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

Stammberger, Uz; Kubisa, Bartosz; Gugger, Matthias; Ayuni, Erick; Claudio, Redaelli; Grodzki, Tomasz; Schmid, Ralph Alexander (2003). Strong additive effect of 1,25-dihydroxycholecalciferol and cyclosporine A but not tacrolimus in rat lung allotransplantation. European journal of cardio-thoracic surgery, 24(2), pp. 196-200. Elsevier Science B.V. 10.1016/S1010-7940(03)00300-2

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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 μg/kg/day, cyclosporine A 2.5 mg/kg/day i.p., and tacrolimus 40 μg/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 str

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