Type 1 diabetes induction in humanized mice
Type 1 diabetes induction in humanized mice
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人源化小鼠中 1 型糖尿病的诱导
DOI：
10.1073/pnas.1710415114
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发表时间：
2017-10-10
影响因子：
11.1
通讯作者：
Yang, Yong-Guang
中科院分区：
文献类型：
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作者：
Tan, Shulian;Li, Yang;Yang, Yong-Guang
对于 1 型糖尿病人源化体内模型来研究免疫发病机制和免疫治疗，特别是抗原特异性治疗，存在着迫切且未得到满足的需求。将患者血液淋巴细胞转移到免疫缺陷小鼠体内与异种移植物抗宿主反应有关，这使自身免疫的评估变得复杂。改进的模型可以识别哪些人类 T 细胞启动并参与 β 细胞破坏，并帮助确定关键目标胰岛自身抗原。我们使用含有强大的人类免疫库但缺乏异种移植物抗宿主反应性的人源化小鼠（hu-mice）来解决这个问题。将HLA-DQ8（+）人胎儿胸腺和CD34（+）细胞移植到HLA-DQ8转基因免疫缺陷小鼠中构建的Hu-小鼠在移植自体HLA-DQ8/胰岛素-B：9-23（InsB：9-23）特异性T细胞受体（TCR）表达人CD4（+）T细胞并免疫后出现高血糖和糖尿病InsB：9-23。输注的人类T细胞的存活依赖于预先存在的自体人类免疫系统，并且在糖尿病小鼠中观察到人类CD3(+)T细胞的胰腺浸润和胰岛炎，只要它们的胰岛受到链脲佐菌素的应激。这项研究符合 Koch 的致病性假设，证明了胰岛自身反应性 CD4(+) T 细胞反应在人类 1 型糖尿病诱导中的致病作用，强调了目标 β 细胞在其免疫命运中的作用，并证明了 T 细胞在存在胰岛炎症时识别 InsB:9-23 表位，从而引发疾病的能力。该临床前模型有潜力用于 1 型糖尿病发病机制的研究和临床相关治疗干预措施的测试。
There is an urgent and unmet need for humanized in vivo models of type 1 diabetes to study immunopathogenesis and immunotherapy, and in particular antigen-specific therapy. Transfer of patient blood lymphocytes to immunodeficient mice is associated with xenogeneic graft-versus-host reactivity that complicates assessment of autoimmunity. Improved models could identify which human T cells initiate and participate in beta-cell destruction and help define critical target islet autoantigens. We used humanized mice (hu-mice) containing robust human immune repertoires lacking xenogeneic graft-versus-host reactivity to address this question. Hu-mice constructed by transplantation of HLA-DQ8(+) human fetal thymus and CD34(+) cells into HLA-DQ8-transgenic immunodeficient mice developed hyperglycemia and diabetes after transfer of autologous HLA-DQ8/insulin-B:9-23 (InsB:9-23)-specific T-cell receptor (TCR)-expressing human CD4(+) T cells and immunization with InsB:9-23. Survival of the infused human T cells depended on the preexisting autologous human immune system, and pancreatic infiltration by human CD3(+) T cells and insulitis were observed in the diabetic hu-mice, provided their islets were stressed by streptozotocin. This study fits Koch's postulate for pathogenicity, demonstrating a pathogenic role of islet autoreactive CD4(+) T-cell responses in type 1 diabetes induction in humans, underscores the role of the target beta-cells in their immunological fate, and demonstrates the capacity to initiate disease with T cells, recognizing the InsB:9-23 epitope in the presence of islet inflammation. This preclinical model has the potential to be used in studies of the pathogenesis of type 1 diabetes and for testing of clinically relevant therapeutic interventions.