Center for Translational Immunology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.
Cancer Immunol Immunother. 2023 Sep;72(9):3063-3077. doi: 10.1007/s00262-023-03478-4. Epub 2023 Jun 20.
Since mice do not express a homologue of the human Fc alpha receptor (FcαRI or CD89), a transgenic mouse model was generated in four different backgrounds (C57BL/6, BALB/c, SCID and NXG) expressing the FcαRI under the endogenous human promoter. In this study, we describe previously unknown characteristics of this model, such as the integration site of the FCAR gene, the CD89 expression pattern in healthy male and female mice and in tumor-bearing mice, expression of myeloid activation markers and FcγRs and IgA/CD89-mediated tumor killing capacity. In all mouse strains, CD89 expression is highest in neutrophils, intermediate on other myeloid cells such as eosinophils and DC subsets and inducible on, among others, monocytes, macrophages and Kupffer cells. CD89 expression levels are highest in BALB/c and SCID, lower in C57BL/6 and lowest in NXG mice. Additionally, CD89 expression on myeloid cells is increased in tumor-bearing mice across all mouse strains. Using Targeted Locus Amplification, we determined that the hCD89 transgene has integrated in chromosome 4. Furthermore, we established that wildtype and hCD89 transgenic mice have a similar composition and phenotype of immune cells. Finally, IgA-mediated killing of tumor cells is most potent with neutrophils from BALB/c and C57BL/6 and less with neutrophils from SCID and NXG mice. However, when effector cells from whole blood are used, SCID and BALB/c are most efficient, since these strains have a much higher number of neutrophils. Overall, hCD89 transgenic mice provide a very powerful model to test the efficacy of IgA immunotherapy against infectious diseases and cancer.
由于小鼠不表达人类 Fcα 受体（FcαRI 或 CD89）的同源物，因此在四个不同背景（C57BL/6、BALB/c、SCID 和 NXG）下生成了表达 FcαRI 的转基因小鼠模型，该模型在人类启动子的控制下表达。在这项研究中，我们描述了该模型以前未知的特征，例如 FCAR 基因的整合位点、健康雄性和雌性小鼠以及荷瘤小鼠中 CD89 的表达模式、髓样细胞激活标志物和 FcγRs 的表达以及 IgA/CD89 介导的肿瘤杀伤能力。在所有小鼠品系中，CD89 表达在中性粒细胞中最高，在其他髓样细胞（如嗜酸性粒细胞和 DC 亚群）中中等，在单核细胞、巨噬细胞和枯否细胞等细胞中可诱导。在 BALB/c 和 SCID 小鼠中 CD89 表达水平最高，在 C57BL/6 中较低，在 NXG 小鼠中最低。此外，在所有小鼠品系中，荷瘤小鼠的髓样细胞上的 CD89 表达增加。通过靶向基因座扩增，我们确定 hCD89 转基因已整合到染色体 4 上。此外，我们还确定了野生型和 hCD89 转基因小鼠具有相似的免疫细胞组成和表型。最后，IgA 介导的肿瘤细胞杀伤作用在 BALB/c 和 C57BL/6 的中性粒细胞中最为有效，而在 SCID 和 NXG 小鼠的中性粒细胞中效果较差。然而，当使用全血中的效应细胞时，SCID 和 BALB/c 最为有效，因为这些品系具有更多的中性粒细胞。总体而言，hCD89 转基因小鼠为测试 IgA 免疫疗法对抗传染病和癌症的疗效提供了一个非常强大的模型。
