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

描述（由申请人提供）：已经开发了造血人源化小鼠（hu-mice），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，可以用类似于小鼠的方法进行操作。因此，胡鼠可以作为一种有效的翻译系统来研究小鼠免疫系统中的观察结果是否适用于人类，并探索近亲繁殖的人类免疫反应的自然变异。尽管最近在建立这种动物模型方面取得了进展，但是，胡鼠还没有为人类免疫系统提供最佳环境。关于B细胞，目前的人鼠模型不支持成熟B细胞的高效和长时间生成和/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是人体和小鼠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，成熟B细胞在小鼠体内的低存活率可能与人类BAFF的缺失有关。为了支持这些观察结果，我们发现人类BAFF的增加与人类成熟B细胞数量的增加相关，但这种人类细胞因子的表达仅在一些动物嵌合体中和较晚的时间点被检测到。在这里，我们提出基因工程一种新的小鼠品系表达人类BAFF代替小鼠BAFF。我们的假设是，表达内源性人BAFF的小鼠将支持更快和更多的成熟人B细胞的产生，并促进更好质量和规模的抗体反应。为了实现这些目标，我们将发展以下两个目标：1)产生人类BAFF敲入小鼠；2)研究人BAFF敲入小鼠成熟B细胞的发育和功能。这些研究的目的是增加胡鼠作为研究人类免疫系统的实验动物模型的相关性，更具体地说，是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，以及在表达人类BAFF的小鼠体内发育的人类B细胞群的特征。我们的假设是，人类BAFF敲入的人类小鼠将显示出更大的人类成熟B细胞群和更高的抗原特异性抗体反应，从而改进了人类抗体反应和B细胞生物学研究的模型。

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.