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

描述（由申请人提供）：已开发造血人源化小鼠（hu-小鼠）以在实验体内模型中研究人免疫系统。这些小鼠具有人类免疫系统，可以用与小鼠中使用的方法类似的方法来操纵。因此，Hu小鼠可以用作有效的翻译系统，以研究在小鼠免疫系统中进行的观察是否在人类中成立，并探索远交人类免疫应答的自然变异。尽管最近在建立这种动物模型方面取得了进展，但是，hu小鼠还没有为人类免疫系统提供最佳环境。关于B细胞，目前的人-小鼠模型不支持成熟B细胞的有效和延长的产生和/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在小鼠和人的B细胞中都是重要的稳态因子。除了维持成熟B细胞的存活外，BAFF还促进IG类转换，从而促进体液应答。最近的研究表明，成熟B细胞在人鼠中的低效存活可能部分是由于缺乏人BAFF。为了支持这些观察结果，我们发现人BAFF的产生增加与人-小鼠中人成熟B细胞的较高数量相关，但是这种人细胞因子的表达仅在这些动物嵌合体中的一些中和在较晚的时间点变得可检测。 在这里，我们建议基因工程一种新的小鼠品系，表达人类BAFF的地方，小鼠BAFF。我们的假设是表达内源性人BAFF的hu小鼠将支持更快和增加的成熟人B细胞的产生，并促进更好质量和幅度的抗体应答。为了实现这些目标，我们将开发以下两个目标：1）产生人BAFF敲入小鼠;和2）表征人BAFF敲入hu-小鼠中成熟B细胞的发育和功能。 这些研究的目的是增加作为人类免疫系统的研究，更具体地说，B细胞和体液反应的实验动物模型的相关性。这项工作的创新在于人BAFF基因敲入小鼠品系的产生和表达人BAFF的人B细胞群在hu小鼠中发育的表征。我们的假设是，人BAFF基因敲入的hu-小鼠将显示出更大的人成熟B细胞群体和增强的抗原特异性抗体应答，从而改进了用于人抗体应答和B细胞生物学研究的该模型。

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.