Enhancement of allograft acceptance by combined dexmedetomidine and rapamycin

BACKGROUND: Dexmedetomidine, an α2-adrenoceptor agonist, is known for its sedative effects and unique pharmacological mechanism. Research increasingly emphasizes its potential to modulate immune responses. Further investigation is needed to fully understand how dexmedetomidine influences T cell differentiation and its potential synergy with tolerance-promoting agents. This study aims to explore a new approach to enhance allograft acceptance by combining dexmedetomidine with the mTOR inhibitor rapamycin.

METHODS: The effects of both drugs on T cell proliferation, regulatory T cell preservation, and allograft survival were examined through both in vitro and in vivo animal experiments, including a fully MHC-mismatched mouse skin transplantation model. The study also evaluated the effect of combined drugs on immune memory via retransplantation surgery.

RESULTS: Our data demonstrate that combining dexmedetomidine with rapamycin effectively inhibits T cell proliferation. This combination also increases the frequency of regulatory T cells, thereby preserving immune regulation. Furthermore, dual therapy significantly extends the median survival time (MST) of the skin compared to dexmedetomidine, or rapamycin alone or no treatment (20 vs. 12 days, p < 0.001; 20 vs. 16 days, p < 0.05; 20 vs. 7 days, p < 0.0001). Similarly, mice treated with the combination therapy have notably prolonged MST of the second allogenic graft, compared to no treatment (11 days versus 7.5 days, p < 0.001).

CONCLUSION: Our findings highlight the potential of combining dexmedetomidine with mTOR inhibitors to enhance graft acceptance and reduce memory responses.