美国德克萨斯大学Paolo Casali研究小组开发出一种能产生成熟的类别转换、高突变和中和抗体反应的人源化小鼠。这一研究成果于2024年6月25日在线发表在国际学术期刊《自然—免疫学》上。

研究人员用人类脐带血CD34⁺细胞移植非γ-辐照、基因缺损的Kit^W-41J突变免疫缺陷幼鼠，然后用17β-estradiol调节促进免疫细胞分化，从而构建了人源化（THX）小鼠。THX小鼠重建了人类淋巴和骨髓免疫系统，包括边缘区B细胞、生发中心B细胞、滤泡辅助性T细胞和中性粒细胞，并发育出成形的淋巴结和肠道淋巴组织，包括佩耶氏斑块和人类胸腺上皮细胞。这些小鼠具有多样化的人类B细胞和T细胞抗原受体谱系，能产生成熟的依赖T细胞和不依赖T细胞的抗体反应，包括体细胞超突变、类转换重组、浆细胞和记忆B细胞分化。

接种鞭毛蛋白或辉瑞冠状病毒病2019 mRNA疫苗后，THX小鼠会对沙门氏菌或严重急性呼吸道综合征冠状病毒2刺突S1受体结合域产生中和抗体反应，血液中的人类细胞因子（包括APRIL、BAFF、TGF-β、IL-4和IFN-γ）会增加，所有这些细胞因子都处于生理水平。注射普利司坦后，这些小鼠也会出现狼疮自身免疫。通过利用雌激素活性支持人类免疫细胞分化和抗体反应成熟，THX小鼠为研究人类免疫系统以及开发人类疫苗和疗法提供了一个平台。

据悉，人源化小鼠在模拟人类免疫方面存在局限性，尤其是在抗体反应方面。

附：英文原文

Title: A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses

Author: Chupp, Daniel P., Rivera, Carlos E., Zhou, Yulai, Xu, Yijiang, Ramsey, Patrick S., Xu, Zhenming, Zan, Hong, Casali, Paolo

Issue&Volume: 2024-06-25

Abstract: Humanized mice are limited in terms of modeling human immunity, particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated KitW-41J mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyer’s patches, and human thymic epithelial cells. These mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, entailing somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon flagellin or Pfizer coronavirus disease 2019 mRNA vaccination, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4 and IFN-γ, all at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics.

DOI: 10.1038/s41590-024-01880-3

Source: https://www.nature.com/articles/s41590-024-01880-3