CTLA4-Fas ligand gene transfer mediated by adenovirus induce long-time survival of murine cardiac allografts
CTLA4-Fas ligand gene transfer mediated by adenovirus induce long-time survival of murine cardiac allografts
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DOI：
10.1016/j.transproceed.2005.03.022
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发表时间：
2005-06-01
影响因子：
0.9
通讯作者：
Xie, SS
中科院分区：
文献类型：
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作者：
Feng, YG;Jin, YZ;Xie, SS
背景Fas配体基因转移诱导外周移植物免疫耐受的动物模型研究结果存在争议。工程化FasL介导的免疫抑制作用取决于同种异体反应性T细胞是否被选择性删除。在本研究中，我们测试了通过融合CTLA 4-FasL基因转移在体内诱导长时间存活的策略的可行性。将来自DA（RT-1（a））大鼠的同种异体心脏异位移植到LEW（RT-1（1））大鼠的心室内。心脏移植后立即通过门静脉给予空斑单位（5 × 10（9））的AdCTLA 4-FasL、AdCTLA 4 Ig或AdEGFP。分别于移植后第5天和第20天，采用一次有限稀释法测定辅助性T淋巴细胞前体（HTLp）和细胞毒性T淋巴细胞前体（CTLp）的频率。与未处理的宿主或用AdEGFP处理的动物（MST分别为5.7 +/- 0.5和5.2 +/- 0.4，n = 6）相比，AdCTLA 4-FasL或AdCTLA 4 Ig处理显著延长了心脏移植物存活（平均存活时间[MST]分别为71.0 +/- 3.7和45.7 +/- 2.4，n = 6）。此外，与AdCTLA 41 g治疗相比，AdCTLA 4-FasL治疗显著延长了同种异体移植物存活。AdCTLA 4-FasL组大鼠第20天的HTLp和CTLp频率低于第5天，而其他各组大鼠第20天的HTLp和CTLp频率与第5天相似。这些结果表明，管理的腺病毒编码融合CTLA 4-FasL基因的大鼠受体有效地减少同种异体反应性T细胞的大小，并诱导心脏移植物的长期存活。
Background. Fas ligand gene transfer to induce peripheral allograft tolerance in animal models has shown controversial results. The immunosuppression effects mediated by engineered FasL depend on whether alloreactive T cells are selectively deleted. In the present study, we tested the feasibility of a strategy to induce long-time survival by fusing CTLA4-FasL gene transfer in vivo.Methods. Cardiac allografts from DA(RT-1(a)) rats were transplanted heterotopically into the abdomens of LEW(RT-1(1)) rats. Plaque units (5 x 10(9)) of either AdCTLA4-FasL, AdCTLA4Ig, or AdEGFP were administered via the portal vein immediately after cardiac transplantation. The frequencies of helper T lymphocyte precursors (HTLp) and cytotoxic T lymphocyte precursors (CTLp) were determined by a combined single limiting dilution assay on days 5 and 20 after transplantation.Results. Cardiac allograft survival was significantly prolonged by either AdCTLA4-FasL or AdCTLA4Ig treatment(mean survival times [MST] of 71.0 +/- 3.7 and 45.7 +/- 2.4, respectively, n = 6) compared with untreated hosts or animals treated with AdEGFP(MST of 5.7 +/- 0.5 and 5.2 +/- 0.4, respectively, n = 6). In addition, treatment with AdCTLA4-FasL led to significantly prolonged allograft survival compared with AdCTLA41g treatment. Furthermore, the frequencies of HTLp and CTLp on day 20 among rats treated with AdCTLA4-FasL was lower than those on day 5, whereas frequencies of HTLp and CTLp on day 20 were similar with those on day 5 in the other groups.Conclusion. These results suggest that administration of an adenovirus encoding fusion CTLA4-FasL gene to rat recipients effectively decreased the size of alloreactive T cells and induced long-term survival of cardiac allografts.