Hepatic overexpression of heme oxygenase-1 improves liver allograft survival by expanding T regulatory cells

J Surg Res. 2011 Apr;166(2):e187-94. doi: 10.1016/j.jss.2010.11.917. Epub 2010 Dec 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Forkhead Transcription Factors / genetics
  • Genetic Therapy / methods*
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Rejection / therapy
  • Graft Survival / immunology*
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase (Decyclizing) / immunology
  • Interleukin-10 / genetics
  • Liver / enzymology
  • Liver / immunology
  • Liver / surgery
  • Liver Transplantation*
  • Male
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Reperfusion Injury / immunology
  • Reperfusion Injury / prevention & control
  • Reperfusion Injury / therapy*
  • Spleen / physiology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / genetics
  • Transplantation Conditioning
  • Transplantation, Homologous

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, rat
  • Transforming Growth Factor beta
  • Interleukin-10
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat