权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10449121
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449121
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.

人胚胎干细胞和人诱导多能干细胞的发育释放了细胞疗法治疗多种人类疾病的潜力。替代疗法使用人类干细胞来源的β(SC-β)和SC-成肌细胞(本项目中使用的两种细胞类型)，以及基本上，美国国立卫生研究院的所有研究所和中心都对多种其他干细胞衍生品感兴趣。至避免排斥，细胞替代疗法将需要通过包裹进行免疫保护，前提是免疫逃避特性，或给予免疫抑制。由于细胞产品来自人类，由于强大的异种移植，不能使用免疫活性动物模型在体内测试免疫原性回应。人们可以在患者身上测试细胞的安全性、有效性和免疫原性，这将是一段时间。耗费，昂贵，而且有潜在的危险。因此，对人的翻译的一个关键要求以干细胞为基础的临床治疗是开发用于评估的强大的临床前动物模型人类细胞疗法的有效性、安全性以及重要的免疫原性。我们建议修改 NOD-SCID IL2rgnull(NSG)人类糖尿病和肌肉疾病模型允许开发强大的人类的免疫系统。这将使快速的临床前评估的功能和免疫原性人的SC-β细胞和SC-成肌细胞(以及其他模型中的SC来源的细胞正在开发中)。我们有证明了目前移植了人类免疫系统的NSG小鼠模型不能完全排斥同种异体人胚胎干细胞或干细胞内皮细胞，在初步研究中，不能排斥人类SC-β细胞。我们的科学前提是移植的人类免疫系统的有限功能人源化NSG小鼠是由于次级淋巴组织缺乏组织化结构所致。我们有观察到新生NSG小鼠植入野生型小鼠HSC将导致淋巴结节和强大的免疫反应，表明缺乏物种特有的因素阻碍人源化NSG小鼠的淋巴发育。在这份多PI、多学科团队提案中，目标1将产生表达人类特定因子的新型糖尿病和肌肉疾病NSG小鼠品系支持淋巴结构和人体免疫功能的物质。AIM 2将移植人SC-β细胞和SC- 将成肌细胞植入我们独特的糖尿病和肌肉疾病人源化小鼠模型中，以测试其功能和免疫原性。AIM 3将向杰克逊实验室(JAX)提供这些经过验证的新菌株供全球发行的生物信息库。我们的提案利用强大的新技术创建人性化小鼠的新模型，并建立在我们在生成、验证和自2005年以来，通过JAX分销网络分享了17个人源化NSG小鼠的新模型。我们相信，我们的创新方法，加上我们的多学科协作团队，将确保开发这些急需的再生医学临床前模型。