Preparation of Immunotolerant Space Under the Skin and Transplantation of Islets in the Space
Preparation of Immunotolerant Space Under the Skin and Transplantation of Islets in the Space
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皮下免疫耐受空间的制备及空间内胰岛移植
DOI：
10.1089/ten.tea.2018.0109
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发表时间：
2019
影响因子：
4.1
通讯作者：
Iwata Hiroo
中科院分区：
文献类型：
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作者：
Kuwabara Rei;Hamaguchi Masahide;Fukuda Takuya;Sakaguchi Shimon;Iwata Hiroo
在1型糖尿病的治疗中，期望在没有免疫抑制治疗的情况下将同种异体胰岛移植到皮下部位的方法。在本研究中，使用了两种供体/受体组合：F344大鼠供体（RT-1 lv 1）和ACI大鼠受体（RT-1a）;以及Wistar大鼠供体（封闭群）和刘易斯大鼠受体（RT-1 l）。将携带碱性成纤维细胞生长因子（bFGF; 50 μg/棒，琼脂糖-bFGF棒）的琼脂糖棒植入链脲佐菌素诱导的糖尿病大鼠的两个背部皮下部位中的每一个7天，并通过移除棒形成空间。将1500个同种异体胰岛移植到每个皮下空间中。胰岛移植前后均未给予免疫抑制药物。用流式细胞术和基因表达技术对琼脂糖-bFGF棒形成的肉芽肿组织进行免疫学分析，为同种异体胰岛的接受机制提供一些信息。通过琼脂糖-bFGF棒植入7天形成由高度血管化的肉芽肿组织包围的皮下空间。所有受体在两种供体/受体组合中都表现出长期的正常活动（>100天）。肉芽肿组织中调节性T（Treg）细胞/CD 4细胞的百分比在琼脂糖-bFGF棒植入后增加，并且在胰岛移植后仍保持较高的百分比。此外，通过植入琼脂糖-bFGF棒，肉芽肿组织中与趋化性和Treg细胞诱导相关的基因的表达水平增加。琼脂糖-bFGF棒植入是制备免疫耐受位点的有用方法，用于成功的同种异体胰岛移植而无需免疫抑制药物，Treg细胞可能在移植物接受中起关键作用。但要使其成为IDDM患者的标准医学治疗，仍存在一些问题。在这项研究中，使用糖尿病大鼠模型，通过琼脂糖-bFGF棒植入形成由高度血管化的肉芽肿组织包围的皮下空间。同种异体胰岛移植到该空间可以存活，并在没有免疫抑制剂的情况下长期释放胰岛素。结合足够的iPS/ES细胞的胰岛供应，我们的方法可以使胰岛移植成为IDDM患者的标准医学治疗。
A method that realizes allogeneic islet transplantation into a subcutaneous site under no immunosuppressive treatment has been desired for the treatment of type 1 diabetes. In this study, two donor/recipient combinations were used: F344 rat donors (RT-1lv1) and ACI rat recipients (RT-1a); and Wistar rat donors (closed colony) and Lewis rat recipients (RT-1l). An agarose rod, which carried basic fibroblast growth factor (bFGF; 50 μg/rod, agarose-bFGF rod), was implanted into each of the two dorsal subcutaneous sites of a streptozotocin-induced diabetic rat for 7 days, and the space was formed by removal of the rod. One thousand five hundred allogeneic islets were transplanted into each of the subcutaneous spaces. No immunosuppressive medication was given before or after islet transplantation. The immunological analyses of the granulomatous tissue formed by agarose-bFGF rod were carried out with flow cytometry and gene expression to get some information for mechanism of acceptance of allogeneic islets. Subcutaneous spaces surrounded with highly vascularized granulomatous tissue were formed by agarose-bFGF rod implantation for 7 days. All recipients demonstrated long-term normoglycemia (>100 days) in both donor/recipient combinations. The percentages of regulatory T (Treg) cells/CD4 cells in the granulomatous tissue increased by the implantation of agarose-bFGF rod and the percentages remained high after islet transplantation. In addition, expression levels of genes associated with chemotaxis and induction of Treg cells increased in the granulomatous tissue by the implantation of agarose-bFGF rod. The agarose-bFGF rod implantation is a useful method for preparation of an immunotolerant site for successful allogeneic islet transplantation without immunosuppressive medication, and Treg cells might play a pivotal role in graft acceptance.Impact StatementAlthough transplantation of islets of Langerhans has been accepted as a fundamental treatment for insulin-dependent diabetes mellitus (IDDM), several problems are still remaining in order that it becomes the standard medical treatment of IDDM patients. In this study, using diabetic rat models, a subcutaneous space surrounded with highly vascularized granulomatous tissue was formed by agarose-bFGF rod implantation. Allogeneic islets transplanted into the space could survive and release insulin for a long period under no immunosuppressive medication. In conjunction with sufficient supply of islets from iPS/ES cells, our method can make islet transplantation the standard medical treatment of IDDM patients.