Inhibition of acute and chronic allograft rejection in mouse models by BXL-628, a nonhypercalcemic vitamin D receptor agonist

Background. Vitamin D receptor (VDR) agonists are immunomodulatory agents that have been shown to prolong allograft survival in several transplantation models, but calcemic liability remains an issue. Methods. To study the effect of VDR agonists on acute rejection, the authors have used the heterotopic vascularized heart model, and to assess their long-term effects, the aortic allograft model, which shows immune-mediated intimal thickening similar to the vascular lesions of human chronic allograft rejection. VDR agonists were administered orally from days -1 to 30, or until allografts were rejected. Aortic allograft recipients were killed at day 60 posttransplantation, and the transplanted aorta was analyzed by histology, immunohistochemistry, and gene microarray. Results. A significant delay in acute rejection was induced by calcitriol and, more markedly, by the less calcemic analogue BXL-628. BXL-628 was also more effective in inhibiting intimal hyperplasia, leading to approximately 80% reduction compared with vehicle-treated controls, an effect significantly superior to dexamethasone administration. Leukocyte recruitment to the graft was significantly inhibited by BXL-628 treatment, with a profound reduction in the number of CD11b(+) macrophages and CD11c(+) dendritic cells infiltrating the adventitia of transplanted aortas. A significant reduction of transcripts coding for several muscle-related genes was observed in aortic allografts from BXL-628-treated mice compared with controls. Conclusions. These results show that the nonhypercalcemic VDR agonist BXL-628 inhibits, as a monotherapy, acute and chronic graft rejection in mouse models.