Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons.
Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons.
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DOI：
10.1111/xen.12715
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发表时间：
2021-11
影响因子：
3.9
通讯作者：
Iwase, Hayato
中科院分区：
文献类型：
--
作者：
Foote, Jeremy B.;Jagdale, Abhijit;Yamamoto, Takayuki;Hara, Hidetaka;Bikhet, Mohamed H.;Schuurman, Henk-Jan;Nguyen, Huy Q.;Ezzelarab, Mohamed;Ayares, David;Anderson, Douglas J.;Fatima, Huma;Eckhoff, Devin E.;Cooper, David K. C.;Iwase, Hayato
关键词：
缺乏三种糖基转移酶的猪（三重敲除[TKO]猪，即不表达三种已知的碳水化合物异种抗原）和表达“保护性”人类转基因的猪被认为是移植到人类受体中的器官的可能来源。一些人血清不具有或具有最小的天然抗体与来自TKO猪的红细胞（RBC）和外周血单核细胞（PBMC）结合。然而，所有旧大陆猴都表现出与TKO猪细胞结合的天然抗体。旧大陆猴天然抗体的异种抗原靶标被假定为当碳水化合物N-羟乙酰神经氨酸（Neu 5Gc）的表达缺失时暴露的碳水化合物部分。本研究的目的是比较狒狒中的存活率和来自猪的肾移植物的组织病理学，所述猪（a）表达Neu 5 Gc（GTKO猪;第1组）或（B）不表达Neu 5 Gc（GTKO/CMAHKO [DKO]或TKO猪;第2组）。在基于抗CD 40 mAb的免疫抑制方案下，使用GTKO（n = 5）或DKO/TKO（n = 5）猪肾进行维持生命的肾移植。第1组狒狒的存活时间长于第2组狒狒（中位数为237天vs. 35天;平均值为196天vs. 57天; p < 0.07），仅在两个肾脏中表现出抗体介导的排斥反应的组织病理学特征。组2表现出抗体介导的排斥反应在所有五个移植物的组织病理学特征，与IgM和IgG结合肾间质动脉和管周毛细血管。第1组的无排斥反应生存期显著延长（p < 0.05）。猪肾移植物上Neu 5Gc表达的缺失与狒狒抗体与猪内皮的结合增加和移植物存活减少相关。
Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs, that is, not expressing the three known carbohydrate xenoantigens) and expressing ‘protective’ human transgenes are considered a likely source of organs for transplantation into human recipients. Some human sera have no or minimal natural antibody binding to red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs. However, all Old World monkeys exhibit natural antibody binding to TKO pig cells. The xenoantigen targets of Old World monkey natural antibodies are postulated to be carbohydrate moieties exposed when the expression of the carbohydrate N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival in baboons and histopathology of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs; Group 1) or (b) did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group 2). Life-supporting renal transplants were carried out using GTKO (n = 5) or DKO/TKO (n = 5) pig kidneys under an anti-CD40mAb-based immunosuppressive regimen. Group 1 baboons survived longer than Group 2 baboons (median 237 vs. 35 days; mean 196 vs. 57 days; p < 0.07) and exhibited histopathological features of antibody-mediated rejection in only two kidneys. Group 2 exhibited histopathological features of antibody-mediated rejection in all five grafts, with IgM and IgG binding to renal interstitial arteries and peritubular capillaries. Rejection-free survival was significantly longer in Group 1 (p < 0.05). The absence of expression of Neu5Gc on pig kidney grafts is associated with increased binding of baboon antibodies to pig endothelium and reduced graft survival.
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影响因子：
2.3
作者：
Liu H;Iwase H;Wijkstrom M;Singh J;Klein E;Wagner R;Humar A;Pasculle W;Cooper DK
通讯作者：
Cooper DK
影响因子：
13.6
作者：
Shimizu, A;Yamada, K;Colvin, RB
通讯作者：
Colvin, RB
影响因子：
19.6
作者：
Shimizu, A;Yamada, K;Colvin, RB
通讯作者：
Colvin, RB
影响因子：
5
作者：
Shimizu, A;Yamada, K;Colvin, RB
通讯作者：
Colvin, RB
影响因子：
1.5
作者：
Iwase H;Ekser B;Satyananda V;Zhou H;Hara H;Bajona P;Wijkstrom M;Bhama JK;Long C;Veroux M;Wang Y;Dai Y;Phelps C;Ayares D;Ezzelarab MB;Cooper DK
通讯作者：
Cooper DK