Human B cell development and function in humanized mice expressing human BAFF

表达人 BAFF 的人源化小鼠中人 B 细胞的发育和功能

基本信息

批准号：
8881912
负责人：
Roberta Pelanda
金额：
$ 11.58万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881912
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 Health 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 response screening

项目摘要

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）：已经开发出造血人性化小鼠（HU--小鼠）来研究实验性体内模型中的人类免疫系统。这些小鼠具有人类免疫系统，可以用类似于小鼠使用的方法来操纵的方法。因此，可以将HU-MICE用作一种有效的翻译系统，以调查小鼠免疫系统中对人类中的观察结果是否成立，并探索刺激人类免疫反应的自然变化。尽管建立了该动物模型，但HU-MICE尚未为人类免疫系统提供最佳环境。关于B细胞，当前的HU-MOUSE模型不支持有效的和/或维持成熟的B细胞限制该模型在需要成熟B细胞功能的研究中的有效性。 Baff Isan在小鼠和人类中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类转换，从而促进体液反应。最近的研究表明，HU - 小鼠中成熟B细胞的生存效率低下可能部分是由于缺乏人类BAFF。为了支持这些观察结果，我们发现人类BAFF的产生增加与HU-MICE中人类成熟的B细胞数量较高相关，但是这种人类细胞因子的表达仅在这些动物嵌合体和后期的某些时间才能检测到。在这里，我们建议从遗传上设计一种新型的小鼠菌株，该菌株表达了人类baff代替小鼠baff。我们的假设是，表达内源性人BAFF的HU-小鼠将更快地支持成熟的人B细胞的产生，并促进质量和幅度的抗体反应。为了实现这些目标，我们将开发以下两个目标：1）在小鼠中产生人类的baff敲； 2）表征人类BAFF敲入Hu-tin的成熟B细胞的发育和功能。这些研究旨在增加HU-MICE作为实验动物模型的相关性，以研究人类免疫系统，更具体地说是B细胞和体液反应的研究。这项工作的创新在于人类BAFF敲打小鼠菌株的产生以及表达人类BAFF的HU-MICE中发展的人类B细胞群体的表征。我们的假设是，Human Baff敲入HU-MICE将显示出更大的人类成熟B细胞群体并增强抗原特异性抗体反应，从而改善了该模型的人类抗体反应和B细胞生物学的研究。