DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts:: Differential sensitivity of CD4+and CD8+T cells to transforming growth factorβ1
DNA-liposome versus adenoviral mediated gene transfer of transforming growth factorβ1 in vascularized cardiac allografts:: Differential sensitivity of CD4+and CD8+T cells to transforming growth factorβ1
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DOI：
10.1097/00007890-200011150-00006
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发表时间：
2000-11-15
期刊：
影响因子：
6.2
通讯作者：
Bishop, DK
中科院分区：
文献类型：
--
作者：
Chan, SY;Goodman, RE;Bishop, DK
我们已经开发了一个模型，转化生长因子（TGF）β 1基因转移到小鼠血管化心脏移植研究使用基因转移作为移植免疫抑制治疗。供体心脏灌注DNA-脂质体复合物或腺病毒载体，编码人TGF β 1的活性形式。DNA-脂质体介导的转染延长了大约三分之二的移植受者的同种异体移植物存活，而TGF β 1的腺病毒递送没有保护作用。保护性TGF β 1基因转移与Th 1应答减少和同种抗体同种型转换抑制相关。外源性白细胞介素-1 α（IL-1a）的应用可逆转TGF-β 1基因转移的保护作用。有趣的是，同种异体反应性CD 4+和CD 8+细胞表现出不同的敏感性TGF β 1基因转移：CD 4 + Th 1功能被废除，这种方式，虽然CD 8 + Th 1功能没有。受体CD 8+细胞的瞬时耗竭显着延长了用DNA-脂质体复合物或腺病毒载体转染的移植物的存活。转基因表达持续了至少60天，并且直到CD 8 + T细胞重新填充外周才检测到Th 1应答。然而，长期转染的同种异体移植物似乎表现出加剧的纤维化和新生内膜的发展。这些慢性排斥反应的表现在长期转染的同种移植物中是不存在的，这表明单独的活性TGF β 1的长期表达不足以诱导移植物的纤维化。总的来说，这些数据说明了免疫抑制基因治疗与其他预处理方案结合时作为移植治疗的效用。此外，他们说明同种异体反应性CD 4+和CD 8+细胞可能受到细胞因子操作策略的不同影响。
We have developed a model of transforming growth factor (TGF)beta1 gene transfer into mouse vascularized cardiac allografts to study the use of gene transfer as an immunosuppressive therapy in transplantation. Donor hearts were perfused with either DNA-liposome complexes or adenoviral vectors that encode the active form of human TGF beta1. DNA-liposome mediated transfection prolonged allograft survival in approximately two-thirds of transplant recipients, while adenoviral delivery of TGF beta1 was not protective. Protective TGF beta1 gene transfer was associated with reduced Th1 responses and an inhibition of the alloantibody isotype switch. The protective effects of TGF beta1 gene transfer were overridden by exogenous interleukin-la administration. Interestingly, alloreactive CD4+ and CD8+ cells exhibited distinct sensitivities to TGF beta1 gene transfer: CD4+ Th1 function was abrogated by this modality, although CD8+ Th1 function was not. Transient depletion of recipient CD8+ cells markedly prolonged the survival of grafts transfected with either DNA-liposome complexes or adenoviral vectors. Transgene expression persisted for at least 60 days, and Th1 responses were not detectable until CD8+ T cells repopulated the periphery. However, long-term transfected allografts appeared to exhibit exacerbated fibrosis and neointimal development. These manifestations of chronic rejection were absent in long-term transfected isografts, suggesting that long-term expression of active TGF beta1 alone is not sufficient to induce fibrosis of the grafts. Collectively, these data illustrate the utility of immunosuppressive gene therapy as a treatment for transplantation when combined with additional conditioning regimens. Further, they illustrate that alloreactive CD4+ and CD8+ cells may be differentially influenced by cytokine manipulation strategies.