PRETREATMENT OF DONOR WITH TACROLIMUS PROLONGS MURINE CARDIAC ALLOGRAFT SURVIVAL

Abstract

Aims: Alloantigens can be presented by donor antigen-presenting cells (APC) or recipient APC. In our previous studies, we have found that immature donor APC decreases recipient APC-mediated immunity. In this study, we want to determine whether pretreatment of donors to suppress donor APC can prolong murine cardiac allograft survival. Methods: In vitro study, donor dendritic cells (DC) were derived from B10 (H-2b; I-Ab) mice bone marrow, and propagated in GM-CSF (1000u/ml) or GM-CSF plus tacrolimus (20ng/ml) to see whether tacrolimus could suppress dendritic cells. Ex vivo study, B10 mice were treated by tacrolimus (2mg/kg) one day, and DC was harvested from spleen to examine the phenotype of the DC and its allostimulatory capacity. In vivo study, B10 mice was treated by tacrolimus (2mg/kg) one day before cardiac harvest, and the cardiac graft was transplanted into C3H (H-2k; I-Ak) mice abdomen heterotopically. Results: Dendritic cells propagated in tacrolimus expressed lower levels of CD80, CD86, and CD40 than the DC propagated without tacrolimus. The allogeneic stimulatory capacity of DC was also suppressed by tacrolimus (0.34±0.001 OD versus 0.45±0.01 OD at stimulator/responder=1/10). When B10 mice were treated by tacrolimus for a day, the DC harvested from spleen expressed lower levels of CD80, CD86, and CD40 than those harvested from naïve mice. The allogeneic stimulatory capacity was also lower than naïve DC (0.29±0.003 versus 0.37±0.01 at stimulator/responder=1/10). While the hearts of tacrolimus-treated B10 mice was transplanted into C3H mice, the cardiac allograft survival could be prolonged from 9.4±0.55 days of naïve hearts to 17.4±5.12 days (p=0.009). Conclusions: Tacrolimus can suppress the maturation and function of DC. Pretreatment of donor with tacrolimus one day before cardiac transplantation can prolong allograft survival.