Success of organ transplantation currently depends on life-time immunosuppression, resulting in severe side effects. Induction of donor specific tolerance is ideal, which actually spontaneously occurs following liver transplantation in many species. In mice liver transplantation, the liver allografts can be accepted across fully mismatched MHC without immunosuppression. Using inbred mice for liver transplantation, it is useful to investigate the mechanism of the tolerance induction. However, in humans, their genes are not identical. In this study, we have used outbred mice which have a genetic diversity for both the donors and the recipients to mimic a clinical situation. Also, the survival days and their immune responses were examined. The liver graft tissues and blood samples were collected from the recipients in the early phase of post transplantation and the time when they were weakened or over 60 days, which was identified as established tolerance induction. The tissues were used for the histological analysis. After liver transplantation, about 40% of the recipients died in 20 days. The histological findings of the liver allografts had a diffuse lymphocyte infiltration, and a typical diagnosis of the rejection was observed. The blood and non-parenchymal cells (NPC) from the liver grafts of the recipients from tolerance and rejection group were stained with anti-mouse CD4, CD8, CD11b, CD19 antibodies and examined by flow analysis. There was no significant difference of their population between both groups. Moreover, the data was also similar to the inbred tolerant model. However, the population of CD4⁺CD25⁺Foxp3⁺ cells in the long surviving liver grafts from outbred model were around 4% and they were much less than the inbred model which showed about 23%. It suggests that the T-reg cells might not be important to maintain the tolerance in the outbred model. We had a rejection model using outbred mice which is similar to the clinical situation. This model will facilitate in elucidating the mechanism of liver transplantation tolerance.

CITATION INFORMATION: Morita M, Miller C, Fung J, Lu L, Qian S. Liver Transplantation Tolerance Using Outbred Mice. Am J Transplant. 2017;17 (suppl 3).

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