DOCSLIB.ORG

NOG Mice Transgenic − Using Human IL-3/GM-CSF Establishment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
NOG Mice Transgenic − Using Human IL-3/GM-CSF Establishment Establishment of a Human Allergy Model Using Human IL-3/GM-CSF−Transgenic NOG Mice This information is current as Ryoji Ito, Takeshi Takahashi, Ikumi Katano, Kenji Kawai, of September 26, 2021. Tsutomu Kamisako, Tomoyuki Ogura, Miyuki Ida-Tanaka, Hiroshi Suemizu, Satoshi Nunomura, Chisei Ra, Akio Mori, Sadakazu Aiso and Mamoru Ito J Immunol 2013; 191:2890-2899; Prepublished online 16 August 2013; Downloaded from doi: 10.4049/jimmunol.1203543 http://www.jimmunol.org/content/191/6/2890 Supplementary http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.120354 http://www.jimmunol.org/ Material 3.DC1 References This article cites 45 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/191/6/2890.full#ref-list-1 Why The JI? Submit online. by guest on September 26, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice Ryoji Ito,*,† Takeshi Takahashi,* Ikumi Katano,* Kenji Kawai,* Tsutomu Kamisako,* Tomoyuki Ogura,* Miyuki Ida-Tanaka,* Hiroshi Suemizu,* Satoshi Nunomura,‡ Chisei Ra,‡ Akio Mori,x Sadakazu Aiso,† and Mamoru Ito* The development of animal models that mimic human allergic responses is crucial to study the pathophysiology of disease and to generate new therapeutic methodologies. Humanized mice reconstituted with human immune systems are essential to study human immune reactions in vivo and are expected to be useful for studying human allergies. However, application of this technology to the study of human allergies has been limited, largely because of the poor development of human myeloid cells, especially granulocytes and mast cells, which are responsible for mediating allergic diseases, in conventional humanized mice. In this study, we developed a novel transgenic (Tg) strain, NOD/Shi-scid-IL2rgnull (NOG), bearing human IL-3 and GM-CSF genes (NOG IL-3/GM–Tg). In Downloaded from this strain, a large number of human myeloid cells of various lineages developed after transplantation of human CD34+ hema- topoietic stem cells. Notably, mature basophils and mast cells expressing Fc«RI were markedly increased. These humanized NOG IL-3/GM–Tg mice developed passive cutaneous anaphylaxis reactions when administered anti–4-hydroxy-3-nitrophenylacetyl IgE Abs and 4-hydroxy-3-nitrophenylacetyl. More importantly, a combination of serum from Japanese cedar pollinosis patients and cedar pollen extract also elicited strong passive cutaneous anaphylaxis responses in mice. Thus, to our knowledge, our NOG IL-3/ GM–Tg mice are the first humanized mouse model to enable the study of human allergic responses in vivo and are excellent tools http://www.jimmunol.org/ for preclinical studies of allergic diseases. The Journal of Immunology, 2013, 191: 2890–2899. odent models for human allergies, including atopic der- humanized mouse technologies within the last 2 decades. These matitis (1), asthma (2), allergic rhinitis (3), and food al- mouse models were expected to recapitulate various human dis- R lergies (4, 5), have allowed researchers to elucidate im- eases, including cancer (6–9), infectious disease (10–14), and portant fundamental principles of the cellular and molecular graft-versus-host-disease (GVHD) (15, 16), and to enhance basic mechanisms of these diseases. However, it was suggested that research in human physiology and pathology, as well as the de- animal models do not always reflect all aspects of human allergic velopment of clinical drugs. Recently, severely immunodeficient by guest on September 26, 2021 diseases because of differences between species. The gap between mouse strains, such as NOD/Shi-scid IL2rgnull (NOG) (17–19), these animal models and human clinical settings has prevented the NOD/LtSz-scid IL2rgnull (NSG) (20), and BALB/c Rag2null development of effective therapeutic strategies for the treatment of IL2rgnull (21, 22), enabled long-term engraftment of human tis- human allergies. sues because of the total lack of the endogenous mouse immune Reconstitution of human hematopoietic and immune systems in system, enormously improving the generation of humanized mice. immunodeficient mouse strains was a major advance in the field of Our group previously demonstrated that efficient human hemato- poiesis could be seen in NOG mice upon transplantation of human hematopoietic stem cells (HSCs; hu-HSC NOG mice) (17, 23). In *Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, Kanagawa particular, lymphopoiesis was evident, and human B and T cells 210-0821, Japan; †Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; ‡Division of Molecular Cell Immunology and accounted for the majority of human cells in hu-HSC NOG mice. Allergology, Nihon University, Graduate School of Medical Science, Itabashi-ku, Accumulating evidence suggests that these human lymphocytes can Tokyo 173-8610, Japan; and xNational Hospital Organization, Sagamihara Na- tional Hospital, Clinical Research Center, Minami-ku, Sagamihara, Kanagawa mediate proper immune reactions, even if the response remains 252-0315, Japan suboptimal. In contrast, the differentiation of human myeloid line- Received for publication December 27, 2012. Accepted for publication July 16, 2013. age cells, especially granulocytes and mast cells, in conventional hu- This work was supported by a grant from the Research Foundation for Pharmaceu- HSC NOG mice has been inefficient (23, 24). Considering the tical Sciences and by Grants-in-Aid for Young Scientists (B) 22700458 and Scientific emerging roles of granulocytes and mast cells in allergic inflam- Research (S) 22220007 from the Ministry of Education, Culture, Sports, Science and matory diseases, it is important to establish useful animal models in Technology of Japan. which we can analyze and manipulate the functions of human Address correspondence and reprint requests to Dr. Mamoru Ito, Central Institute for Experimental Animals, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa granulocytes and mast cells. Poor differentiation of these cells may 210-0821, Japan. E-mail address: [email protected] be attributed, in part, to an insufficient supply of cytokines, such as The online version of this article contains supplemental material. G-CSF, GM-CSF, IL-3, IL-6, Fms-related tyrosine kinase 3 ligand, Abbreviations used in this article: BALF, bronchoalveolar lavage fluid; BM, bone thrombopoietin (TPO), and stem cell factor (SCF) (25–29). Re- marrow; CIEA, Central Institute for Experimental Animals; GVHD, graft-versus-host cently, several groups attempted to improve the efficiency of human disease; h, human; HSC, hematopoietic stem cell; KI, knock-in; m, mouse; MCC, mast cell chymase; MCT, mast cell containing tryptase; MCTC, mast cell containing granulopoiesis in humanized mice by engineering mice to express tryptase and chymase; NOG, NOD/Shi-scid IL2rgnull; NP, 4-hydroxy-3-nitrophenyl- human genes encoding these cytokines. Billerbeck et al. (30) de- null acetyl; NSG, NOD/LtSz-scid IL2rg ; PB, peripheral blood; PCA, passive cutane- veloped a transgenic (Tg) NSG mouse strain expressing human (h) ous anaphylaxis; SCF, stem cell factor; Tg, transgenic; TPO, thrombopoietin. SCF, hGM-CSF, and hIL-3 (SGM3-Tg) and demonstrated that the + + Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 development of CD33 myeloid cells and CD15 granulocytes was www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203543 The Journal of Immunology 2891 slightly enhanced in SGM3-Tg mice compared with non-Tg control hCD56–PE, anti-hCD203c–PE, anti-hCD38–PE, anti-hCD34–PE–Cy7, mice following transplantation with hHSCs. Furthermore, Rongvaux anti-hCD3–PE–Cy7, anti–hc-kit–PE–Cy7, anti-CD14–PE–Cy7, anti-hFcεRI– et al. (31) established hTPO knock-in (KI) mice in which the mouse allophycocyanin, and anti-hCD11c–allophycocyanin (BioLegend, San Diego, CA). TPO gene locus was replaced with the corresponding human gene locus. Upon transplantation of hHSCs, this strain showed remark- Determination of human granulocytes able differentiation of monocytes and granulocytes. However, gen- At 11 wk after HSC transplantation, PB was collected from the orbital vein eration of mast cells and several granulocyte subpopulations of humanized NOG IL-3/GM–Tg and non-Tg NOG mice under anesthesia. remained insufficient. Moreover, although the efficient develop- Single-cell suspensions were prepared using BD Pharm Lyse (BD Bio- + + ment of human granulocytes and mast cells was demonstrated in sciences), and hCD45 cells were purified by eliminating mCD45 cells using MACS. Briefly, the cells were stained with biotinylated anti-mCD45 humanized membrane-bound SCF-Tg NSG mice (32), the func- Abs in MACS running buffer
Load more

Recommended publications
  • Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A- NOG Mice S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/02/23/jpet.117.247288.DC1 1521-0103/365/2/272–280$35.00 https://doi.org/10.1124/jpet.117.247288 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 365:272–280, May 2018 Copyright ª 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A- NOG Mice s JoEllyn M. McMillan, Denise A. Cobb, Zhiyi Lin, Mary G. Banoub, Raghubendra S. Dagur, Amanda A. Branch Woods, Weimin Wang, Edward Makarov, Ted Kocher, Poonam S. Joshi, Rolen M. Quadros, Donald W. Harms, Samuel M. Cohen, Howard E. Gendelman, Channabasavaiah B. Gurumurthy, Santhi Gorantla, and Larisa Y. Poluektova Department of Pharmacology and Experimental Neuroscience (J.M.M., D.A.C., M.G.B., R.S.D., A.A.B.W., W.W., E.M., T.K., P.S. J., H.E.G., S.G., L.Y.P.), Developmental Neuroscience, Munroe Meyer Institute for Genetics and Rehabilitation (C.B.G.), Department of Pharmaceutical Sciences (Z.L.), Mouse Genome Engineering Core Facility, Vice Chancellor for Research Office Downloaded from (R.M.Q., D.W.H., C.B.G.), and Department of Pathology and Microbiology (S.M.C.), University of Nebraska Medical Center, Omaha, Nebraska Received December 18, 2017; accepted February 22, 2018 ABSTRACT jpet.aspetjournals.org Antiretroviral drug (ARV) metabolism is linked largely to hepatic studies we used nanoformulated atazanavir (nanoATV) with or cytochrome P450 activity.
    [Show full text]
  • Humanized Mouse Models for the Study of Hepatitis C and Host Interactions
    cells Review Humanized Mouse Models for the Study of Hepatitis C and Host Interactions Kylie Su Mei Yong 1, Zhisheng Her 1 and Qingfeng Chen 1,2,3,* 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, Singapore 138673, Singapore; [email protected] (K.S.M.Y.); [email protected] (Z.H.) 2 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore 3 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China * Correspondence: [email protected]; Tel.: +65-6586-9873 Received: 15 May 2019; Accepted: 13 June 2019; Published: 17 June 2019 Abstract: Hepatitis C virus (HCV) infection is commonly attributed as a major cause of chronic hepatotropic diseases, such as, steatosis, cirrhosis and hepatocellular carcinoma. As HCV infects only humans and primates, its narrow host tropism hampers in vivo studies of HCV-mammalian host interactions and the development of effective therapeutics and vaccines. In this context, we will focus our discussion on humanized mice in HCV research. Here, these humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research will be discussed. Keywords: humanized mice; hepatitis C virus; liver; hepatotropic disease; steatosis; cirrhosis; hepatocellular carcinoma 1. Introduction First identified in 1989, hepatitis C virus (HCV) is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) virus belonging to the genus Hepacivirus of family Flaviviridae [1,2].
    [Show full text]
  • Modeling HIV Infection and Therapies in Humanized Mice
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 Modeling HIV infection and therapies in humanized mice Nischang, Marc ; Gers-Huber, Gustavo ; Audigé, Annette ; Akkina, Ramesh ; Speck, Robert F Abstract: The human immunodeficiency virus (HIV) type-1 is a human-specific virus. The lack ofa widely available small-animal model has seriously hampered HIV research. In 2004, a new humanised mouse model was reported. It was based on the intrahepatic injection of human CD34+ cord blood cells into newborn, highly immunodeficient mice. These mice develop a lymphoid system of human origin and are highly susceptible to HIV infection and showed disseminated infection, persistent viraemia and characteristic helper CD4+ T-cell loss. Here, we will briefly review the various existing humanised mouse models and highlight their value to the study of HIV infection. DOI: https://doi.org/10.4414/smw.2012.13618 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-68798 Journal Article Published Version Originally published at: Nischang, Marc; Gers-Huber, Gustavo; Audigé, Annette; Akkina, Ramesh; Speck, Robert F (2012). Modeling HIV infection and therapies in humanized mice. Swiss Medical Weekly, 142:w13618. DOI: https://doi.org/10.4414/smw.2012.13618 Review article: Medical intelligence | Published 9 July 2012, doi:10.4414/smw.2012.13618 Cite this as: Swiss Med Wkly. 2012;142:w13618 Modelling HIV infection and therapies in humanised mice Marc Nischanga, Gustavo Gers-Hubera, Annette Audigé a, Ramesh Akkinab, Roberto F. Specka a Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, University of Zurich, Switzerland b Department of Microbiology, Immunology and Pathology, Colorado State University, Colorado, USA Summary somewhat permissive to HIV infection [1].
    [Show full text]
  • Modeling EBV Infection and Pathogenesis in New-Generation Humanized Mice
    OPEN Experimental & Molecular Medicine (2015) 47, e135; doi:10.1038/emm.2014.88 & 2015 KSBMB. All rights reserved 2092-6413/15 www.nature.com/emm REVIEW Modeling EBV infection and pathogenesis in new-generation humanized mice Shigeyoshi Fujiwara1,2, Ken-Ichi Imadome1 and Masami Takei2 The development of highly immunodeficient mouse strains has allowed the reconstitution of functional human immune system components in mice. New-generation humanized mice generated in this manner have been extensively used for modeling viral infections that are exclusively human tropic. Epstein–Barr virus (EBV)-infected humanized mice reproduce cardinal features of EBV-associated B-cell lymphoproliferative disease and EBV-associated hemophagocytic lymphohistiocytosis (HLH). Erosive arthritis morphologically resembling rheumatoid arthritis (RA) has also been recapitulated in these mice. Low-dose EBV infection of humanized mice results in asymptomatic, persistent infection. Innate immune responses involving natural killer cells, EBV-specific adaptive T-cell responses restricted by human major histocompatibility and EBV-specific antibody responses are also elicited in humanized mice. EBV-associated T-/natural killer cell lymphoproliferative disease, by contrast, can be reproduced in a distinct mouse xenograft model. In this review, recent findings on the recapitulation of human EBV infection and pathogenesis in these mouse models, as well as their application to preclinical studies of experimental anti-EBV therapies, are described. Experimental & Molecular Medicine (2015) 47, e135; doi:10.1038/emm.2014.88; published online 23 January 2015 ANIMAL MODELS OF EPSTEIN–BARR VIRUS INFECTION EBV belongs to the genus lymphocryptovirus (LCV) of the Humans are the only natural host of Epstein–Barr virus (EBV). γ-herpesvirus subfamily.
    [Show full text]
  • Humanized Mouse Models Fact Sheet
    ALZET Research Application Humanized Mouse Models The nude mouse and severe combined immunodeficiency (SCID) mouse have ALZET Pump Highlights traditionally been used as recipients for human cells or tissues because they lack host immunity and easily accept heterologous cells. The introduction of • Small size for implantation • 9 pump models for mice the non-obese diabetic (NOD)/SCID mouse led to the development of highly • Continuous and controlled immunodeficient strains, able to engraft human cells and tissues more delivery of agents efficiently, which are more appropriate for generating humanized mouse • Minimize side effects and models. experimental variables • Convenient and cost- effective dosing method The humanized mouse – a mouse carrying functional human genes, cells, • Reduced animal handling tissues, and/or organs – is now a powerful research tool for the in vivo study of and stress • Delivery rates ranging from human biology and disease. Humanized mouse models enable a better 0.11 µl/hr to 8 µl/hr understanding of disease pathways and ultimately improve the translational • Delivery durations ranging value of preclinical studies. Various humanized mouse models have been from 1 day to 6 weeks developed for the study of infectious diseases, autoimmunity, transplantation, vaccine development, cancer immunotherapy, regenerative medicine, cell development, and more. Immunodeficient Strains* ALZET® Osmotic Pumps are used extensively with immunodeficient mice, and Nude Mouse hundreds of publications attest to their research value in these species. These SCID Mouse implantable infusion pumps offer a convenient alternative to repetitive NOD/SCID Mouse injections for continuous dosing of unrestrained lab animals. Their automatic NSG Mouse operation, small size and simple design make them suitable for chronic dosing NOG Mouse studies in humanized mouse models.
    [Show full text]
  • Humanized Mouse Model Supports Development, Function, and Tissue Residency of Human Natural Killer Cells
    Humanized mouse model supports development, function, and tissue residency of human natural killer cells Dietmar Herndler-Brandstettera,1, Liang Shana,1,2, Yi Yaob,3, Carmen Stechera, Valerie Plajera, Melanie Lietzenmayera, Till Strowiga,4, Marcel R. de Zoetea,5, Noah W. Palma, Jie Chena, Catherine A. Blishc, Davor Frletad, Cagan Gurerd, Lynn E. Macdonaldd, Andrew J. Murphyd, George D. Yancopoulosd, Ruth R. Montgomeryb, and Richard A. Flavella,e,6 aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06519; bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519; cDepartment of Medicine, Stanford University School of Medicine, Stanford, CA 94305; dRegeneron Pharmaceuticals Inc., Tarrytown, NY 10591; and eHoward Hughes Medical Institute, New Haven, CT 06519 Contributed by Richard A. Flavell, September 18, 2017 (sent for review March 30, 2017; reviewed by Hergen Spits and Wayne M. Yokoyama) Immunodeficient mice reconstituted with a human immune sys- acids identical between humans and mice, is interleukin 15 (IL- tem represent a promising tool for translational research as they 15). IL-15 is essential for the development and/or function of NK may allow modeling and therapy of human diseases in vivo. cells, memory CD8 T cells, CD8αα intraepithelial lymphocytes However, insufficient development and function of human natural (IELs), and tissue-resident NK cells (10, 11). In addition, phys- killer (NK) cells and T cell subsets limit the applicability of human- iological levels of IL-15 are essential for functional antitumor ized mice for studying cancer biology and therapy. Here, we de- responses of NK and T cells in cancer immunotherapy (12).
    [Show full text]
  • Human PBMC-Transferred Murine MHC Class I/II-Deficient NOG Mice
    Cellular & Molecular Immunology (2018) 15, 953–962 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi RESEARCH ARTICLE Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses Tomonori Yaguchi1,5,6, Asuka Kobayashi1,5, Takashi Inozume2, Kenji Morii1, Haruna Nagumo1, Hiroshi Nishio1,3, Takashi Iwata1,3, Yuyo Ka4, Ikumi Katano4, Ryoji Ito4, Mamoru Ito4 and Yutaka Kawakami1,6 Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses. However, when human peripheral blood mononuclear cells (PBMCs) are transferred into NOG (NOD/Shi-scid, IL-2rgnull) mice, severe graft versus host disease (GVHD) hinders long term detailed analysis. Administration 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 GVHD. Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab, indicating induction of antigen-specific B cells in the NOG-dKO mice. Immunization 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 mice. Adoptive 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 cells.
    [Show full text]
  • (PD-1) Blockade in Humanized the NOG-Major Histocompatibility Complex (MHC) Double Knockout Mouse
    Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Antitumor effect of programmed death-1 (PD-1) blockade in humanized the NOG-major histocompatibility complex (MHC) double knockout mouse Tadashi Ashizawa1, Akira Iizuka1, Chizu Nonomura1, Ryota Kondo1, Chie Maeda1, Haruo Miyata1, Takashi Sugino4, Koichi Mitsuya3, Nakamasa Hayashi3, Yoko Nakasu3, Kouji Maruyama2, Ken Yamaguchi5, Ikumi Katano6, Mamoru Ito6, Yasuto Akiyama1, 3* 1Immunotherapy Division, 2Experimental Animal Facility, Shizuoka Cancer Center Research Institute, 3Division of Neurosurgery, 4Division of Pathology, 5Office of the President, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan 6Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan Running title; Antitumor effect of anti-PD-1 antibody in NOG-MHC dKO mice Keywords; Immune checkpoint antibody, anti-PD-1 antibody, humanized NOG mouse, NOG-MHC dKO mouse, autologous immunotherapy model Financial support; This work was supported by a grant to Akira Iizuka from JSPS KAKENHI (Grant Number 26430178), Japan. Address correspondence to: Yasuto Akiyama, M.D., Immunotherapy Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Sunto-gun, Shizuoka 411-8777, Japan. Tel: (+81) 559895222 (Ext. 5330), Fax: (+81) 559896085, e-mail; [email protected] Conflict of interest The authors declare that they have no conflict of interest.
    [Show full text]
  • Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap J
    Published OnlineFirst September 1, 2016; DOI: 10.1158/0008-5472.CAN-16-1260 Cancer Review Research Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap J. Jason Morton1, Gregory Bird2, Yosef Refaeli2,3, and Antonio Jimeno1,3,4 Abstract Cancer research has long been hampered by the limitations patients. This setting also facilitates the examination of inves- of the current model systems. Both cultured cells and mouse tigational cancer therapies, including new immunotherapies. xenografts grow in an environment highly dissimilar to that of This review discusses recent advancements in the generation their originating tumor, frequently resulting in promising treat- and application of HM models, their promise in cancer ments that are ultimately clinically ineffective. The develop- research, and their potential in generating clinically relevant ment of highly immunodeficient mouse strains into which treatments. This review also focuses on current efforts to human immune systems can be engrafted can help bridge this improve HM models by engineering mouse strains expressing gap. Humanized mice (HM) allow researchers to examine human cytokines or HLA proteins and implanting human xenograft growth in the context of a human immune system bone, liver, and thymus tissue to facilitate immune cell and resultant tumor microenvironment, and recent studies maturation and trafficking. Finally, we discuss how these have highlighted the increased similarities in attendant tumor improvements may help direct future HM model cancer structure, metastasis, and signaling to those features in cancer studies. Cancer Res; 1–6. Ó2016 AACR. Introduction an immune response against implanted tissues. NOD mice lack innate immunity. The subsequently identified SCID mice lack Humanized mice: innovative research tools both T and B cells and can be successfully engrafted not only with A barrier to the adequate study of human disease is the human tissues but also with hematopoietic cells.
    [Show full text]
  • The Journal of Toxicological Sciences (J
    The Journal of Toxicological Sciences (J. Toxicol. Sci.) 689 Vol.42, No.6, 689-705, 2017 Original Article Background data on NOD/Shi-scid IL-2Rγnull mice (NOG mice) Kenichiro Kasahara1, Yachiyo Fukunaga1, Saori Igura1, Rie Andoh2, Tsubasa Saito2, Isamu Suzuki2, Hiroyuki Kanemitsu1, Daisuke Suzuki1, Ken Goto2, Daichi Nakamura1, Masahiro Mochizuki2, Masahiko Yasuda3, Ryo Inoue3, Kazutoshi Tamura2 and Mariko Nagatani2 1BoZo Research Center Inc., Tsukuba Research Institute, 8 Okubo, Tsukuba, Ibaraki, 300-2611, Japan 2BoZo Research Center Inc., Gotemba Research Institute, 1284 Kamado, Gotemba, Shizuoka, 412-0039, Japan 3Central Institute for Experimental Animals, 3-25-12, Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-0821, Japan (Received June 5, 2017; Accepted August 29, 2017) ABSTRACT — To obtain background data of NOD/Shi-scid IL-2Rγnull (NOG) mice, severely immune- deficient mice, a total of 120 animals were examined at 7, 26 and 52 weeks-old (20 mice/sex/group). The survival rate at 52 weeks-old was 95% (19/20) in both sexes. Clinically, circling behavior in one direction along the cage wall was observed in males after 8 weeks and females after 47 weeks-old, and hunchback position was found in males after 32 weeks-old. Hematologically, lymphocyte count marked- ly decreased at all ages, while white blood cell count increased in several mice at 52 weeks-old. Blood chemistry results revealed high values of aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase in some females at 26 weeks-old, without any related histological change. Histologically, lymphoid hypoplasia characterized by severe lymphocyte depletion with poorly developed tissue architec- tures was observed. In addition, spongiotic change in the nerve tissue was observed in both sexes at 7 and 26 weeks-old, and intracytoplasmic materials known as tubular aggregates in the skeletal muscles were found in males terminated at 26 and 52 weeks-old and in females at 52 weeks-old.
    [Show full text]
  • Radiosensitivity of Immunodeficient Mice in Oncology Studies
    Research Models and Services Oncology - Mutant Mice Radiosensitivity of immunodeficient mice in oncology studies Introduction Mouse models are powerful in vivo systems that A major limitation of these relatively simple models play an important role in biomedical research. In is the presence of residual immunity, particularly a recent years, there has been growing interest in high level of natural killer (NK) cell activity. To address the use of immunodeficient mice for a wide variety this limitation, strains were developed carrying of applications, including immunology, infectious multiple genetic alterations to further compromise diseases, autoimmunity, and cancer. Mice with the immune system. Perhaps the most well-known of compromised immune systems are invaluable tools these strains is the non-obese diabetic (NOD)-SCID that not only provide critical insight into genes mouse (Shultz, 1995). The breeding of SCID mice into essential for immune function, but when combined the NOD model impairs (but does not completely with the transplantation of human cells or tissues, eliminate) NK-cell activity. These animals have been they also have enormous potential to provide invaluable to the study of hematopoiesis (Dick, scientists with relevant models of human disease. 1997). The development of immunodeficient mice completely lacking NK cells was made possible with Numerous immunodeficient mouse strains mice carrying a deletion or truncation of the common have been developed, and they can be broadly gamma chain/Il2rg (Cao, 1995; DiSanto,1995; Ohbo, grouped into three categories, with each strain 1996). Since Il2rg is required to mediate the effects of carrying different genetic mutations and levels of multiple cytokines including IL-2, IL-4, IL-7, IL-9, and immune deficiencies (Belizario, 2009).
    [Show full text]
  • Long-Term Maintenance of Peripheral Blood Derived Human NK Cells in A
    www.nature.com/scientificreports OPEN Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15- Received: 16 May 2017 Accepted: 27 November 2017 transgenic NOG mouse Published: xx xx xxxx Ikumi Katano1,2, Chiyoko Nishime1, Ryoji Ito1, Tsutomu Kamisako1, Takuma Mizusawa1, Yuyo Ka1, Tomoyuki Ogura1, Hiroshi Suemizu1, Yutaka Kawakami2, Mamoru Ito1 & Takeshi Takahashi1 We generated a novel mouse strain expressing transgenic human interleukin-15 (IL-15) using the severe immunodefcient NOD/Shi-scid-IL-2Rγnull (NOG) mouse genetic background (NOG-IL-15 Tg). Human natural killer (NK) cells, purifed from the peripheral blood (hu-PB-NK) of normal healthy donors, proliferated when transferred into NOG-IL-15 Tg mice. In addition, the cell number increased, and the hu-PB-NK cells persisted for 3 months without signs of xenogeneic graft versus host diseases (xGVHD). These in vivo-expanded hu-PB-NK cells maintained the original expression patterns of various surface antigens, including NK receptors and killer cell immunoglobulin-like receptor (KIR) molecules. They also contained signifcant amounts of granzyme A and perforin. Inoculation of K562 leukemia cells into hu-PB-NK-transplanted NOG-IL-15 Tg mice resulted in signifcant suppression of tumor growth compared with non-transplanted mice. Furthermore, NOG-IL-15 Tg mice allowed for engraftment of in vitro-expanded NK cells prepared for clinical cell therapy. These cells exerted antibody-dependent cell-mediated cytotoxicity (ADCC) on Her2-positive gastric cancer cells in the presence of therapeutic anti-Her2 antibody, and subsequently suppressed tumor growth. Our results collectively suggest that the NOG-IL-15 Tg mice are a useful model for studying human NK biology and evaluating human NK cell-mediated in vivo cytotoxicity.
    [Show full text]