Tacrolimus and Mycophenolate Mofetil Provide Effective Immunosuppression in Rat Laryngeal Transplantation

Abstract

Tacrolimus is efficacious in several transplantation settings. Some studies have demonstrated improved results using combination therapy with mycophenolate mofetil. Our primary objective was to evaluate the efficacy and optimal dosing of tacrolimus in preventing rejection, using an established rat model of laryngeal transplantation. Further, the ability of mycophenolate to allow lower dosing of tacrolimus while achieving equivalent immunosuppression was investigated. A dosage efficacy study with 10 experimental arms was conducted. Dosage groups were 0.1, 0.2, 0.3, and 0.6 mg/kg tacrolimus alone and 0.1 mg/kg tacrolimus combined with 15 mg/kg mycophenolate mofetil, 0.1 mg/kg tacrolimus combined with 30 mg/kg mycophenolate mofetil, 0.1 mg/kg tacrolimus combined with 40 mg/kg mycophenolate mofetil, 0.2 mg/kg tacrolimus combined with 15 mg/kg mycophenolate mofetil, 0.2 mg/kg tacrolimus combined with 30 mg/kg mycophenolate mofetil (30 d only), and 0.2 mg/kg tacrolimus combined with 40 mg/kg mycophenolate mofetil. Each group contained 8 to 10 rats. Grafts were harvested for histopathological analysis on day 15 or 30 after transplantation. Histopathological appearance of the graft was blindly graded according to an established scale. Dosage groups were compared on rejection score using Wilcoxon's rank sum test and the Jonckheere-Terpstra test for trend. There was a significant association between increasing dose of tacrolimus and decreasing rejection score at both 15 and 30 days (P <.001). In the groups treated with 0.1 mg/kg T, an increasing dose of mycophenolate was associated with lower rejection scores at both 15 and 30 days (P =.001). In the group treated with 0.2 mg/kg T, there was no evidence that the addition of mycophenolate resulted in lower rejection at 15 days. However, at 30 days, combination therapy with increasing doses of mycophenolate was associated with decreasing rejection score (P =.002). Tacrolimus is an effective immunosuppressive agent for laryngeal transplantation. Mycophenolate mofetil allows lower doses of tacrolimus to be used while preserving graft viability in the early post-transplantation period.