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Development of a humanized HLA-A30 transgenic mouse model

Animal Models and Experimental Medicine 2022年第4期5卷 350-361页

作者： Meng-min Zhu Bo-wen Niu Ling-ling Liu Hua Yang Bo-yin Qin Xiu-hua Peng Li-xiang Chen Yang Liu Chao Wang Xiao-nan Ren Chun-hua Xu Xiao-hui Zhou Feng Li Department of Laboratory Animal Science Shanghai Public Health Clinical CenterShanghaiChina

Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)*** transgenic humanized mouse model systems offer a much better method to study the HLA-A-related principal mechanisms for vaccine development and HLA-Arestricted responses against infection in ***:A recombinant gene encoding the chimeric HLA-A30 monochain was *** HHD molecule contains the following:α1-α2 domains of HLA-A30,α3 and cytoplasmic domains of H-2D~b,linked at its N-terminus to the C-terminus of humanβ2m by a 15-amino-acid peptide *** recombinant gene encoding the chimeric HLA-A30 monochain cassette was introduced into bacterial artificial chromosome(BAC)CH502-67J3 containing the HLA-A01 gene locus by Red-mediated homologous *** BAC CH502-67J3 was microinjected into the pronuclei of wild-type mouse *** humanized mouse model was further used to assess the immune responses against influenza A virus(H1N1)pdm09 clinically isolated from human *** cell population,cytokine production,and histopathology in the lung were ***:We describe a novel humanβ2m-HLA-A30(α1α2)-H-2D~b(α3 transmembrane cytoplasmic)(HHD)monochain transgenic mouse strain,which contains the intact HLA-A01 gene locus including 49 kb 5’-UTR and 74 kb 3’-UTR of HLA-A01**** transgenic lines integrated into the large genomic region of HLA-A gene locus were obtained,and the robust expression of exogenous transgene was detected in various tissues from A30-18#and A30-19#lines encompassing the intact flanking *** cytometry revealed that the introduction of a large genomic region in HLA-A gene locus can influence the immune cell constitution in humanized ***09 infection caused a similar immune response among HLA-A30 Tg humanized mice and wild-type mice,and induced the rapid increase of cytokines,including IFN-γ,TNF-α,and IL-6,in both HLA-A30 humanized

关键词： HLA-A30 humanized mouse immunology major histocompatibility complex(MHC)

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Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses

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Cellular & Molecular Immunology 2018年第11期15卷 953-962页

作者： Tomonori Yaguchi Asuka Kobayashi Takashi Inozume Kenji Morii Haruna Nagumo Hiroshi Nishio Takashi Iwata Yuyo Ka Ikumi Katano Ryoji Ito Mamoru Ito Yutaka Kawakami Division of Cellular Signaling Institute for Advanced Medical ResearchKeio University School of MedicineTokyo 160-8582Japan Department of Dermatology Yamanashi University School of MedicineYamanashi 409-3898Japan Department of Obstetrics and Gynecology Keio University School of MedicineTokyo 160-8582Japan Central Institute for Experimental Animals Kanagawa 210-0821Japan

Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune ***,when human peripheral blood mononuclear cells(PBMCs)are transferred into NOG(NOD/Shi-scid,IL-2rg null)mice,severe graft versus host disease(GVHD)hinders long term detailed *** of human PBMCs into newly developed murine MHC class I-and class II-deficient NOG(NOG-dKO;NOG-Iab,B2m-double-knockout)mice showed sufficient engraftment of human immune cells with little sign of *** with influenza vaccine resulted in an increase in influenza-specific human IgG Ab,indicating induction of antigen-specific B cells in the NOG-dKO *** with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells,indicating the induction of antigen-specific T cells in the NOG-dKO *** cell therapies(ACTs)using melanoma antigen recognized by T cells(MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T *** using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice,in which changes in human cancer phenotypes by immune intervention,such as increased CD271 expression,could be ***,NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.

关键词： adoptive cell therapy humanized mouse vaccine

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Human lymphohematopoietic reconstitution and immune function in immunodeficient mice receiving cotransplantation of human thymic tissue and CD34＋ cells

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Cellular & Molecular Immunology 2012年第3期9卷 232-236页

作者： Zheng Hu Yong-Guang Yang Columbia Center for Translational Immunology Columbia University College of Physicians and Surgeons New York NY USA First Bethune Hospital of Jilin University Changchun China

Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous efforts have been devoted towards the development of such humanized mouse models. This review is focused on human lymphohematopoietic reconstitution and immune function in humanized mice by cotransplantation of human fetal thymic tissue and CD34＋ cells. The potential use of these humanized mice in translational biomedical research is also discussed.

关键词： humanized mouse hematopoiesis immune system immunodeficient mouse thymopoiesis

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Large-cohort humanized NPI mice reconstituted with CD34+ hematopoietic stem cells are feasible for evaluating preclinical cancer immunotherapy

Large-cohort humanized NPI mice reconstituted with CD34+ hem...

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第十四届全国免疫学学术大会

作者： Xiongfei Xu Haihui Gu Hongwei Li Suizhi Gao Xiaohan Shi Jing Shen Bo Li Huan Wang Kailian Zheng Zhuo Shao Siying Peng Yongzhan Nie Zhaoshen Li Shiwei Guo Baohua Qian Gang Jin Changhai Hospital Second Military Medical University 空军军医大学附属西京医院

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and even some patients have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate pre-clinical efficacy and safety in cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34

关键词： humanized mouse T cell cancer immunotherapy checkpoint blockade chimeric antigen receptor T cell Bispecific antibody

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Human CD4 T cells engineered to express a patient-derived islet autoreactive T-cell receptor cause type 1 diabetes in humanized mice

Human CD4 T cells engineered to express a patient-derived is...

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第十一届全国免疫学学术大会

作者： Tan Shulian Xia Jinxing Hu Zheng Yang Yong-Guang The First Hospital and Institute of Immunology Jilin University Columbia Center for Translational Immunology Department of MedicineColumbia University College of Physicians and Surgeons

Objective: To establish T1 D in humanized mice(hu-mice) induced by human immune ***: Streptozotocin-conditioned hu-mice, which were constructed by transplantation of HLA-DQ8 fetal thymus and CD34 cells into HLA-DQ8-transgenic immunodeficient mice, were developed hyperglycemia and diabetes following transfer of autologous HLA-DQ8/insulin-B:9-23(Ins B:9-23)-specific TCR human CD4 T cells and immunization with Ins B:9-23. Result: Our data showed that adoptive transfer of HLA-DQ8-restricted Ins B:9-23-specific human CD4 T cells is capable of inducing diabetes in HLA-DQ8-Tg hu-mice, providing definitive evidence for an important pathogenic role of T cell responses to the Ins B:9-23 epitope in T1 D in ***: These hu-mice offer a potentially useful animal model for investigating immunopathogenesis and therapeutic interventions in human T1 D. Our data directly demonstrate an important pathogenic role of CD4 T cell responses to the Ins B:9-23 epitope in T1 D induction in humans.

关键词： Type Ι diabetes humanized mouse insulin specific TCR T cell engineering

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