Blockade Of Costimulation With CTLA4-Ig Prevents Liver Transplant Rejection In Rats And Clinical Application Of Living Donor Liver Transplantation

Part 1: Partial orthotopic liver transplantation in rats Objective A shortage of donor liver is one of the major obstacle for liver transplantation. To resolve this problem, living donor partial liver transplantation will undoubtedly be a promising option. Our purpose of this study was to develop a rat model of partial orthotopic liver transplantation, and, to evaluate the graft function and regeneration in this model.Methods The partial orthotopic liver transplantation (POLT) was performed using the 2-cuff technique. Three experimental groups were set up: I - control, partial liver resection; II = orthotopic liver transplantation; III = partial orthotopic liver transplantation. Liver function test, morphological investigations and liver regeneration were studied in different time point after transplantation. The regenerative response of transplanted partial liver graft in rats were evaluated by Flow Cytometry and compared it to liver regeneration following resection.Results (1) There was no significant difference in the survival time between POLT and orthotopic liver transplantation (OLT). (2) The Serum concentrations of ALT, AST, TB, DB increased in first week, but returned gradually to normal level within one month after transplantation. (3) A large numbers of mononuclear cells infiltrating into the portal areas. Hepatocellular necrosis was observed on day 7-14 after transplantation. On day 30, the parenchyma cell showed a nearly normal appearance, bile duct proliferation was seen in portal areas. In addition to these finding, a few diploid hepatocytes were found after liver resection and POLT. Dilation of the central veins,adjoining sinusoids and interlobar veins was seen in all animals. On day 30, liver allografts showed virtually normal organization and structure. (4) The liver graft is capable of regeneration similar to the situation following partial hepatectomy. The peak of liver regeneration was seen on day 1,2,4 following a hepatectomy and POLT and OLT, respectively.Conclusion The partial liver transplantation technique in rats, which is comparable with the LDLT in adult humans, provides a ideal model for studies of preservation, liver regeneration, immunology, and rejection following transplantation. The transplant liver showed same and/or enhanced regeneration compared to controls. It is likely that this is caused by activation of the immune system and it might be related to regulation of cytokines and hormone. There are several possible explanations for the slight delay in achieving the maximal regenerative response in rats undergoing the POLT and OLT. These might be related to the damage induced by the operation itself, preservation, and reperfusion injuries. The long lasting time of regeneration might be relevant to the cytokines generated by the immune system in recipients and regulation of hormone.