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

Transplantation. 2005 Jul 15;80(1):81-7. doi: 10.1097/


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.

MeSH terms

  • Acute Disease
  • Animals
  • Aorta / pathology
  • Aorta / transplantation*
  • Calcitriol / analogs & derivatives*
  • Calcitriol / therapeutic use
  • Cell Division / drug effects
  • Chronic Disease
  • Disease Models, Animal
  • Graft Rejection / prevention & control*
  • Graft Survival / physiology
  • Heart Transplantation / immunology*
  • Heart Transplantation / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Calcitriol / agonists
  • Time Factors
  • Transplantation, Homologous / immunology*
  • Transplantation, Homologous / pathology


  • BXL628
  • Receptors, Calcitriol
  • Calcitriol