Long-term immunosuppression of rabbits through oral tacrolimus administration.

Abstract

Background: The absence of well-established immunosuppressed rabbit models poses a significant hurdle in xenograft experiments. Tacrolimus has been identified as a highly promising immunosuppressive agent for rabbits. However, determining the optimal dosage and route of administration to minimize toxicity while maintaining efficacy remains challenging.

Methods: In this study, we investigated the effect of orally administered tacrolimus in rabbits, with an aim to achieve a whole blood target trough level of 3-10 ng/mL, and looked at signs of tissue rejection after the transplantation of a human nerve conduit to repair a severed fibular nerve. An oral dosage range of 0.25-1.5 mg/kg/d was studied for up to 1 year in 63 New Zealand rabbits.

Results: We demonstrated the feasibility of long-term grafting in rabbits while maintaining safe immunosuppression, with side effects mainly limited to diarrhea. Customizing the administered dose proved crucial for graft efficacy and low toxicity, which translated into 100% individual survival. We suggest an oral tacrolimus dose of 1.0-1.5 mg/kg depending on individual heterogeneity and recommend to implement a close therapeutic drug monitoring in the rabbits to maintain a whole blood tacrolimus trough level within the range of 5-12 ng/mL, as levels below 5 ng/mL showed signs of inflammation in the graft.

Conclusion: The oral administration of tacrolimus enabled efficient immunosuppression of rabbits over a 1-year period without significant side effects or loss of animals.