Jonathan Robert
authors: JR
authors: Lamb
authors: Paul Kwong Hang
authors: PK
authors: Tam
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005802:Genes, MHC Class II; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D015848:Interleukin-5; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone