Hancock W W, Buelow R, Sayegh M H, Turka L A
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Nat Med. 1998 Dec;4(12):1392-6. doi: 10.1038/3982.
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 CD40L 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.
我们研究了小鼠心脏同种异体移植中慢性移植物排斥反应的发病机制。给予抗CD4或CD40配体（CD40L）单克隆抗体加供体细胞后实现了长期存活。两种治疗方法均诱导了移植物的永久存活，但与接受CD4单克隆抗体治疗的小鼠移植情况不同，接受CD40L单克隆抗体治疗的小鼠移植物没有慢性排斥反应的迹象，包括移植性动脉硬化。接受CD40L单克隆抗体治疗的组中无慢性排斥反应与“保护性”基因血红素加氧酶-1（HO-1）、Bcl-xL和A20的血管表达相关。此外，仅当在保护性基因表达之前进行抗体转移时，通过抗体转移才会在免疫球蛋白缺陷小鼠的同种异体移植物中诱发动脉硬化。体外实验证明了内皮细胞中保护性基因表达的直接作用，其中HO-1或Bcl-xL的诱导抑制了同种抗体刺激的内皮细胞活化。最后，体内诱导HO-1可保护同种异体移植物免受慢性损伤。这些数据表明保护性基因在预防慢性排斥反应中发挥作用，并指出了保护移植物免受移植性动脉硬化发展影响的新方法。
