PMID- 27608727 OWN - NLM STAT- MEDLINE DCOM- 20170911 LR - 20191101 IS - 1557-8534 (Electronic) IS - 1547-3287 (Print) IS - 1547-3287 (Linking) VI - 25 IP - 24 DP - 2016 Dec 15 TI - Propagating Humanized BLT Mice for the Study of Human Immunology and Immunotherapy. PG - 1863-1873 AB - The humanized bone marrow-liver-thymus (BLT) mouse model harbors a nearly complete human immune system, therefore providing a powerful tool to study human immunology and immunotherapy. However, its application is greatly limited by the restricted supply of human CD34(+) hematopoietic stem cells and fetal thymus tissues that are needed to generate these mice. The restriction is especially significant for the study of human immune systems with special genetic traits, such as certain human leukocyte antigen (HLA) haplotypes or monogene deficiencies. To circumvent this critical limitation, we have developed a method to quickly propagate established BLT mice. Through secondary transfer of bone marrow cells and human thymus implants from BLT mice into NSG (NOD/SCID/IL-2Rgamma(-/-)) recipient mice, we were able to expand one primary BLT mouse into a colony of 4-5 proBLT (propagated BLT) mice in 6-8 weeks. These proBLT mice reconstituted human immune cells, including T cells, at levels comparable to those of their primary BLT donor mouse. They also faithfully inherited the human immune cell genetic traits from their donor BLT mouse, such as the HLA-A2 haplotype that is of special interest for studying HLA-A2-restricted human T cell immunotherapies. Moreover, an EGFP reporter gene engineered into the human immune system was stably passed from BLT to proBLT mice, making proBLT mice suitable for studying human immune cell gene therapy. This method provides an opportunity to overcome a critical hurdle to utilizing the BLT humanized mouse model and enables its more widespread use as a valuable preclinical research tool. FAU - Smith, Drake J AU - Smith DJ AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. AD - 2 Molecular Biology Interdepartmental PhD Program, University of California , Los Angeles, California. FAU - Lin, Levina J AU - Lin LJ AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Moon, Heesung AU - Moon H AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Pham, Alexander T AU - Pham AT AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Wang, Xi AU - Wang X AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Liu, Siyuan AU - Liu S AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Ji, Sunjong AU - Ji S AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. FAU - Rezek, Valerie AU - Rezek V AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 4 Department of Medicine, University of California , Los Angeles, California. AD - 5 AIDS Institute, University of California , Los Angeles, California. FAU - Shimizu, Saki AU - Shimizu S AD - 5 AIDS Institute, University of California , Los Angeles, California. AD - 6 School of Nursing, University of California , Los Angeles, California. FAU - Ruiz, Marlene AU - Ruiz M AD - 5 AIDS Institute, University of California , Los Angeles, California. AD - 6 School of Nursing, University of California , Los Angeles, California. FAU - Lam, Jennifer AU - Lam J AD - 5 AIDS Institute, University of California , Los Angeles, California. AD - 6 School of Nursing, University of California , Los Angeles, California. FAU - Janzen, Deanna M AU - Janzen DM AD - 6 School of Nursing, University of California , Los Angeles, California. AD - 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California , Los Angeles, California. FAU - Memarzadeh, Sanaz AU - Memarzadeh S AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California , Los Angeles, California. AD - 8 Molecular Biology Institute, University of California , Los Angeles, California. AD - 9 Department of Obstetrics and Gynecology, University of California , Los Angeles, California. FAU - Kohn, Donald B AU - Kohn DB AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California , Los Angeles, California. AD - 10 Department of Pediatrics, Division of Hematology/Oncology, University of California , Los Angeles, California. FAU - Zack, Jerome A AU - Zack JA AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 5 AIDS Institute, University of California , Los Angeles, California. AD - 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California , Los Angeles, California. FAU - Kitchen, Scott G AU - Kitchen SG AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 4 Department of Medicine, University of California , Los Angeles, California. AD - 5 AIDS Institute, University of California , Los Angeles, California. FAU - An, Dong Sung AU - An DS AD - 5 AIDS Institute, University of California , Los Angeles, California. AD - 6 School of Nursing, University of California , Los Angeles, California. FAU - Yang, Lili AU - Yang L AD - 1 Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, California. AD - 3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California , Los Angeles, California. AD - 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California , Los Angeles, California. AD - 8 Molecular Biology Institute, University of California , Los Angeles, California. LA - eng GR - DP2 CA196335/CA/NCI NIH HHS/United States GR - P30 AI028697/AI/NIAID NIH HHS/United States GR - P30 CA016042/CA/NCI NIH HHS/United States GR - R01 AI100652/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20161018 PL - United States TA - Stem Cells Dev JT - Stem cells and development JID - 101197107 SB - IM MH - *Allergy and Immunology MH - Animals MH - Bone Marrow/*physiology MH - Cell Lineage MH - Humans MH - *Immunotherapy MH - Inheritance Patterns/genetics MH - Liver/*physiology MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - T-Lymphocytes/cytology MH - Thymus Gland/cytology/*physiology PMC - PMC5165681 OTO - NOTNLM OT - CD34 OT - HSC OT - human immunology OT - human immunotherapy OT - humanized BLT mice OT - propagating COIS- Author Disclosure Statement No competing financial interests exist. EDAT- 2016/10/19 06:00 MHDA- 2017/09/12 06:00 PMCR- 2017/12/15 CRDT- 2016/09/10 06:00 PHST- 2016/10/19 06:00 [pubmed] PHST- 2017/09/12 06:00 [medline] PHST- 2016/09/10 06:00 [entrez] PHST- 2017/12/15 00:00 [pmc-release] AID - 10.1089/scd.2016.0193 [pii] AID - 10.1089/scd.2016.0193 [doi] PST - ppublish SO - Stem Cells Dev. 2016 Dec 15;25(24):1863-1873. doi: 10.1089/scd.2016.0193. Epub 2016 Oct 18.