Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes
Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes
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DOI：
10.1038/3982
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发表时间：
1998-12-01
期刊：
影响因子：
82.9
通讯作者：
Turka, LA
中科院分区：
文献类型：
--
作者：
Hancock, WW;Buelow, R;Turka, LA
我们研究了小鼠同种异体心脏移植慢性排斥反应的发病机制。给予CD4或cd40配体（CD40L）单克隆抗体加供体细胞后出现长期存活。两种治疗方法都能诱导移植物永久存活，但是，与CD4单克隆抗体治疗的小鼠移植物相比，CD40L单克隆抗体治疗的小鼠移植物缺乏慢性排斥反应的证据，包括移植动脉硬化。CD IOL单克隆抗体治疗组的慢性排斥反应与血管中“保护性”基因血红素氧合酶-1 （HO-1）、Bcl-xL和A20的表达相关。此外，在免疫球蛋白缺陷小鼠的同种异体移植物中，只有在保护基因表达之前进行抗体转移才能诱导动脉硬化。在体外实验中，HO-1或Bcl-xL的诱导抑制了同种异体抗体刺激的内皮细胞活化，证明了其在内皮细胞中保护基因表达的直接作用。最后，体内HO-1的诱导可保护同种异体移植物免受慢性损伤。这些数据显示了保护性基因在预防慢性排斥反应中的作用，并提示了保护移植物免受移植动脉硬化发展的新方法。
We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis, Freedom from chronic rejection in the group treated with CD IOL monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.