Immunological Rejection in a Heterotopic Rat Liver Transplant Model

Rat liver transplant (LT) studies typically utilize the technically demanding orthotopic transplant model, which is stressful for the recipient animal. Therefore, we developed a less technically challenging heterotopic LT model that reduces post-operative animal stress and used this model to characterize rejection in 2 genetically mismatched rat pairs.

Syngeneic transplants were performed with Lewis rats as liver donors and recipients. Allogeneic transplants utilized Dark Agouti donors and Lewis recipients or Lewis donors and Brown Norway recipients. The whole donor liver was transplanted in a heterotopic position in the left side of the abdominal cavity after a left nephrectomy. At pre-defined endpoints, liver grafts were excised and examined using the Banff rejection activity index (RAI).

In 9 sequential syngeneic transplants there were 2 technical errors that resulted in deaths. The Dark Agouti-Lewis cohort of 7 allogeneic transplants had 1 technical error resulting in death and 2 thrombosis-related graft failures. The Lewis-Brown Norway cohort of 10 transplants had 2 technical errors resulting in death and 3 thrombosis-related graft failures. All technical errors and thrombosis occurred early in each series. Syngeneic transplants demonstrated no rejection (mean RAI of 0). Allogeneic transplants demonstrated mild rejection by post-operative day 3 (mean RAI of 4.5) and severe rejection by post-operative day 8 (mean RAI of 9).

Heterotopic LT is a viable rejection model that minimizes surgical complexity and animal distress. Allogeneic heterotopic LT demonstrated severe rejection in a timeline similar to the commonly used orthotopic model.