In Vitro and in Vivo Prevention of Human CD8+ CTL‐Mediated Xenocytotoxicity by Pig c‐FLIP Expression in Porcine Endothelial Cells
In Vitro and in Vivo Prevention of Human CD8+ CTL‐Mediated Xenocytotoxicity by Pig c‐FLIP Expression in Porcine Endothelial Cells
复制标题
通过猪内皮细胞中的猪 c-FLIP 表达在体外和体内预防人 CD8+ CTL 介导的异细胞毒性
DOI：
10.1111/j.1600-6143.2007.02077.x
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发表时间：
2008
影响因子：
8.8
通讯作者：
T. Ito
中科院分区：
文献类型：
--
作者：
M. Tanemura;A. Saga;K. Kawamoto;T. Deguchi;T. Machida;T. Nishida;Y. Sawa;T. Ito
克服细胞介导的免疫，特别是人类CD8+ ctl的免疫，对于异种移植的成功至关重要。我们的研究小组先前报道了人CD8+ ctl对猪内皮细胞（PEC）的细胞毒性是高度有害的，主要是由Fas/FasL凋亡途径介导的。细胞FLICE抑制蛋白（c‐FLIP）最初被认为是一种死亡受体信号的抑制剂，通过与caspase‐8的结合竞争，通过死亡结构域（FADD）募集Fas相关蛋白。两种主要的c‐FLIP变体由不同的mRNA剪接产生：短的26‐KDa蛋白（c‐FLIPS）和长的55‐KDa蛋白（c‐FLIPL）。c‐FLIPS/L在异种移植物细胞中的细胞保护作用仍然存在争议。本研究表明，c‐FLIPS/L基因的过表达可显著抑制人CD8+ CTL介导的异种细胞毒性，此外，c‐FLIPS的细胞保护作用似乎明显强于c‐FLIPS。此外，为了证明异种移植物存活的延长效应，将带有c‐FLIPS/L基因的PEC转染物移植到大鼠肾胶囊中。移植后第5天，flps /L转基因诱导的存活时间延长，而亲本PEC则完全被排斥。因此，异种移植物细胞中c‐FLIPS/L过表达的细胞内重塑可以避免对异种移植物的先天细胞攻击，并促进异种移植物的长期存活。
Overcoming cell‐mediated immunity, especially of human CD8+ CTLs, is important for the success of xenotransplantation. Our group has previously reported that the cytotoxicity of human CD8+ CTLs against pig endothelial cells (PEC) is highly detrimental and mediated in major part by the Fas/FasL apoptotic pathway. Cellular FLICE inhibitory protein (c‐FLIP) was originally identified as an inhibitor of death‐receptor signaling through binding competition with caspase‐8 for recruitment to Fas‐associated via death domain (FADD). Two major c‐FLIP variants result from alternative mRNA splicing: a short, 26‐KDa protein (c‐FLIPS) and a long, 55‐KDa form (c‐FLIPL). The cytoprotective effects of c‐FLIPS/L in xenograft cells remain controversial. This study demonstrates that the overexpression of c‐FLIPS/L genes markedly suppress human CD8+ CTL‐mediated xenocytotoxicity and, in addition, the cytoprotective effects of c‐FLIPL appear to be significantly stronger than those of c‐FLIPS. Furthermore, to prove the prolonged effects of xenograft survival, PEC transfectants with c‐FLIPS/L genes were transplanted under rat kidney capsules. Prolonged survival was elicited from FLIPS/L transfectants, whereas parental PEC was completely rejected through day 5, posttransplant. Thus, intracellular remodeling with the overexpression of c‐FLIPS/L in xenograft cells may avoid innate cellular attacks against xenografts and facilitate long‐term xenograft survival.
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DOI：
10.1073/pnas.94.21.11333
发表时间：
1997-10-14
影响因子：
11.1
作者：
Han, DKM;Chaudhary, PM;Hood, L
通讯作者：
Hood, L
影响因子：
32.4
作者：
MURRAY, AG;KHODADOUST, MM;BOTHWELL, ALM
通讯作者：
BOTHWELL, ALM
DOI：
10.1073/pnas.94.20.10717
发表时间：
1997-09-30
影响因子：
11.1
作者：
Inohara, N;Koseki, T;Nunez, G
通讯作者：
Nunez, G
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
N. Danial;S. Korsmeyer;H Robert
通讯作者：
N. Danial;S. Korsmeyer;H Robert
影响因子：
4.1
作者：
Boatright, KM;Deis, C;Salvesen, GS
通讯作者：
Salvesen, GS