PMID- 36575861 OWN - NLM STAT- MEDLINE DCOM- 20230307 LR - 20230313 IS - 1365-2893 (Electronic) IS - 1352-0504 (Linking) VI - 30 IP - 3 DP - 2023 Mar TI - A novel cDNA-uPA/SCID/Rag2(-/-) /Jak3(-/-) mouse model for hepatitis virus infection and reconstruction of human immune system. PG - 262-272 LID - 10.1111/jvh.13793 [doi] AB - 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. CI - (c) 2023 John Wiley&Sons Ltd. FAU - Uchida, Takuro AU - Uchida T AUID- ORCID: 0000-0002-6002-5213 AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Teraoka, Yuji AU - Teraoka Y AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Imamura, Michio AU - Imamura M AUID- ORCID: 0000-0002-0745-991X AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Abe-Chayama, Hiromi AU - Abe-Chayama H AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. FAU - Makokha, Grace Naswa AU - Makokha GN AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Hayes, Clair Nelson AU - Hayes CN AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Aikata, Hiroshi AU - Aikata H AUID- ORCID: 0000-0002-3409-2156 AD - Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Hamamura, Satoko AU - Hamamura S AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - PhoenixBio Co., Ltd., Higashihiroshima, Japan. FAU - Ishida, Yuji AU - Ishida Y AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - PhoenixBio Co., Ltd., Higashihiroshima, Japan. FAU - Tateno, Chise AU - Tateno C AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - PhoenixBio Co., Ltd., Higashihiroshima, Japan. FAU - Shirouzu, Takayuki AU - Shirouzu T AD - Molecular Diagnostics Division, Wakunaga Pharmaceutical Co., Ltd., Tokyo, Japan. FAU - Kawai, Shintaro AU - Kawai S AD - Molecular Diagnostics Division, Wakunaga Pharmaceutical Co., Ltd., Tokyo, Japan. FAU - Tanaka, Yuka AU - Tanaka Y AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Ohdan, Hideki AU - Ohdan H AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. FAU - Okada, Seiji AU - Okada S AD - Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan. FAU - Chayama, Kazuaki AU - Chayama K AUID- ORCID: 0000-0002-5530-5341 AD - Research Center for Hepatology and Gastroenterology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan. AD - RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. AD - Hiroshima Institute of Life Sciences, Hiroshima, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230112 PL - England TA - J Viral Hepat JT - Journal of viral hepatitis JID - 9435672 RN - 0 (DNA, Complementary) RN - 0 (HLA-A24 Antigen) RN - EC 2.7.10.2 (JAK3 protein, human) RN - EC 2.7.10.2 (Janus Kinase 3) RN - 0 (RAG2 protein, human) RN - 0 (Rag2 protein, mouse) RN - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator) SB - IM MH - Animals MH - Humans MH - Mice MH - Disease Models, Animal MH - DNA, Complementary MH - Hepacivirus MH - *Hepatitis C/immunology/pathology MH - *Hepatitis Viruses/pathogenicity MH - Hepatocytes MH - HLA-A24 Antigen MH - Janus Kinase 3/immunology/metabolism MH - Leukocytes, Mononuclear MH - Liver/pathology MH - Mice, SCID MH - Mice, Transgenic MH - Urokinase-Type Plasminogen Activator/genetics OTO - NOTNLM OT - HBV OT - HCV OT - human hepatocyte chimeric mice OT - human leukocyte antigen OT - humanized mice EDAT- 2022/12/29 06:00 MHDA- 2023/02/17 06:00 CRDT- 2022/12/28 02:22 PHST- 2022/10/26 00:00 [revised] PHST- 2022/08/12 00:00 [received] PHST- 2022/11/20 00:00 [accepted] PHST- 2022/12/29 06:00 [pubmed] PHST- 2023/02/17 06:00 [medline] PHST- 2022/12/28 02:22 [entrez] AID - 10.1111/jvh.13793 [doi] PST - ppublish SO - J Viral Hepat. 2023 Mar;30(3):262-272. doi: 10.1111/jvh.13793. Epub 2023 Jan 12.