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. 2025 Oct;57(8):1668-1673.
doi: 10.1016/j.transproceed.2025.06.024. Epub 2025 Sep 17.

Immunological Rejection in a Heterotopic Rat Liver Transplant Model

Camryn Thompson  1 , Bret Verhoven  2 , Min Zhang  1 , Weifeng Zeng  2 , Isaac Alderete  1 , Ahmed Hassan  1 , Peter Chlebeck  2 , Kristina Matkowskyj  3 , Heather Jennings  2 , Andrew S Barbas  1 , David Al-Adra  4
Affiliations

Immunological Rejection in a Heterotopic Rat Liver Transplant Model

Camryn Thompson et al. Transplant Proc. 2025 Oct.

Abstract

Background: 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.

Methods: 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).

Results: 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).

Conclusion: 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.

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Conflict of interest statement

Declaration of competing interest David Al-Adra reports financial support was provided by National Institutes of Health National Institute of Allergy and Infectious Diseases. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This research was supported by the National Institute of Health (NIH)K08AI155816 awarded to DA.

Figures

Fig. 1.
Fig. 1.
Histology of livers from experimental end-points. Representative histology of Lewis-to-Lewis liver grafts excised at post-operative day 8 (A) and 30 (D), Lewis-to-Brown Norway grafts excised at post-operative day 3 (B) and 8 (E), and Dark Agouti-to-Lewis grafts excised at post-operative day 3 (C) and 8 (F). Abbreviations: Syn; syngeneic. DA, Dark Agouti; BN, Brown Norway.
See this image and copyright information in PMC

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