Oshima Kiyohiro, Sen Luyi, Cui Guanggen, Tung Thomas, Sacks Benjamin M, Arellano-Kruse Anthony, Laks Hillel
Division of Cardiothoracic Surgery, Department of Surgery, University of California Los Angeles, School of Medicine, Los Angeles, CA 90095-1679, USA.
Transplantation. 2002 Apr 15;73(7):1019-26. doi: 10.1097/00007890-200204150-00002.
We hypothesized that localized IL-10 gene transfer can induce alloreactive T cell apoptosis and tested this hypothesis with liposome-mediated ex vivo intracoronary IL-10 gene transfer using a functional heterotopic allograft heart transplant model in rabbits. Localized IL-10 overexpression prolonged cardiac allograft survival over three folds. In parallel with the time-course of IL-10 overexpression, the percentage of apoptotic CD3+ cells among total CD3+ cells was significantly increased in the gene therapy group (36.5+/-3.9%) compared with that in the control group (6.2+/-2.6%, P<0.01) on postoperative day (POD) 3-6, and it was further increased (45.8+/-5.7%) on POD7-10. Apoptotic CD4+ and CD8+ cells were also significantly increased in the gene group (P<0.01). In contrast, the percentage of apoptotic myocytes significantly decreased from 10.1+/-0.8% in the control group to 3.5+/-0.4% in the gene group on POD7-10 (P<0.01). This reduction was inversely correlated with the increase in the percentages of apoptotic CD4+ and CD8+ cells (P<0.01). The percentage of caspase-3 positive myocytes was significantly reduced, although percentages of caspase-3 positive CD4+ and CD8+ cells were markedly increased in the gene group (P<0.01). Moreover, about 60-80% of apoptotic T lymphocytes expressed Fas in the gene group compared with less than 10% in the control group (P<0.01). These results suggest that localized IL-10 gene transfer induces alloreactive T cell apoptosis via the Fas/FasL pathway that may contribute to the alleviated acute rejection, improved cardiac function, and prolonged survival in the IL-10 gene-treated cardiac allografts.
我们推测局部白细胞介素-10（IL-10）基因转移可诱导同种异体反应性T细胞凋亡，并使用功能性异位同种异体心脏移植模型，通过脂质体介导的体外冠状动脉内IL-10基因转移在兔身上验证了这一推测。局部IL-10过表达使心脏同种异体移植存活时间延长了三倍多。与IL-10过表达的时间进程一致，基因治疗组术后第3至6天总CD3⁺细胞中凋亡CD3⁺细胞的百分比显著高于对照组（36.5±3.9% vs 6.2±2.6%，P<0.01），术后第7至10天进一步升高（45.8±5.7%）。基因组中凋亡CD4⁺和CD8⁺细胞也显著增加（P<0.01）。相比之下术后第7至10天，凋亡心肌细胞的百分比从对照组的10.1±0.8%显著降至基因组的3.5±0.4%（P<0.01）。这种降低与凋亡CD4⁺和CD8⁺细胞百分比的增加呈负相关（P<0.01）。基因组中caspase-3阳性心肌细胞的百分比显著降低，尽管caspase-3阳性CD4⁺和CD8⁺细胞的百分比显著增加（P<0.01）。此外，基因组中约60-80%的凋亡T淋巴细胞表达Fas，而对照组中这一比例不到10%（P<0.01）。这些结果表明，局部IL-10基因转移通过Fas/FasL途径诱导同种异体反应性T细胞凋亡，这可能有助于减轻IL-10基因治疗的心脏同种异体移植中的急性排斥反应、改善心脏功能并延长存活时间。
