A novel cDNA-uPA/SCID/Rag2-/-/Jak3-/- mouse model for hepatitis virus infection and reconstruction of human immune system
A novel cDNA-uPA/SCID/Rag2-/-/Jak3-/- mouse model for hepatitis virus infection and reconstruction of human immune system
复制标题
一种用于肝炎病毒感染和重建人体免疫系统的新型cDNA-uPA/SCID/Rag2-/-/Jak3-/-小鼠模型
DOI：
10.1111/jvh.13793
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发表时间：
2023
影响因子：
2.5
通讯作者：
Chayama Kazuaki
中科院分区：
文献类型：
--
作者：
Uchida Takuro;Teraoka Yuji;Imamura Michio;Abe‐Chayama Hiromi;Makokha Grace Naswa;Hayes Clair Nelson;Aikata Hiroshi;Hamamura Satoko;Ishida Yuji;Tateno Chise;Shirouzu Takayuki;Kawai Shintaro;Tanaka Yuka;Ohdan Hideki;Okada Seiji;Chayama Kazuaki
尽管人类肝细胞移植免疫缺陷小鼠支持肝炎病毒感染，但由于缺乏适应性免疫系统，这些小鼠无法发展病毒性肝炎。在这项研究中，我们产生了新的免疫缺陷cDNA-尿激酶-型纤溶酶原激活剂（uPA）/SCID/Rag 2 −/−/Jak 3 −/−小鼠，并建立了具有人源化肝脏和免疫系统的小鼠模型。移植人类白细胞抗原（HLA）-A24的人肝细胞导致在cDNA-uPA/SCID/Rag 2-/-/Jak 3-/-小鼠中建立高度替代的肝脏。这些小鼠成功感染了B型肝炎病毒（HBV）和丙型肝炎病毒（HCV），并有助于分析抗HCV药物的效果。在未进行人肝细胞移植的cDNA-uPA/SCID/Rag 2 −/−/Jak 3 −/−小鼠中，给予从HLA-A24供体获得的外周血单核细胞（PBMC）导致在肝浸润细胞中建立22.6%-81.3%的人CD 45阳性单核细胞嵌合体，而不会引起移植物抗宿主病。当小鼠移植人肝细胞，然后给予HLA-A24阳性人PBMC时，移植的人肝细胞和PBMC之间发生同种免疫应答，产生移植的肝细胞特异性抗HLA抗体。总之，我们成功地建立了一个人源化的肝脏/免疫系统，其特征是移植的人免疫细胞和人肝脏之间的同种异体反应，使用一种新的cDNA-uPA/SCID/Rag 2-/-/Jak 3-/-小鼠。该小鼠模型可用于产生具有人类免疫系统的慢性肝炎小鼠模型，不仅可用于肝炎病毒学，还可用于研究移植后肝排斥反应的病理学。
Although human hepatocyte‐transplanted immunodeficient mice support infection with hepatitis viruses, these mice fail to develop viral hepatitis due to the lack of an adaptive immune system. In this study, we generated new immunodeficiency cDNA‐urokinase‐type plasminogen activator (uPA)/SCID/Rag2−/−/Jak3−/−mice and established a mouse model with both a humanized liver and immune system. Transplantation of human hepatocytes with human leukocyte antigen (HLA)‐A24 resulted in establishment of a highly replaced liver in cDNA‐uPA/SCID/Rag2−/−/Jak3−/−mice. These mice were successfully infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) for a prolonged period and facilitate analysis of the effect of anti‐HCV drugs. Administration of peripheral blood mononuclear cells (PBMCs) obtained from an HLA‐A24 donor resulted in establishment of 22.6%–81.3% human CD45‐positive mononuclear cell chimerism in liver‐infiltrating cells without causing graft‐versus‐host disease in cDNA‐uPA/SCID/Rag2−/−/Jak3−/−mice without human hepatocyte transplantation. When mice were transplanted with human hepatocytes and then administered HLA‐A24‐positive human PBMCs, an alloimmune response between transplanted human hepatocytes and PBMCs occurred, with production of transplanted hepatocyte‐specific anti‐HLA antibody. In conclusion, we succeeded in establishing a humanized liver/immune system characterized by an allo‐reaction between transplanted human immune cells and human liver using a novel cDNA‐uPA/SCID/Rag2−/−/Jak3−/−mouse. This mouse model can be used to generate a chronic hepatitis mouse model with a human immune system with application not only to hepatitis virus virology but also to investigation of the pathology of post‐transplantation liver rejection.