- 作者：Liang Sun ; M.D.&lowast ; ; Tiefeng Shi ; M.D.&dagger ; ; Haiquan Qiao ; M.D. ; Ph.D.&lowast ; ; qiaohaiquan2008@yahoo.com.cn ; Xian Jiang ; M.D. ; Ph.D.&lowast ; ; Hongchi Jiang ; M.D. ; Ph.D.&lowast ; ; Geoffrey W. Krissansen ; Ph.D.&Dagger ; ; Xueying Sun ; M.D. ; Ph.D.&lowast ; ; &Dagger ; ; k.sun@auckland.ac.nz
- 关键词：heme oxygenase-1 ; liver transplantation ; immune rejection ; T regulatory cells ; adeno-associated virus
- 刊名：Journal of Surgical Research
- 出版年：2011
- 出版时间：April, 2011
- 年：2011
- 卷：166
- 期：1
- 页码：e187-e194
- 全文大小：1K
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-¦Á, infiltration of CD4+, CD8+, and Treg (CD4+CD25+Foxp3+) cells into donor livers, and expression of Foxp3, TGF-¦Â, 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-¦Á, inhibited infiltration of CD4+ and CD8+ cells, and increased infiltration of Treg cells, into donor livers. The spleens of recipients expressed higher levels of Foxp3, TGF-¦Â, and IL-10 than those of control rats, and the transplanted livers expressed higher levels of Foxp3 and TGF-¦Â. Splenocytes from the tolerant recipients had higher percentages of Treg 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 Treg cells. HO-1-based therapies, as described herein, promise new strategies to prevent the rejection of liver transplants.