The mechanisms of graft failure in cardiac xenografts from α1,3-galactosyltransferase, gene-knockout (GalT-KO) pigs in babooons

狒狒α1,3-半乳糖基转移酶基因敲除（GalT-KO）猪心脏异种移植物移植失败的机制

• 批准号: 18591787
• 负责人: SHIMIZU Akira
• 金额: $ 2.44万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591787/
• 关键词: xenotransplantation; α1,3-galactosyltransferase gene-knockout pig; acute rejection; chronic rejection; humoral rejection; cellular rejection; chronic immunosuppression; baboon; ブタ; ヒヒ

Heterotopic cardiac xenotransplantation from α1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons has been performed. The pathology of the GalT-K0 cardiac xenografts was assessed to characterize the immunologic reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection.Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppression. Histologic and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection occurred. Three baboons were euthanized or died 16 to 56 days after transplantation. The other 5 grafts ceased beating between days 59 and 179 (median 78). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL+ endothelial cell death and endothelial cell procoagulant activation (increased expression of tissue factor and von Willebrand factor, with concomitant decreased expression of CD39). CD3+T cell infiltration occurred in all grafts. Slowly progressive humoral rejection, likely associated with elicited nonGal antibodies, and possibly disordered thromboregulation represents a major remaining immunologic barrier to long-term xenograft survival, even when using GalT-KO swine donors. In addition, acute cellular xenograft rejection and chronic rejection also developed in grafts, maintained by chronic immunosupression.

研究了α1,3-半乳糖转移酶基因敲除（GalT-KO）猪对狒狒的异位心脏移植。在没有抗gal抗体介导的排斥反应的情况下，评估GalT-K0心脏异种移植物的病理特征，以表征对异种移植物的免疫反应。8只狒狒接受了来自GalT-KO猪供体的异位心脏移植。所有狒狒均接受慢性免疫抑制治疗。对活检和移植物切除标本进行组织学和免疫组织化学研究。未发生超急性排斥反应。三只狒狒在移植后16至56天被安乐死或死亡。其余5例移植物在第59 ~ 179天停止跳动（中位78天）。所有失败的移植物均表现为血栓性微血管病变（TM），微血管中有富含血小板的纤维蛋白血栓，心肌缺血坏死，局灶性间质出血。TM的发展与免疫球蛋白（IgM和IgG）和补体（C3、C4d和C5b-9）沉积的增加，以及随后TUNEL+内皮细胞死亡和内皮细胞促凝激活的增加（组织因子和血管性血液病因子的表达增加，同时CD39的表达降低）同时发生。所有移植物均有CD3+T细胞浸润。缓慢进行性体液排斥反应，可能与诱导的非免疫抗体和可能的血栓调节紊乱有关，是长期异种移植物存活的主要免疫障碍，即使使用GalT-KO猪供体也是如此。此外，急性细胞异种移植物排斥反应和慢性排斥反应也发生在移植物中，并由慢性免疫抑制维持。

项目成果

Xenotransplantation from miniature swine into baboons

从小型猪到狒狒的异种移植

• 发表时间: 2007
• 作者: Shimizu;A
• 通讯作者: A

超急性拒絶反応:ブタ臓器を用いたヒヒへの異種移植

超急性排斥反应：使用猪器官异种移植到狒狒体内

• 发表时间: 2006
• 期刊: 日本医科大学医学会雑誌 2
• 作者: 清水 章;福田 悠;Sachs DH;Yamada K;Colvin RB
• 通讯作者: Colvin RB

Hyperacute rejection : Pig to baboon xenotransplantation.

超急性排斥反应：猪到狒狒的异种移植。

• 发表时间: 2006
• 期刊: Nippon Ikadaigaku Zashi 2
• 作者: Shimizu;A.;Fukuda;Y.;Sachs;DH;Yamada;K.;Colvin;RB
• 通讯作者: RB

Thrombotic microangiopathy associated with humoral rejection incardiac xenografts from a 1,3-galactosyltransferase gene-knockout(GalT-KO)pigs in babooons

狒狒体内 1,3-半乳糖基转移酶基因敲除 (GalT-KO) 猪心脏异种移植物中与体液排斥相关的血栓性微血管病

• 期刊: Am J Pathol (In press)
• 作者: Shimizu A;Hisashi Y;Kuwaki K;Tseng Y-L;Dor FJMF;Stuart LH;Robson SC;Schuurman H-J;Cooper DKC;Sachs DH;Yamada K;Colvin RB
• 通讯作者: Colvin RB

Thrombotic microangiopathy associated with humoral rejection in cardiac xenografts from α1,3-galactosyltransferase gene-knockout (GalT-KO) pigs in babooons.

血栓性微血管病与 α1,3-半乳糖基转移酶基因敲除 (GalT-KO) 猪狒狒心脏异种移植物的体液排斥相关。

• 期刊: Am J Pathol (in press)
• 作者: Shimizu;A.;Hisashi;Y.;Kuwaki;K.;Tseng;Y-L.;Dor;FJMF;Stuart;LH.;Robson;SC.;Schuurman;H-J;Cooper;DKC;Sachs;DH.;Yamada;K.;Colvin;RB
• 通讯作者: RB