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.