Strong additive effect of 1,25-dihydroxycholecalciferol and cyclosporine A but not tacrolimus in rat lung allotransplantation.

Objectives: 1,25-Dihydroxycholecalciferol (calcitriol, vitamin D3) has immunosuppressive properties. This study evaluates the effect of calcitriol in combination with either cyclosporine A or tacrolimus on acute lung allograft rejection in a rat model of unilateral left lung allotransplantation.

Methods: Unilateral left lung transplantation was performed in male rats (Brown-Norway to Fischer F344, 200-250 g body weight). For immunosuppression, the following subtherapeutic doses were used: calcitriol 0.5 microg/kg/day, cyclosporine A 2.5 mg/kg/day i.p., and tacrolimus 40 microg/kg i.m. Five groups (n = 5) were analyzed: cyclosporine A; cyclosporine A and calcitriol; calcitriol; tacrolimus and calcitriol; and tacrolimus. The injections were performed for 5 days starting from the day of transplantation. Recipients were sacrificed on day 5 post-transplant. The contralateral right main bronchus and pulmonary artery were occluded for 5 min and blood was drawn for blood gas analysis. The grafts were excised, fixed in formaline and embedded in paraffin. Histological evaluation was done in blinded fashion (ISHLT 1999/rank scale). The mean and standard error of the mean (PaO2) or the median and range (rejection grading) are given. ANOVA followed by planned comparison for the PaO2 and Kruskal-Wallis ANOVA for rejection grading were applied, p < 0.05 considered significant.

Results: Arterial PaO2 on day 5 was very low in animals treated with subtherapeutic dosages of either cyclosporine A (48 +/- 10 mmHg), calcitriol (51 +/- 3) or tacrolimus (86 +/- 22). Combined treatment with cyclosporine A and calcitriol revealed a significant improvement (248 +/- 78; p < 0.05 vs. other groups), whereas the combination of tacrolimus with calcitriol did not reveal any benefit (65 +/- 9). Rejection grading with these subtherapeutic doses did not show any significant difference between groups.

Conclusions: Our data indicate that cyclosporine A, but not tacrolimus, has a strong additive effect with calcitriol on acute rat lung allograft rejection.