Immunogenicity of Human Stem Cell-Derived Beta Cells and Muscle Cells in Humanized Mice

人类干细胞衍生的β细胞和肌肉细胞在人源化小鼠中的免疫原性

基本信息

批准号：
10218287
负责人：
Michael Allen Brehm
金额：
$ 82.38万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218287
关键词：
Address Allogenic Animal Model Architecture BLT mice Beta Cell Cell Therapy Cell physiology Cells Clinic Consumption Dangerousness Deposition Development Diabetes Mellitus Diabetic mouse Disease model Endothelial Cells Engraftment Ensure Evaluation Fetal Liver Genes Human Immune Immune response Immune system Immunity Immunocompetent Immunodeficient Mouse Immunosuppression Impairment Institutes International Laboratories Lymphoid Lymphoid Tissue Modeling Mouse Strains Mus Muscle Muscle Cells Muscular Dystrophies Myoblasts Myopathy Natural Immunity Newborn Infant Outcome Patients Pre-Clinical Model Property Recording of previous events Regenerative Medicine Replacement Therapy Reporting Research Research Personnel Resources Safety Scientist Structure Testing The Jackson Laboratory Thymus Gland Time Tissues Transgenic Organisms Translations Transplantation United States National Institutes of Health Xenograft procedure biobank cell replacement therapy cell type clinical translation efficacy evaluation embryonic stem cell human disease human embryonic stem cell human model human stem cells humanized mouse immune function immunogenicity improved in vivo in vivo evaluation induced pluripotent stem cell innovation interest islet knockout gene lymph nodes lymphoid structures mouse model multidisciplinary new technology next generation novel pre-clinical preclinical evaluation regenerative tissue response stem cell therapy stem cells tool

项目摘要

Development of human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) has unleashed the potential of cellular therapy for a number of human diseases. Replacement therapies using human stem cell-derived β (SC-β) and SC-myoblasts (the two cell types used in this project), and multiple other stem cell derivatives are of interest to essentially all of the Institutes and Centers at NIH. To avoid rejection, cell replacement therapies will require immune protection by encapsulation, provided immune-evading properties, or given with immunosuppression. As the cell products are of human origin, immunogenicity can't be tested in vivo using immunocompetent animal models due to potent xenograft responses. One can test the cells for safety, efficacy, and immunogenicity in patients, which will be time consuming, expensive, and potentially dangerous. Thus, a critical requirement for the translation of human stem cell-based therapy to the clinic is the development of robust pre-clinical animal models for evaluation of the efficacy, safety and importantly, immunogenicity of human cellular therapy. We propose to modify NOD-scid IL2rgnull (NSG) models of human diabetes and muscle disease to permit development of robust human immune systems. This will allow rapid preclinical evaluation of the function and immunogenicity of human SC-β cells and SC-myoblasts (and SC-derived cells in other models under development). We have documented that current models of NSG mice engrafted with human immune systems cannot fully reject allogeneic human ESCs or SC-endothelial cells, and in preliminary studies, cannot reject human SC-β cells. Our Scientific Premise is that the limited function of the engrafted human immune system in humanized NSG mice is due to lack of organized structure in secondary lymphoid tissues. We have observed that engraftment of newborn NSG mice with wildtype murine HSC will lead to the development of lymph nodes and robust immune responses, suggesting that a lack of species-specific factors impede lymphoid development in humanized NSG mice. In this multi-PI, multi-disciplinary team proposal, Aim 1 will generate novel NSG mouse strains of diabetes and muscular disease that express human specific factors that support lymphoid structure and human immune function. Aim 2 will engraft human SC-β cells and SC- myoblasts into our unique humanized mouse models of diabetes and muscle disease to test for function and immunogenicity. Aim 3 will provide these validated new strains to The Jackson Laboratory (JAX) Biorepository for worldwide distribution. Our proposal takes advantage of powerful new technologies for creating new models of humanized mice, and builds on our track record for generating, validating, and to date, sharing through the JAX distribution network of 17 novel models of humanized NSG mice since 2005. We believe that our innovative approaches, combined with our multi-disciplinary collaborative team will ensure the development of these much-needed preclinical models for regenerative medicine.

人类胚胎干细胞（ESC）和人类诱导的多能干细胞（IPSC）的发展已经释放出了许多人类疾病的细胞疗法的潜力。替代疗法使用人类干细胞衍生的β（SC-β）和SC蛋白细胞（该项目中使用的两种细胞类型），并且基本上，其他多个干细胞衍生物对NIH的所有研究所和中心都很感兴趣。到避免拒绝，细胞置换疗法将需要通过封装（提供）进行免疫保护免疫蒸发特性，或给予免疫抑制。由于细胞产品是人类的，由于有效的异种移植物，不能使用免疫能力的动物模型在体内测试免疫原性回答。可以在患者中测试细胞的安全性，效率和免疫原性，这将是时间消费，昂贵且潜在的危险。这是对人类翻译的关键要求诊所的基于干细胞的治疗是稳健的临床前动物模型的发展人类细胞疗法的效率，安全性以及重要的是免疫原性。我们建议修改人类糖尿病和肌肉疾病的点数IL2RGNULL（NSG）模型允许发展稳健人类免疫系统。这将允许对功能和免疫原性的快速评估人类SC-β细胞和SC蛋白细胞（以及正在开发的其他模型中的SC衍生细胞）。我们有记录的是，当前植入人类免疫系统的NSG小鼠的模型无法完全拒绝同种异体人ESC或SC-内皮细胞，在初步研究中，不能拒绝人类SC-β细胞。我们的科学前提是，植入人类免疫系统的功能有限人源化的NSG小鼠是由于次级淋巴组织中缺乏有组织的结构。我们有观察到与野生型鼠HSC植入新生儿NSG小鼠将导致发展淋巴结和鲁棒的免疫反应，表明缺乏物种特异性因素会阻碍人源化NSG小鼠的淋巴发育。在这个多学科的多学科团队建议中，AIM 1将产生新型的NSG小鼠糖尿病和肌肉疾病的小鼠菌株，以表达人类特异性因素 AIM 2将植入人类SC-β细胞和SC- 成肌细胞进入我们独特的人源化糖尿病和肌肉疾病的模型，以测试功能和免疫原性。 AIM 3将为杰克逊实验室（JAX）提供这些经过验证的新菌株全球分布的生物座席。我们的建议利用强大的新技术创建人性化小鼠的新模型，并建立在我们的往绩记录上，以生成，验证和日期，自2005年以来，通过17种人构化NSG小鼠的新型新型模型的JAX分销网络共享。我们相信，我们的创新方法，结合我们的多学科合作团队确保开发这些急需的再生医学临床前模型。