Improved Humanized Mouse Models for Vaccine Development

用于疫苗开发的改进人源化小鼠模型

• 批准号: 7689165
• 负责人: DONALD E MOSIER
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689165
• 关键词: ABO blood group system; AIDS Vaccines; AIDS/HIV problem; Animal Model; Antibodies; Antibody Formation; Antigens; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Polysaccharides; Biological Models; Blood Group Antigens; CD34 gene; Carbohydrates; Carrier Proteins; Cell Differentiation process; Cell Line; Cell Maturation; Cell Survival; Cell Transplants; Cells; Complex; Development; Drug Formulations; Engraftment; Epithelial Cells; Exploratory/Developmental Grant; Fetal Liver; Figs - dietary; Follicular Dendritic Cells; Galactose; Generations; Genes; Genetic; Glycoconjugates; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Hematopoietic stem cells; Heterophile Antigens; Histocompatibility Antigens Class II; Human; Immune response; Immunodeficient Mouse; Inbred BALB C Mice; Infection; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin-7; Knockout Mice; Laboratories; Licensing; Lymphopoiesis; MHC antigen; Mannose; Mesenchymal; Modeling; Monoclonal Antibodies; Mus; Oligonucleotides; Outcome; Patients; Polysaccharides; Primates; Proteins; Reliance; Research Proposals; Screening procedure; Self Tolerance; Series; Signal Transduction; Speed; Stromal Cells; Supporting Cell; T-Lymphocyte; TSLP gene; Techniques; Testing; Tonsil; Transgenic Mice; Vaccines; Viral Load result; Virus; Virus Diseases; Work; Xenograft procedure; base; carbohydrate structure; cell type; immune function; immunogenicity; implantation; improved; improved functioning; lymph nodes; macrophage; mouse model; prevent; protective efficacy; repaired; research study; response; retransplantation; success; sugar; thymocyte; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): This goal of this project is to improve the immune function of "humanized" mice in order to provide a better model for testing candidate vaccines for HIV/AIDS. Over the past 20 years, techniques for generating human immune function following transfer of human cells to immunodeficient mice have gradually improved. This project begins with the best of the current models, transfer of human CD34-positive hematopoietic progenitor cells to mice with genetic disruption of Rag-2 and IL-2 receptor common gamma chain genes, and systematically evaluates strategies to improve the function of the many engrafted human B lymphocytes observed in this model. The project specifically focuses on two subsets of human B cells, the B1 subset responsible for "natural antibodies" and the marginal zone (MZ) B2 subset responsible for antibodies to carbohydrate antigens, because we are evaluating glycoconjugate vaccines (produced by Dennis Burton and collaborators) that target carbohydrates on the envelope spike of HIV-1. Recent advances in understanding the differentiation of B1 and MZ B cells provide the rationale for supplying supporting stromal cells and differentiation factors that should enhance the survival and function of these human B cells. The deficits recognized in the current humanized mouse model, absence of human follicular dendritic cells and human T cells that are positively selected on mouse epithelial cells, will be repaired by additional cell transplants. An "artificial lymph node" approach that is more amenable to replacing missing supporting cells will also be used to more rapidly evaluate which cell type is critical for fully functional immune responses. This research proposal is directly responsive to RFA-AI-07-015 in that it attempts to characterize B1 and MZ B cell responses to carbohydrates that shield HIV-1 from attack by conventional antibodies targeting protein components of the envelope. Successful execution of the project specific aims will result in a humanized mouse model capable of rapidly screening multiple HIV-1 candidate vaccines for both immunogenicity and protection against HIV-1 infection. This would speed vaccine development and reduce reliance on primate challenge models. There are many challenges to developing an effective vaccine to prevent HIV/AIDS, and one way to more effectively confront these challenges is to develop a small animal model system that accurately reflects the human immune response to candidate vaccines. After many years of work, that goal seems close. This proposal will attempt to fix the few remaining problems in "humanized mice", and use them to test a new AIDS vaccine decorated with sugar groups from the virus.

描述（由申请人提供）：该项目的目标是改善“人源化”小鼠的免疫功能，以便为测试艾滋病毒/艾滋病候选疫苗提供更好的模型。过去20年来，将人体细胞移植到免疫缺陷小鼠体内产生人体免疫功能的技术逐渐完善。该项目从当前最好的模型开始，将人类 CD34 阳性造血祖细胞转移到 Rag-2 和 IL-2 受体共同伽马链基因遗传破坏的小鼠中，并系统地评估改善该模型中观察到的许多移植人类 B 淋巴细胞功能的策略。该项目特别关注人类 B 细胞的两个子集，即负责“天然抗体”的 B1 子集和负责碳水化合物抗原抗体的边缘区 (MZ) B2 子集，因为我们正在评估针对 HIV-1 包膜刺突上的碳水化合物的糖复合物疫苗（由 Dennis Burton 及其合作者生产）。在了解 B1 和 MZ B 细胞分化方面的最新进展为提供支持基质细胞和分化因子提供了理论基础，从而增强这些人类 B 细胞的存活和功能。目前人源化小鼠模型中存在的缺陷，即缺乏在小鼠上皮细胞上阳性选择的人滤泡树突状细胞和人T细胞，将通过额外的细胞移植来修复。更适合替换缺失的支持细胞的“人工淋巴结”方法也将用于更快速地评估哪种细胞类型对于功能齐全的免疫反应至关重要。该研究提案直接响应 RFA-AI-07-015，因为它试图表征 B1 和 MZ B 细胞对碳水化合物的反应，这些碳水化合物可以保护 HIV-1 免受针对包膜蛋白质成分的传统抗体的攻击。成功执行该项目的具体目标将产生一种人源化小鼠模型，该模型能够快速筛选多种 HIV-1 候选疫苗的免疫原性和针对 HIV-1 感染的保护作用。这将加速疫苗开发并减少对灵长类动物挑战模型的依赖。开发有效预防艾滋病毒/艾滋病的疫苗面临许多挑战，更有效应对这些挑战的一种方法是开发能够准确反映人类对候选疫苗的免疫反应的小动物模型系统。经过多年的努力，这个目标似乎已经很接近了。该提案将尝试解决“人源化小鼠”中剩下的一些问题，并用它们来测试一种用病毒糖基修饰的新型艾滋病疫苗。