Preparation of hybrid porcine thymus containing non-human primate thymic epithelial cells in miniature swine.
Preparation of hybrid porcine thymus containing non-human primate thymic epithelial cells in miniature swine.
复制标题
小型猪含非人灵长类胸腺上皮细胞的杂交猪胸腺的制备。
DOI：
10.1111/xen.12543
复制
发表时间：
2019
影响因子：
3.9
通讯作者：
Yamada,Kazuhiko
中科院分区：
文献类型：
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作者：
Sekijima,Mitsuhiro;Sahara,Hisashi;Shimizu,Akira;Iwanaga,Takehiro;Murokawa,Takahiro;Ariyoshi,Yuichi;Pomposelli,Thomas;KhosraviMaharlooei,Mohsen;Sykes,Megan;Yamada,Kazuhiko
背景我们已经将维持生命的肾脏与血管化胸腺移植物共同移植到非人灵长类动物（NHP）体内，存活时间超过6个月。尽管我们已经在体外实现了猪特异性无反应性，但免疫抑制无法完全解除。在小鼠和人源化小鼠中的研究表明，含有宿主胸腺上皮细胞（TEC）的杂交猪胸腺（Hyb ‐thy）可以优化胸腺内选择，实现异种移植耐受，改善T细胞功能的重建。我们首先在xeno-Tx前2 - 3周在供体猪中制备Hyb-thy。我们在6只幼年小型猪中进行了6例混合制备。两只猪接受了未经处理的食蟹猴胸腺细胞，这些细胞是通过注射至其胸腺叶中从切除的萎缩胸腺中分离的（第1组）。其余4只接受从非萎缩胸腺中分离的胸腺细胞（组2和3）。第2组中的猪在一个胸腺叶中接受未操作的胸腺细胞，以及在对侧叶中接受CD 2阳性细胞耗尽的TEC富集细胞。第3组中的猪只接受TEC富集的细胞单独。ResultsAll thymus-injected pigs接受他克莫司和雷帕霉素，直到终点（POD 16）。我们在第1组和第3组的猪胸腺中检测到食蟹猴TEC网络，而第2组的猪排斥胸腺细胞。我们证明了使用他克莫司加雷帕霉素therapy.ConclusionsOur结果表明，从切除的NHP胸腺TEC的富集促进NHP TEC植入猪胸腺中的Hyb‐thy的制备。
BackgroundWe have achieved greater than a 6‐month survival of a life‐supporting kidney co‐transplanted with a vascularized thymic graft into non‐human primates (NHPs). Although we have achieved pig‐specific unresponsiveness in vitro, immunosuppression was not able to be fully weaned. Studies in mice and humanized mice suggest that a hybrid pig thymus (Hyb‐thy)‐containing host thymic epithelial cells (TECs) can optimize intra‐thymic selection, achieving xenograft tolerance with improved reconstitution of T‐cell function.MethodsWe have tested the feasibility of the preparation of a Hyb‐thy that contains NHP TECs in the donor thymic grafts. We first prepared the Hyb‐thy in the donor pigs 2‐3 weeks before xeno‐Tx. We performed six cases of Hyb‐thy preparation in six juvenile miniature swine. Two pigs received non‐manipulated cynomolgus monkey thymic cells that were isolated from an excised atrophic thymus via injection into their thymic lobes (Group 1). The remaining four received thymic cells that were isolated from non‐atrophic thymic glands (Groups 2 and 3). Pigs in Group 2 received unmanipulated thymic cells in one thymic lobe, as well as CD2‐positive cell‐depleted TEC‐enriched cells in the contralateral lobe. Pigs in Group 3 received TEC‐enriched cells alone.ResultsAll thymus‐injected pigs received tacrolimus and rapamycin until endpoint (POD16). We detected cynomolgus monkey TEC networks in pig thymus from Groups 1 and 3, while pigs in Group 2 rejected the thymic cells. We demonstrated the preparation of Hyb‐thy in pigs using tacrolimus plus rapamycin therapy.ConclusionsOur results suggest that the enrichment of TEC from the excised NHP thymus facilitated NHP TEC engraftment in pig thymus.