Costimulation blockade in pig artery patch xenotransplantation - a simple model to monitor the adaptive immune response in nonhuman primates
Costimulation blockade in pig artery patch xenotransplantation - a simple model to monitor the adaptive immune response in nonhuman primates
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DOI：
10.1111/j.1399-3089.2012.00711.x
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发表时间：
2012-07-01
影响因子：
3.9
通讯作者：
Cooper, David K. C.
中科院分区：
文献类型：
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作者：
Ezzelarab, Mohamed B.;Ekser, Burcin;Cooper, David K. C.
Ezzelarab MB, Ekser B, Echeverri G, Hara H, Ezzelarab C, Long C, Bajona P, Garcia B, Murase N, Ayares D, Cooper DKC。猪动脉斑块异种移植的共刺激阻断是监测非人灵长类动物适应性免疫反应的简单模型。异种移植2012;19日:221232。(c) 2012年John Wiley & Sons公司。摘要：背景：CD154阻断免疫抑制成功地阻止了接受α 1,3-半乳糖转移酶基因敲除（GTKO）猪器官的狒狒的体液和细胞适应性免疫反应。利用GTKO猪动脉移植狒狒模型，我们评估了CD28/B7共刺激通路阻断与CD154阻断的效果。方法：狒狒接受GTKO猪动脉斑块移植，不进行（第1组）、基于抗cd154mab（第2组）或基于ctla4 - ig（第3组）的免疫抑制治疗。检测抗猪IgM和IgG抗体及细胞反应。异种移植物免疫组织学评价抗体和补体沉积和细胞浸润。结果：1组狒狒对GTKO抗原的IgM和IgG抗体和细胞应答增加。在第2组中，单独抗cd154mab可阻止IgM和IgG抗体的产生和细胞反应，但不能阻止移植物的细胞浸润。在接受抗胸腺细胞球蛋白(ATG) +霉酚酸酯(MMF) +抗cd154mab的单只狒狒中，没有观察到移植物的细胞浸润。在第3组中，CTLA4-Ig与ATG + MMF的结合抑制了猪抗原对细胞的增殖反应，但没有阻止IgG反应或细胞浸润。结论：(1)动脉贴片移植是监测异种移植物适应性免疫反应的简单模型；（ii）抗cd154mab可阻止致敏，但不能阻止细胞浸润（但如果不抗凝，可能导致猪异种移植物早期血栓形成）；（iii）虽然只在一只狒狒中，添加ATG和MMF可以阻止细胞浸润；（iv）用CTLA4-Ig（使用的剂量）替代抗cd154mab，即使与ATG和MMF联合使用，也可以阻止细胞对GTKO猪抗原的增殖反应，但不足以阻止抗猪抗体的产生。
Ezzelarab MB, Ekser B, Echeverri G, Hara H, Ezzelarab C, Long C, Bajona P, Garcia B, Murase N, Ayares D, Cooper DKC. Costimulation blockade in pig artery patch xenotransplantation a simple model to monitor the adaptive immune response in nonhuman primates. Xenotransplantation 2012; 19: 221232. (c) 2012 John Wiley & Sons A/S. Abstract: Background: CD154 blockade-based immunosuppression successfully prevents both humoral and cellular adaptive immune responses in baboons receiving alpha 1,3-galactosyltransferase gene-knockout (GTKO) pig organs. Using a GTKO pig artery transplantation model in baboons, we evaluated the efficacy of CD28/B7 costimulatory pathway blockade in comparison with CD154 blockade. Methods: Baboons received artery patch grafts from GTKO pigs, with no (Group1), anti-CD154mAb-based (Group2), or CTLA4-Ig-based (Group3) immunosuppressive therapy. Anti-pig IgM and IgG antibody and cellular responses were monitored. Xenografts were immunohistologically evaluated for antibody and complement deposition, and cellular infiltration. Results: Group1 baboons developed increased IgM and IgG antibody and cellular responses against GTKO antigens. In Group2, anti-CD154mAb alone prevented the development of both IgM and IgG antibody and cellular responses,but not cellular infiltration of the graft. In the single baboon that received anti-thymocyte globulin (ATG) + mycophenolate mofetil (MMF) + anti-CD154mAb, cellular infiltration of the graft was not seen. In Group3, CTLA4-Ig with ATG + MMF inhibited the cellular proliferative response to pig antigens but did not prevent the IgG response or cellular infiltration. Conclusions: (i) Artery patch transplantation is a simple model to monitor the adaptive immune response to xenografts; (ii) anti-CD154mAb prevents sensitization but not cellular infiltration (but, without anticoagulation, may result in early thrombosis of a pig xenograft); (iii) although in only one baboon, the addition of ATG and MMF prevents cellular infiltration and (iv) replacement of anti-CD154mAb by CTLA4-Ig (at the doses used), even in combination with ATG and MMF, prevents the cellular proliferative response to GTKO pig antigens but is insufficient to prevent the development of anti-pig antibodies.