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  1. Article ; Online: Humanized mouse models for immuno-oncology research.

    Chuprin, Jane / Buettner, Hannah / Seedhom, Mina O / Greiner, Dale L / Keck, James G / Ishikawa, Fumihiko / Shultz, Leonard D / Brehm, Michael A

    Nature reviews. Clinical oncology

    2023  Volume 20, Issue 3, Page(s) 192–206

    Abstract: Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical ... ...

    Abstract Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.
    MeSH term(s) Animals ; Mice ; Humans ; Neoplasms/therapy ; Disease Models, Animal ; Immunotherapy ; Biomarkers ; Immune System
    Chemical Substances Biomarkers
    Language English
    Publishing date 2023-01-12
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2491410-1
    ISSN 1759-4782 ; 1759-4774
    ISSN (online) 1759-4782
    ISSN 1759-4774
    DOI 10.1038/s41571-022-00721-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Enhanced development of functional human NK cells in NOD-scid-IL2rg

    Aryee, Ken-Edwin / Burzenski, Lisa M / Yao, Li-Chin / Keck, James G / Greiner, Dale L / Shultz, Leonard D / Brehm, Michael A

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2022  Volume 36, Issue 9, Page(s) e22476

    Abstract: Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell ... ...

    Abstract Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell subsets that mediate tumor cell cytotoxicity and subsets with regulatory function that contribute to the tumor immune suppressive environment. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. However, human NK cell development and survival in humanized NOD-scid-IL2rg
    MeSH term(s) Animals ; Disease Models, Animal ; Humans ; Immunity, Innate ; Interleukin Receptor Common gamma Subunit/genetics ; Interleukin-15/genetics ; Killer Cells, Natural ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID
    Chemical Substances IL2RG protein, human ; Il2rg protein, mouse ; Interleukin Receptor Common gamma Subunit ; Interleukin-15
    Language English
    Publishing date 2022-08-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202200045R
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  3. Article ; Online: Generation of the NeoThy mouse model for human immune system studies.

    Del Rio, Natalia M / Huang, Liupei / Murphy, Lydia / Babu, Jayalaxmi Suresh / Daffada, Cross Matthew / Haynes, William John / Keck, James G / Brehm, Michael A / Shultz, Leonard D / Brown, Matthew E

    Lab animal

    2023  Volume 52, Issue 7, Page(s) 149–168

    Abstract: Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone ... ...

    Abstract Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone marrow, liver, thymus humanized mouse, which uses fetal tissues for generating a chimeric human immune system, the NeoThy humanized mouse uses nonfetal tissue sources. Specifically, the NeoThy model incorporates hematopoietic stem and progenitor cells from umbilical cord blood (UCB) as well as thymus tissue that is typically discarded as medical waste during neonatal cardiac surgeries. Compared with fetal thymus tissue, the abundant quantity of neonatal thymus tissue offers the opportunity to prepare over 1,000 NeoThy mice from an individual thymus donor. Here we describe a protocol for processing of the neonatal tissues (thymus and UCB) and hematopoietic stem and progenitor cell separation, human leukocyte antigen typing and matching of allogenic thymus and UCB tissues, creation of NeoThy mice, assessment of human immune cell reconstitution and all experimental steps from planning and design to data analysis. This entire protocol takes a total of ~19 h to complete, with steps broken up into multiple sessions of 4 h or less that can be paused and completed over multiple days. The protocol can be completed, after practice, by individuals with intermediate laboratory and animal handling skills, enabling researchers to make effective use of this promising in vivo model of human immune function.
    MeSH term(s) Humans ; Animals ; Mice ; Immune System ; Thymus Gland ; Disease Models, Animal ; Liver ; Research Personnel
    Language English
    Publishing date 2023-06-29
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ISSN 1548-4475
    ISSN (online) 1548-4475
    DOI 10.1038/s41684-023-01196-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Creation of PDX-Bearing Humanized Mice to Study Immuno-oncology.

    Yao, Li-Chin / Aryee, Ken-Edwin / Cheng, Mingshan / Kaur, Pali / Keck, James G / Brehm, Michael A

    Methods in molecular biology (Clifton, N.J.)

    2019  Volume 1953, Page(s) 241–252

    Abstract: A significant obstacle to the study of human cancer biology and the testing of human specific immunotherapeutics is the paucity of translational models that recapitulate both the growth of human tumors and the functionality of human immune systems. ... ...

    Abstract A significant obstacle to the study of human cancer biology and the testing of human specific immunotherapeutics is the paucity of translational models that recapitulate both the growth of human tumors and the functionality of human immune systems. Humanized mice engrafted with human hematopoietic stem cells (HSC) and patient-derived xenografts (PDX) enable preclinical investigation of the interactions between the human immune system and human cancer. We use immunodeficient non-obese diabetic (NOD, scid, gamma) NSG™ or NSG™-SGM3 mice as hosts for establishment of human immunity following HSC injection and for engraftment of human tumors. Here we describe a refined protocol for the subcutaneous implant of solid PDX tumors into humanized mice. Protocols to recover infiltrating immune cells from growing tumors and to evaluate the immune cell subsets by flow cytometry are also described.
    MeSH term(s) Animals ; Flow Cytometry/methods ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immunity ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/pathology ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation/methods ; Neoplasms/immunology ; Neoplasms/pathology ; Transplantation, Heterologous/methods
    Language English
    Publishing date 2019-03-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-9145-7_15
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  5. Article ; Online: Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

    Yang, Jiwon / Jiao, Jing / Draheim, Kyle M / Yang, Guoxiang / Yang, Hongyuan / Yao, Li-Chin / Shultz, Leonard D / Greiner, Dale L / Rajagopal, Deepa / Vessillier, Sandrine / Maier, Curtis C / Mohanan, Sunish / Cai, Danying / Cheng, Mingshan / Brehm, Michael A / Keck, James G

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2023  Volume 37, Issue 6, Page(s) e22995

    Abstract: Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of ... ...

    Abstract Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rg
    MeSH term(s) Humans ; Animals ; Mice ; Mice, Inbred NOD ; Leukocytes, Mononuclear ; T-Lymphocytes ; Treatment Outcome ; Cytokine Release Syndrome ; Cytokines ; Disease Models, Animal ; Mice, Knockout ; Mice, SCID
    Chemical Substances Cytokines
    Language English
    Publishing date 2023-05-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202300040R
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  6. Article ; Online: A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome.

    Ye, Chunting / Yang, Hongyuan / Cheng, Mingshan / Shultz, Leonard D / Greiner, Dale L / Brehm, Michael A / Keck, James G

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2020  Volume 34, Issue 9, Page(s) 12963–12975

    Abstract: Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential ... ...

    Abstract Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential for severe adverse events, including cytokine release syndrome (CRS). CRS is characterized by the rapid production of inflammatory cytokines following delivery of therapy, with symptoms ranging from mild fever to life-threating pathology and multi-organ failure. Overall there is a paucity of models to reliably and accurately predict the induction of CRS by immune therapeutics. Here, we describe the development of a humanized mouse model based on the NOD-scid IL2rg
    MeSH term(s) Animals ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/immunology ; Cytokine Release Syndrome/chemically induced ; Cytokine Release Syndrome/immunology ; Cytokines/immunology ; Disease Models, Animal ; Female ; Leukocytes, Mononuclear/immunology ; Mice ; Mice, Inbred NOD ; Mice, SCID
    Chemical Substances Antibodies, Monoclonal ; Cytokines
    Keywords covid19
    Language English
    Publishing date 2020-08-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202001203R
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  7. Article: A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome

    Ye, Chunting / Yang, Hongyuan / Cheng, Mingshan / Shultz, Leonard D / Greiner, Dale L / Brehm, Michael A / Keck, James G

    FASEB j

    Abstract: Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential ... ...

    Abstract Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential for severe adverse events, including cytokine release syndrome (CRS). CRS is characterized by the rapid production of inflammatory cytokines following delivery of therapy, with symptoms ranging from mild fever to life-threating pathology and multi-organ failure. Overall there is a paucity of models to reliably and accurately predict the induction of CRS by immune therapeutics. Here, we describe the development of a humanized mouse model based on the NOD-scid IL2rgnull (NSG) mouse to study CRS in vivo. PBMC-engrafted NSG, NSG-MHC-DKO, and NSG-SGM3 mice were used to study cytokine release in response to treatment with mAb immunotherapies. Our data show that therapeutic-stimulated cytokine release in these PBMC-based NSG models captures the variation in cytokine release between individual donors, is drug dependent, occurs in the absence of acute xeno-GVHD, highlighting the specificity of the assay, and shows a robust response following treatment with a TGN1412 analog, a CD28 superagonist. Overall our results demonstrate that PBMC-engrafted NSG models are rapid, sensitive, and reproducible platforms to screen novel therapeutics for CRS.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #702550
    Database COVID19

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  8. Article ; Online: Human immune cell engraftment does not alter development of severe acute Rift Valley fever in mice.

    Spengler, Jessica R / McElroy, Anita K / Harmon, Jessica R / Coleman-McCray, JoAnn D / Welch, Stephen R / Keck, James G / Nichol, Stuart T / Spiropoulou, Christina F

    PloS one

    2018  Volume 13, Issue 7, Page(s) e0201104

    Abstract: Rift Valley fever (RVF) in humans is usually mild, but, in a subset of cases, can progress to severe hepatic and neurological disease. Rodent models of RVF generally develop acute severe clinical disease. Here, we inoculated humanized NSG-SGM3 mice with ... ...

    Abstract Rift Valley fever (RVF) in humans is usually mild, but, in a subset of cases, can progress to severe hepatic and neurological disease. Rodent models of RVF generally develop acute severe clinical disease. Here, we inoculated humanized NSG-SGM3 mice with Rift Valley fever virus (RVFV) to investigate whether the presence of human immune cells in mice would alter the progression of RVFV infection to more closely model human disease. Despite increased human cytokine expression, including responses mirroring those seen in human disease, and decreased hepatic viral RNA levels at terminal euthanasia, both high- and low-dose RVFV inoculation resulted in lethal disease in all mice with comparable time-to-death as unengrafted mice.
    MeSH term(s) Acute Disease ; Animals ; Antigens, CD34/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/metabolism ; Humans ; Liver/immunology ; Liver/virology ; Mice ; RNA, Viral/metabolism ; Rift Valley Fever/immunology ; Rift Valley Fever/therapy ; Rift Valley fever virus/physiology ; Severity of Illness Index
    Chemical Substances Antigens, CD34 ; Cytokines ; RNA, Viral
    Language English
    Publishing date 2018-07-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0201104
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  9. Article ; Online: Severity of Disease in Humanized Mice Infected With Ebola Virus or Reston Virus Is Associated With Magnitude of Early Viral Replication in Liver.

    Spengler, Jessica R / Saturday, Greg / Lavender, Kerry J / Martellaro, Cynthia / Keck, James G / Nichol, Stuart T / Spiropoulou, Christina F / Feldmann, Heinz / Prescott, Joseph

    The Journal of infectious diseases

    2017  Volume 217, Issue 1, Page(s) 58–63

    Abstract: Both Ebola virus (EBOV) and Reston virus (RESTV) cause disease in nonhuman primates, yet only EBOV causes disease in humans. To investigate differences in viral pathogenicity, humanized mice (hu-NSG-SGM3) were inoculated with EBOV or RESTV. Consistent ... ...

    Abstract Both Ebola virus (EBOV) and Reston virus (RESTV) cause disease in nonhuman primates, yet only EBOV causes disease in humans. To investigate differences in viral pathogenicity, humanized mice (hu-NSG-SGM3) were inoculated with EBOV or RESTV. Consistent with differences in disease in human infection, pronounced weight loss and markers of hepatic damage and disease were observed exclusively in EBOV-infected mice. These abnormalities were associated with significantly higher EBOV replication in the liver but not in the spleen, suggesting that in this model, efficiency of viral replication in select tissues early in infection may contribute to differences in viral pathogenicity.
    MeSH term(s) Animals ; Body Weight ; Disease Models, Animal ; Ebolavirus/growth & development ; Hemorrhagic Fever, Ebola/pathology ; Hemorrhagic Fever, Ebola/virology ; Humans ; Liver/virology ; Liver Function Tests ; Mice ; Mice, SCID ; Virus Replication
    Language English
    Publishing date 2017-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jix562
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  10. Article ; Online: Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

    Wang, Minan / Yao, Li-Chin / Cheng, Mingshan / Cai, Danying / Martinek, Jan / Pan, Chong-Xian / Shi, Wei / Ma, Ai-Hong / De Vere White, Ralph W / Airhart, Susan / Liu, Edison T / Banchereau, Jacques / Brehm, Michael A / Greiner, Dale L / Shultz, Leonard D / Palucka, Karolina / Keck, James G

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2018  Volume 32, Issue 3, Page(s) 1537–1549

    Abstract: Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- ... ...

    Abstract Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- Prkdc
    MeSH term(s) Animals ; Antibodies, Monoclonal, Humanized/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cell Line, Tumor ; Female ; Humans ; Immunity, Cellular/drug effects ; Immunotherapy ; Mice ; Mice, Inbred NOD ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Programmed Cell Death 1 Receptor/immunology ; Xenograft Model Antitumor Assays
    Chemical Substances Antibodies, Monoclonal, Humanized ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; pembrolizumab (DPT0O3T46P)
    Language English
    Publishing date 2018-01-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.201700740R
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