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表达多种人蛋白的三重基因敲除猪肾移植到食蟹猴中。

Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques.

机构信息

Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

出版信息

Am J Transplant. 2022 Jan;22(1):46-57. doi: 10.1111/ajt.16780. Epub 2021 Aug 31.

Abstract

Porcine cells devoid of three major carbohydrate xenoantigens, αGal, Neu5GC, and SDa (TKO) exhibit markedly reduced binding of human natural antibodies. Therefore, it is anticipated that TKO pigs will be better donors for human xenotransplantation. However, previous studies on TKO pigs using old world monkeys (OWMs) have been disappointing because of higher anti-TKO pig antibodies in OWMs than humans. Here, we show that long-term survival of renal xenografts from TKO pigs that express additional human transgenes (hTGs) can be achieved in cynomolgus monkeys. Kidney xenografts from TKO-hTG pigs were transplanted into eight cynomolgus recipients without pre-screening for low anti-pig antibody titers. Two recipients of TKO-hTG xenografts with low expression of human complement regulatory proteins (CRPs) (TKO-A) survived for 2 and 61 days, whereas six recipients of TKO-hTG xenografts with high CRP expression (TKO-B) survived for 15, 20, 71, 135, 265, and 316 days. Prolonged CD4 T cell depletion and low anti-pig antibody titers, which were previously reported important for long-term survival of αGal knock-out (GTKO) xenografts, were not always required for long-term survival of TKO-hTG renal xenografts. This study indicates that OWMs such as cynomolgus monkeys can be used as a relevant model for clinical application of xenotransplantation using TKO pigs.

摘要

缺乏三种主要碳水化合物异种抗原αGal、Neu5GC 和 SDa(TKO)的猪细胞与人源天然抗体的结合显著减少。因此,预计 TKO 猪将成为更好的人类异种移植供体。然而,之前使用旧世界猴(OWM)进行的 TKO 猪研究结果令人失望,因为 OWM 中的抗 TKO 猪抗体高于人类。在这里,我们表明,在食蟹猴中,表达额外人类转基因(hTGs)的 TKO 猪的肾脏异种移植物可以长期存活。来自 TKO-hTG 猪的肾脏异种移植物在没有预先筛选低抗猪抗体滴度的情况下被移植到 8 只食蟹猴受体中。两名 TKO-hTG 异种移植物受体(TKO-A)的人类补体调节蛋白(CRP)表达水平较低,存活了 2 天和 61 天,而 6 名 TKO-hTG 异种移植物受体(TKO-B)的 CRP 表达水平较高,存活了 15、20、71、135、265 和 316 天。此前报道,αGal 敲除(GTKO)异种移植物长期存活的重要因素是 CD4 T 细胞耗竭和低抗猪抗体滴度,而在 TKO-hTG 肾脏异种移植物的长期存活中并不总是需要这两个因素。这项研究表明,食蟹猴等 OWM 可以作为使用 TKO 猪进行异种移植临床应用的相关模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b1d/9291868/2ac08101c25e/AJT-22-46-g006.jpg

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