An immunosufficient murine model for the study of human islets.
An immunosufficient murine model for the study of human islets.
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用于研究人类胰岛的免疫足够的小鼠模型。
DOI：
10.1111/xen.12126
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发表时间：
2014
影响因子：
3.9
通讯作者：
Deng,Shaoping
中科院分区：
文献类型：
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作者：
Zhao,Gaoping;Moore,DanielJ;Kim,JamesI;Lee,KangMi;O'Connor,Matthew;Yang,Maozhu;Marshall,AndrewF;Lei,Ji;Schuetz,Christian;Markmann,JamesF;Deng,Shaoping
为了治疗糖尿病，了解人体β细胞在健康和疾病中的详细功能至关重要。目前对体内人β细胞生理学的研究大多限于免疫缺陷小鼠模型，其具有显著的技术局限性。本研究旨在通过诱导免疫功能低下小鼠的移植耐受，为人类胰岛的研究建立一种新的模型。将人胰岛移植到B6糖尿病小鼠中，并用抗CD 45 RB治疗。为了评估抗CD 45 RB诱导的移植耐受是否需要B细胞，B6受体接受了额外的抗CD 20或使用了B6μMT-/-小鼠。对于一些抗CD 45 RB处理的B6μMT−/−小鼠，在移植后早期或晚期应用额外的抗CD 25 mAb。进行免疫组织学以显示移植的抗CD 45 RB/抗CD 20处理的Foxp 3-GFP B6小鼠中的Foxp 3细胞。结果显示，单独使用抗CD 45 RB可使26.6%的B6小鼠的移植物无限期存活，但同时使用抗CD 20治疗的小鼠的异种移植物接受率为100%，抗CD 45 RB治疗的μMT−/−小鼠的异种移植物接受率为88.9%。这些μMT−/−小鼠接受了来自另一个人类供体的胰岛，但拒绝了来自狒狒的胰岛。在移植时额外给予抗CD 25 mAb导致100%的排斥反应，而在移植后60天给予抗体时，40%的移植物发生排斥反应。免疫组织化学检查显示Foxp 3+细胞聚集在移植物周围。我们的结论是，诱导免疫功能不全的小鼠模型中的人胰岛的耐受性，可以通过靶向鼠CD 45 RB和CD 20。这一新系统将促进对人类胰岛的研究，并加速对人类疾病中胰岛健康的关键机制的剖析。
For the sake of therapy of diabetes, it is critical to understand human beta cell function in detail in health and disease. Current studies of human beta cell physiology in vivo are mostly limited to immunodeficient mouse models, which possess significant technical limitations. This study aimed to create a new model for the study of human islets through induction of transplant tolerance in immunosufficient mice. B6 diabetic mice were transplanted with human islets and treated with anti‐CD45RB. To assess whether anti‐CD45RB‐induced transplant tolerance requires B cells, B6 recipients received additional anti‐CD20 or B6μMT−/− mice were used. For some anti‐CD45RB‐treated B6μMT−/− mice, additional anti‐CD25 mAb was applied at the early or late stage post‐transplant. Immunohistology was performed to show the Foxp3 cells in grafted anti‐CD45RB/anti‐CD20‐treated Foxp3‐GFP B6 mice. The results showed that anti‐CD45RB alone allowed indefinite graft survival in 26.6% of B6 mice, however 100% of xenografts were accepted in mice treated simultaneously with anti‐CD20, and 88.9% of xenografts accepted in anti‐CD45RB‐treated μMT−/− mice. These μMT−/− mice accepted the islets from another human donor but rejected the islets from baboon. Additional administration of anti‐CD25 mAb at the time of transplantation resulted in 100% rejection, whereas 40% of grafts were rejected while the antibody was administrated at days 60 post‐transplant. Immunohistologic examination showed Foxp3+ cells accumulated around grafts. We conclude that induction of tolerance to human islets in an immunosufficient mouse model could be generated by targeting murine CD45RB and CD20. This new system will facilitate study of human islets and accelerate the dissection of the critical mechanisms underlying islet health in human disease.