Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on-off gene recombination in vivo
Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on-off gene recombination in vivo
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DOI：
10.1016/j.cardiores.2005.07.021
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发表时间：
2006-01-01
影响因子：
10.8
通讯作者：
Uede, T
中科院分区：
文献类型：
--
作者：
Izawa, A;Sano, K;Uede, T
目的：CTLA4Ig G基因转移可诱导CTLA41gG长期高水平表达，从而导致全身免疫抑制。在这项研究中，我们利用Cre/loxP介导的开关重组来消除小鼠心脏移植后CTLA4IgG的转基因表达。方法：将BALB/c供体小鼠MHC完全不相合的心脏移植到C3H/He受体小鼠体内。移植后立即通过受体尾静脉注射位于两个loxP位点之间的携带CTLA41gG的腺病毒。结果：接受CTLA41gG基因的受者移植物长期存活。Cre介导的重组降低了CTLA4Ig G基因的表达，对移植物存活无不良影响。在接受同种异体心脏移植的受者中，供体类型和第三方的二次皮肤移植立即被拒绝。此外，高水平血清CTLA41gG抑制B细胞对卵清蛋白的反应，但在Cre介导的CTLA4Ig基因失活后B细胞反应恢复。结论：CTLA4Ig基因转移促进了小鼠心脏移植物的长期存活，但这不足以诱导耐受。Cre/loxP介导的开关重组有助于失活CTLA41gG基因，从而在不影响移植物存活的情况下恢复受体对新抗原的免疫应答。这个系统可能开启新的策略来协调临床相关的免疫抑制。(C)2005年欧洲心脏病学会。爱思唯尔B.V.出版。保留所有比赛。
Objective: Transfer of the CTLA4IgG gene induces long-term and high levels of CTLA41gG expression, which can result in generalized immunosuppression. In this study, we utilized Cre/loxP-mediated on-off switch recombination to eliminate transgene expression of CTLA4IgG following acceptance of murine cardiac allografts.Methods: Fully MHC-mismatched hearts from BALB/c donor mice were transplanted into C3H/He recipient mice. Adenovirus-containing CTLA41gG flanked between two loxP sites was administered via a recipient tail vein immediately after transplantation. Cre-recombinase gene was subsequently transferred at day 30 posttransplantation.Results: Long-term allograft survival was observed in recipients that received the CTLA41gG gene. Cre-mediated recombination reduced CTLA4IgG gene expression without any adverse effect on the graft survival. Secondary skin grafts of donor type and of third party were promptly rejected in the recipients that accepted cardiac allografts. In addition, the B cell response against ovalbumin was suppressed during high levels of serum CTLA41gG, but recovered after Cre-mediated inactivation of CTLA4IgG gene.Conclusion: CTLA4IgG gene transfer promoted long-term survival of murine cardiac allografts; however, this was not sufficient to induce tolerance. Cre/loxP-mediated on-off switch recombination was useful to inactivate the CTLA41gG gene so that recipients' immune responses against neoantigens were restored without an influence on the allograft survival. This system may open novel strategies to orchestrate clinically relevant immunosuppression. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All fights reserved.