Knock out of α1,3-galactosyltransferase or expression of α1,2-fucosyltransferase further protects CD55- and CD59-expressing mouse hearts in an ex vivo model of xenograft rejection
Knock out of α1,3-galactosyltransferase or expression of α1,2-fucosyltransferase further protects CD55- and CD59-expressing mouse hearts in an ex vivo model of xenograft rejection
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DOI：
10.1097/00007890-199806270-00010
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发表时间：
1998-06-27
期刊：
影响因子：
6.2
通讯作者：
D'Apice, AJF
中科院分区：
文献类型：
--
作者：
Cowan, PJ;Chen, CG;D'Apice, AJF
背景资料。来自高水平内皮表达人类补体调节因子CD55和CD59的转基因动物的器官可以显著保护免受人类补体介导的损伤。通过敲除α-1，3-半乳糖基转移酶基因(GalKO)或表达人α-1，2-岩藻糖基转移酶(H-转移酶或HTF)来消除或减少主要的异种表位α-Gal也提供了保护，尽管程度较小。在这项研究中，我们研究了CD55和CD59的强表达是否可以通过Gal KO或HTF的修饰来增强保护作用。将4组小鼠(野生型、CD55/CD59、CD55/CD59/HTF和CD55/CD59/GalKO)的心脏用40%的人血浆进行体外灌流。比较每组在60分钟内的平均心脏做功。结果，野生型心脏在加入血浆后15分钟内停止有效功能。CD55/CD59心脏显示存活时间延长，并在灌流结束时维持约10%的最大做功。在CD55/CD59背景上引入GalKO或HTF可进一步延长，作功维持在最大值的20%-30%。我们使用一个体外模型来证明，消除AGAL的表达可以进一步延长高表达CD55和CD59的小鼠心脏的功能，此外，我们还证明了通过表达HTF来减少α-Gal在延长CD55/CD59心功能方面与敲除Gal转移酶同样有效，从而为将这些进展转化到猪身上提供了一种可行的策略。
Background. Organs from transgenic animals with high-level endothelial expression of the human complement regulatory factors CD55 and CD59 are significantly protected from human complement-mediated injury. Elimination or reduction of the major xeno-epitope alpha Gal, achieved by knocking out the alpha 1,3-galactosyltransferase gene (Gal KO) or expressing human alpha 1,2-fucosyltransferase (H transferase or HTF), also affords protection, although to a lesser degree. In this study, we examined whether the protection provided by strong CD55 and CD59 expression can be augmented by the Gal KO or HTF modifications.Methods. Hearts from four groups of mice (wild type, CD55/CD59, CD55/CD59/HTF, and CD55/CD59/Gal KO) were perfused ex vivo with 40% human plasma. Mean heart work for each group was compared over a 60-min period.Results, Wild-type hearts ceased to function effectively within 15 min of plasma addition. CD55/CD59 hearts displayed prolonged survival and maintained approximately 10% maximum work at the end of perfusion. Introduction of Gal KO or HTF onto the CD55/ CD59 background resulted in a further prolongation, with work maintained at 20-30% of the maximum level.Conclusions. We used an ex vivo model to demonstrate that eliminating aGal expression further prolongs the function of mouse hearts expressing high levels of CD55 and CD59, In addition, we showed that reducing alpha Gal by expressing HTF is equally as effective in prolonging CD55/CD59 heart function as knocking out Gal transferase, thus providing a feasible strategy for translating these advances to the pig.