A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation.

IF 5.3 2区 医学 Q1 IMMUNOLOGY Transplantation Pub Date : 2025-02-01 Epub Date: 2024-08-06 DOI:10.1097/TP.0000000000005152
Kenta Nakano, Motohito Goto, Satsuki Fukuda, Rieko Yanobu-Takanashi, Shigeharu G Yabe, Yukiko Shimizu, Tetsushi Sakuma, Takashi Yamamoto, Masayuki Shimoda, Hitoshi Okochi, Riichi Takahashi, Tadashi Okamura
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Abstract

Background: For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term.

Methods: We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγc null (NOG) mice ( Ins1 C96Y/C96Y NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice.

Results: All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation.

Conclusions: The Ins1C96Y/C96Y NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.

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用于异种胰岛细胞移植的携带 Ins1 秋田突变的新型免疫缺陷型高血糖小鼠
背景:对于即使使用胰岛素也难以控制血糖的患者,异种胰岛细胞,包括人类干细胞衍生胰岛(hSC-islet)和猪胰岛,作为解决供体短缺相关挑战的潜在方案,已引起人们的关注。为了开发使用细胞移植疗法的糖尿病治疗模式,必须使用实验动物长期评估移植细胞的有效性和安全性:方法:我们通过在NOD/Shi-scid IL2rγcnull (NOG)小鼠(Ins1C96Y/C96Y NOG)的啮齿动物特异性胰岛素1基因中引入秋田(C96Y)突变,培育出了永久性糖尿病免疫缺陷小鼠(Ins1C96Y/C96Y NOG)。从小鼠 4 周龄开始测量其体重、非空腹血糖和存活率。胰岛素敏感性通过耐受试验进行评估。为了阐明这些小鼠在异种移植实验中的作用,我们在这些小鼠的肾囊下移植了造血干细胞-胰岛细胞或猪胰岛:结果:所有雌雄同卵小鼠在4周龄时均表现出与β细胞耗竭相关的持续性严重高血糖,但胰岛素敏感性正常。这些小鼠可以稳定地移植造血干细胞小鼠,接受猪胰岛移植的小鼠血糖水平迅速降低,在移植后至少52周内血糖水平一直维持在正常血糖范围以下:结论:Ins1C96Y/C96Y NOG 小鼠模型为评估长期异种移植的有效性和安全性提供了一个有效的平台,而不会受到其免疫反应的干扰。这项研究有望为胰岛细胞移植的临床应用提供重要的基础信息。
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来源期刊
Transplantation
Transplantation 医学-免疫学
CiteScore
8.50
自引率
11.30%
发文量
1906
审稿时长
1 months
期刊介绍: The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation. ​
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