Human B Cell Development and Function in Humanized Mice Expressing Human BAFF

表达人类 BAFF 的人源化小鼠中人类 B 细胞的发育和功能

• 批准号: 8605522
• 负责人: Roberta Pelanda
• 金额: $ 11.93万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605522
• 关键词: Alleles; Animal Model; Animals; Antibody Formation; Antigens; B-Cell Development; B-Lymphocytes; Biological; Biological Process; Breeding; Cell physiology; Cellular biology; Chimera organism; Complement Factor B; Development; Environment; Experimental Animal Model; Gene Targeting; Generations; Genes; Genetic Engineering; Goals; Hematopoietic; Human; Human Biology; Immune response; Immune system; Immunodeficient Mouse; Immunoglobulin Class Switching; Inbred BALB C Mice; Infection; Investigation; Knock-in Mouse; Knockout Mice; Maintenance; Mature B-Lymphocyte; Methodology; Modeling; Mouse Strains; Mus; Population; Production; Property; Recombinants; Study models; System; Time; Transplantation; Ursidae Family; Vaccines; Variant; Work; animal model development; cytokine; embryonic stem cell; improved; improved functioning; in vivo Model; innovation; mouse model; mutant; novel; novel vaccines; public health relevance; response; screening

DESCRIPTION (provided by applicant): Hematopoietic humanized mice (hu-mice) have been developed to study the human immune system in an experimental in vivo model. These mice bear a human immune system that can be manipulated with methodologies similar to those utilized in mice. Hu-mice, therefore, can be used as an effective translational system to investigate whether observations made in the mouse immune system hold true in the human, and to explore the natural variation of outbred human immune responses. Despite recent advances in the establishment of this animal model, however, hu-mice do not yet provide an optimal environment to the human immune system. With regard to B cells, the current hu-mouse model does not support efficient and prolonged generation and/or maintenance of mature B cells limiting the validity of this model in studies that require mature B cell functions. BAFF isan important homeostatic factor for B cells both in mice and in humans. In addition to sustaining the survival of mature B cells, BAFF also promotes Ig class switch and, therefore humoral responses. Recent studies have suggested that the inefficient survival of mature B cell in hu-mice might be in part due to the absence of human BAFF. In support of these observations, we have found that increased production of human BAFF correlates with higher numbers of human mature B cells in hu-mice, but that expression of this human cytokine becomes detectable only in some of these animal chimeras and at late time points. Here we propose to genetically engineer a novel mouse strain that expresses human BAFF in place of mouse BAFF. Our hypothesis is that hu-mice expressing endogenous human BAFF will support faster and increased generation of mature human B cells and promote antibody responses of better quality and magnitude. To achieve these goals, we will develop the following two aims: 1) to generate human BAFF knock- in mice; and 2) to characterize the development and function of mature B cells in human BAFF knock-in hu- mice. These studies aim at increasing the relevance of hu-mice as experimental animal models for the investigation of the human immune system and, more specifically, of B cell and humoral responses. The innovation of this work lies in the generation of the human BAFF knock-in mouse strain and in the characterization of the human B cell population developing in hu-mice that express human BAFF. Our hypothesis is that human BAFF knock-in hu-mice will display a larger human mature B cell population and heightened antigen-specific antibody responses, improving this model for studies of human antibody responses and B cell biology.

描述（由申请人提供）：造血人源化小鼠（hu-mice）已被开发用于在实验体内模型中研究人类免疫系统。这些小鼠具有人类免疫系统，可以通过与小鼠相似的方法进行操作。因此，Hu-小鼠可用作有效的转化系统，以研究小鼠免疫系统中的观察结果是否适用于人类，并探索远交人类免疫反应的自然变异。然而，尽管最近在建立这种动物模型方面取得了进展，但腐殖质小鼠尚未为人类免疫系统提供最佳环境。对于 B 细胞，当前的 hu-小鼠模型不支持成熟 B 细胞的有效且长期的生成和/或维持，限制了该模型在需要成熟 B 细胞功能的研究中的有效性。 BAFF 是小鼠和人类 B 细胞的重要稳态因子。除了维持成熟 B 细胞的存活外，BAFF 还促进 Ig 类别转换，从而促进体液反应。最近的研究表明，hu-mice 中成熟 B 细胞的低效存活可能部分归因于人类 BAFF 的缺失。为了支持这些观察结果，我们发现人类 BAFF 产量的增加与胡小鼠中较高数量的人类成熟 B 细胞相关，但这种人类细胞因子的表达仅在某些动物嵌合体中且在较晚的时间点才可检测到。 在这里，我们建议通过基因工程改造一种新型小鼠品系，表达人类 BAFF 来代替小鼠 BAFF。我们的假设是，表达内源性人类 BAFF 的 hu-mice 将支持更快、更多地产生成熟人类 B 细胞，并促进更好质量和幅度的抗体反应。为了实现这些目标，我们将制定以下两个目标：1）产生人类BAFF敲入小鼠； 2) 表征人类 BAFF 敲入小鼠中成熟 B 细胞的发育和功能。 这些研究旨在提高胡鼠作为实验动物模型的相关性，用于研究人类免疫系统，更具体地说，研究 B 细胞和体液反应。这项工作的创新之处在于人类 BAFF 敲入小鼠品系的产生以及表达人类 BAFF 的 hu-mice 中发育的人类 B 细胞群的特征。我们的假设是，人类 BAFF 敲入 hu 小鼠将表现出更大的人类成熟 B 细胞群和增强的抗原特异性抗体反应，从而改进该模型，用于研究人类抗体反应和 B 细胞生物学。