title: Hepatic overexpression of heme oxygenase-1 improves liver allograft survival by expanding T regulatory cells.
abstract: BACKGROUND
  Heme oxygenase (HO)-1 protects transplanted organs from ischemia reperfusion injury and immune rejection. This study sought to investigate whether persistent overexpression of HO-1 in donor livers could improve the survival by expanding T regulatory cells in a rat model of orthotopic liver transplantation.
  
  
  METHODS
  Livers of Dark Agouti rats were intraportally perfused with an AAV expression vector encoding rat HO-1 (AAV-HO-1), and then transplanted into Lewis rats. The survival, HO-1 activity, Banff rejection activity index, serum levels of IL-2 and TNF-α, infiltration of CD4(+), CD8(+), and T(reg) (CD4(+)CD25(+)Foxp3(+)) cells into donor livers, and expression of Foxp3, TGF-β, and IL-10 were examined. A mixed lymphocyte reaction (MLR) was performed.
  
  
  RESULTS
  Intraportal delivery of AAV-HO-1 resulted in persistent expression of HO-1 and increased activity of HO-1 in transplanted livers, leading to prolonged survival of recipients. Overexpression of HO-1 reduced the Banff rejection activity index, and production of IL-2 and TNF-α, inhibited infiltration of CD4(+) and CD8(+) cells, and increased infiltration of T(reg) cells, into donor livers. The spleens of recipients expressed higher levels of Foxp3, TGF-β, and IL-10 than those of control rats, and the transplanted livers expressed higher levels of Foxp3 and TGF-β. Splenocytes from the tolerant recipients had higher percentages of T(reg) cells, and responded poorly to the allogeneic donor splenocytes.
  
  
  CONCLUSIONS
  Persistent expression of HO-1 in donor livers by intraportal delivery of AAV-HO-1 improves the survival by expanding T(reg) cells. HO-1-based therapies, as described herein, promise new strategies to prevent the rejection of liver transplants.
authors.affiliation: Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Tiefeng
authors.initials: T
authors.lastname: Shi
authors.forename: Haiquan
authors.initials: H
authors.lastname: Qiao
authors.forename: Xian
authors.initials: X
authors.lastname: Jiang
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D006085:Graft Survival / Q000276:immunology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D013154:Spleen / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat