Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells

Background. Hemeoxygenase(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-alpha, infiltration of CD4(+), CD8(+), and T-reg (CD4(+)CD25(+)Foxp3(+)) cells into donor livers, and expression of Foxp3, TGF-beta, 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-alpha, 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-beta, and IL-10 than those of control rats, and the transplanted livers expressed higher levels of Foxp3 and TGF-beta. 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 T-reg cells. HO-1-based therapies, as described herein, promise new strategies to prevent the rejection of liver transplants. (C) 2011 Elsevier Inc. All rights reserved.