Inhibition of acute and chronic allograft rejection in mouse models by BXL-628, a nonhypercalcemic vitamin D receptor agonist
Inhibition of acute and chronic allograft rejection in mouse models by BXL-628, a nonhypercalcemic vitamin D receptor agonist
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DOI：
10.1097/01.tp.0000164619.49828.7a
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发表时间：
2005-07-15
期刊：
影响因子：
6.2
通讯作者：
Adorini, L
中科院分区：
文献类型：
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作者：
Amuchastegui, S;Daniel, KC;Adorini, L
背景资料。维生素D受体(VDR)激动剂是免疫调节剂，已被证明在几种移植模型中可以延长同种异体移植物的存活，但钙化倾向仍然是一个问题。为了研究VDR激动剂在急性排斥反应中的作用，作者使用了异位血管心脏模型，并评估了其长期效果，该模型表现为免疫介导的内膜增厚，类似于人类慢性同种异体排斥反应的血管病变。口服VDR激动剂的天数为-1天至30天，或直到同种异体移植排斥反应为止。移植后60天处死受者，对移植的主动脉进行组织学、免疫组织化学和基因芯片分析。骨化三醇和降钙剂类似物BXL-628显著延缓了急性排斥反应的发生。BXL-628在抑制内膜增生方面也更有效，与赋形剂治疗的对照组相比，减少了约80%，效果明显优于地塞米松治疗。BXL-628可显著抑制移植物中白细胞的募集，显著减少CD11b(+)巨噬细胞和CD11c(+)树突状细胞在移植物血管外膜的表达。与对照组相比，BXL-628处理的小鼠的同种异体主动脉中几个肌肉相关基因的转录本显著减少。这些结果表明，非高钙VDR激动剂BXL-628作为一种单一疗法，可以抑制小鼠模型的急性和慢性移植物排斥反应。
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.