建立人源化自身免疫疾病模型研究T1DM的发病机制

Type 1 Diabetes Mellitus (T1DM) is caused by the autoimmune destruction of the pancreatic β cells, leading to insulin deficiency and abnormal glucose metabolism. Whileinsulin replacement therapy is a routine treatment forT1DM, it cannot control the glucose levels in T1DM patients on a regular basis, leading to severe medical complications such as hypoglycemia. Therefore, it is of great importance to elucidate the mechanism underlying the autoimmunity in T1DM in order to develop new therapies for T1DM. The T1DM autoimmunity has been extensively studied in various T1DM-mimicking mouse models. However, the findings in mouse models are usually not recapitulated in T1DM patients due to the apparent difference between the immune system of mouse and human. Therefore, it is important to develop physiologically relevant humanized T1DM autoimmunity models. Based on the achievements in regenerative medicine and transplantation immunology, including the development of high efficiency gene targeting technology in pluripotent stem cells, the discovery of the immunogenicity of iPSCs, and the development of humanized mouse models to establish new strategies to protect hESC-derived cells from allogeneic immune responses, the applicant proposes to establish the first humanized T1DM mouse models to overcome this key challenge in human T1DM research.Once accomplished, the humanizedT1DMautoimmunitymodel will be used to elucidatethe mechanism of T1DM autoimmunity, providingthe foundation to develop cell therapy for T1DM.

1型糖尿病（T1DM）是由于自体免疫反应破坏了胰腺β细胞, 而导致胰岛素缺失和糖代谢异常。胰岛素是T1DM治疗的支柱，但其无法将患者血糖水平时刻维持在正常范围内，还会导致急性低血糖等严重并发症。因此，阐明T1DM自身免疫反应的机制，开发治疗T1DM的新方法有重大意义。小鼠模型在研究T1DM发病机制及治疗策略中得到了广泛应用。然而，小鼠和人类的免疫系统有明显差异，小鼠模型的研究结果通常不能反映T1DM病人的真实情况，因此，急需创建与人生理相关的T1DM模型。申请人已创建多能干细胞的高效基因修饰技术，发现了iPSC的免疫源性，首次利用具有人免疫系统的人源化小鼠研究了针对hESC分化细胞的异体免疫排斥机制，建立逃逸异体免疫排斥的新策略。申请人将创建T1DM人源化鼠模型，并利用该模型阐明T1DM自身免疫的发病机理及免疫抑制调节机制，为开发T1DM的细胞治疗奠定基础。

1型糖尿病（T1DM）是由于自体免疫反应破坏了胰腺β细胞, 而导致胰岛素缺失和高血糖，当前还没有根治TIDM的策略。胰岛素对T1DM 的治疗不能时刻将血糖维持在正常范围内，长期使用会导致失明、肾衰等严重并发症。所以，开发新型有效的TIDM治疗策略具有重大的临床意义。利用免疫系统人源化鼠模型，我们成功创建了与临床密切相关的免疫系统人源化TIDM模型，并利用该模型研发了能够使移植的β细胞同时逃逸自身免疫排斥及异体免疫排斥的策略。既然该策略可以导致移植细胞逃避免疫监督，这些细胞存在较高的癌变风险，我们进一步解决这一安全瓶颈。 通过该项目的资助，项目负责人以通讯作者发表了SCI论文12篇, 包括1篇Cell Stem Cell（IF：23.2），1篇Cancer Cell（IF：23.9），并申请了三项专利。总之，通过将新型有效的免疫逃逸策略用于人胚胎干细胞分化的胰岛β细胞，我们建立了安全有效的胚胎干细胞分化的β细胞 治疗TIDM的策略，为开发人胚胎干细胞治疗TIDM的临床应用奠定了基础。