1932

Abstract

Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice, have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain () in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft-versus-host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly personalized medicine in the clinic. This review discusses recent progress in the development and use of humanized mice and highlights their utility for the study of human diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-052016-100332
2017-01-24
2024-06-21
Loading full text...

Full text loading...

/deliver/fulltext/pathol/12/1/annurev-pathol-052016-100332.html?itemId=/content/journals/10.1146/annurev-pathol-052016-100332&mimeType=html&fmt=ahah

Literature Cited

  1. Zschaler J, Schlorke D, Arnhold J. 1.  2014. Differences in innate immune response between man and mouse. Crit. Rev. Immunol. 34:433–54 [Google Scholar]
  2. Ai M, Curran MA. 2.  2015. Immune checkpoint combinations from mouse to man. Cancer Immunol. Immunother. 64:885–92 [Google Scholar]
  3. Brehm MA, Bortell R, Verma M, Shultz LD, Greiner DL. 3.  2016. Humanized mice in translational immunology. Translational Immunology: Mechanisms and Pharmacological Approaches S-L Tan 285–326 Boston: Academic [Google Scholar]
  4. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 4.  2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12:786–98 [Google Scholar]
  5. Shultz LD, Ishikawa F, Greiner DL. 5.  2007. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 7:118–30 [Google Scholar]
  6. Theocharides AP, Rongvaux A, Fritsch K, Flavell RA, Manz MG. 6.  2016. Humanized hemato-lymphoid system mice. Haematologica 101:5–19 [Google Scholar]
  7. Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC. 7.  et al. 2016. Improvements and limitations of humanized mouse models for HIV research: NIH/NIAID “Meet the Experts” 2015 Workshop Summary. AIDS Res. Hum. Retrovir. 32:109–19 [Google Scholar]
  8. King MA, Covassin L, Brehm MA, Racki W, Pearson T. 8.  et al. 2009. Hu-PBL-NOD-scid IL2rgnull mouse model of xenogeneic graft-versus-host-like disease and the role of host MHC. Clin. Exp. Immunol. 157:104–18 [Google Scholar]
  9. Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N. 9.  et al. 2009. The analysis of the functions of human B and T cells in humanized NOD/shi-scid/γcnull (NOG) mice (hu-HSC NOG mice). Int. Immunol. 21:843–58 [Google Scholar]
  10. Halkias J, Yen B, Taylor KT, Reinhartz O, Winoto A. 10.  et al. 2015. Conserved and divergent aspects of human T-cell development and migration in humanized mice. Immunol. Cell Biol. 93:716–26 [Google Scholar]
  11. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW. 11.  et al. 2006. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat. Med. 12:1316–2211 and 12. Describe the development of the BLT model, the most robust human immune system engraftment model available. [Google Scholar]
  12. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG. 12.  2006. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108:487–9211 and 12. Describe the development of the BLT model, the most robust human immune system engraftment model available. [Google Scholar]
  13. Policicchio BB, Pandrea I, Apetrei C. 13.  2016. Animal models for HIV cure research. Front. Immunol. 7:12 [Google Scholar]
  14. Denton PW, Sogaard OS, Tolstrup M. 14.  2016. Using animal models to overcome temporal, spatial and combinatorial challenges in HIV persistence research. J. Transl. Med. 14:44 [Google Scholar]
  15. Veselinovic M, Charlins P, Akkina R. 15.  2016. Modeling HIV-1 mucosal transmission and prevention in humanized mice. Methods Mol. Biol. 1354:203–20 [Google Scholar]
  16. Gaska JM, Ploss A. 16.  2015. Study of viral pathogenesis in humanized mice. Curr. Opin. Virol. 11:14–20 [Google Scholar]
  17. Karpel ME, Boutwell CL, Allen TM. 17.  2015. BLT humanized mice as a small animal model of HIV infection. Curr. Opin. Virol. 13:75–80 [Google Scholar]
  18. Yamada E, Yoshikawa R, Nakano Y, Misawa N, Koyanagi Y, Sato K. 18.  2015. Impacts of humanized mouse models on the investigation of HIV-1 infection: illuminating the roles of viral accessory proteins in vivo. Viruses 7:1373–90 [Google Scholar]
  19. Akkina R. 19.  2013. New generation humanized mice for virus research: comparative aspects and future prospects. Virology 435:14–28 [Google Scholar]
  20. Choudhary SK, Archin NM, Cheema M, Dahl NP, Garcia JV, Margolis DM. 20.  2012. Latent HIV-1 infection of resting CD4+ T cells in the humanized Rag2−/− γc−/− mouse. J. Virol. 86:114–2020, 21, and 22. Describe humanized mouse latency models for HIV, a critical tool needed for identification of treatments that can eliminate this reservoir of HIV. [Google Scholar]
  21. Honeycutt JB, Wahl A, Archin N, Choudhary S, Margolis D, Garcia JV. 21.  2013. HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. Retrovirology 10:12120, 21, and 22. Describe humanized mouse latency models for HIV, a critical tool needed for identification of treatments that can eliminate this reservoir of HIV. [Google Scholar]
  22. Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R. 22.  et al. 2012. HIV latency in the humanized BLT mouse. J. Virol. 86:339–4720, 21, 22. Describe humanized mouse latency models for HIV, a critical tool needed for identification of treatments that can eliminate this reservoir of HIV. [Google Scholar]
  23. Honeycutt JB, Sheridan PA, Matsushima GK, Garcia JV. 23.  2015. Humanized mouse models for HIV-1 infection of the CNS. J. Neurovirol. 21:301–9 [Google Scholar]
  24. Olesen R, Swanson MD, Kovarova M, Nochi T, Chateau M. 24.  et al. 2016. ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions. J. Clin. Investig. 126:892 [Google Scholar]
  25. Sewald X, Ladinsky MS, Uchil PD, Beloor J, Pi R. 25.  et al. 2015. Retroviruses use CD169-mediated trans-infection of permissive lymphocytes to establish infection. Science 350:563–67 [Google Scholar]
  26. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC. 26.  et al. 2011. Prevention of HIV-1 infection with early antiretroviral therapy. N. Engl. J. Med. 365:493–505 [Google Scholar]
  27. Holt N, Wang J, Kim K, Friedman G, Wang X. 27.  et al. 2010. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat. Biotechnol. 28:839–47 [Google Scholar]
  28. Myburgh R, Ivic S, Pepper MS, Gers-Huber G, Li D. 28.  et al. 2015. Lentivector knockdown of CCR5 in hematopoietic stem and progenitor cells confers functional and persistent HIV-1 resistance in humanized mice. J. Virol. 89:6761–72 [Google Scholar]
  29. Kordelas L, Verheyen J, Beelen DW, Horn PA, Heinold A. 29.  et al. 2014. Shift of HIV tropism in stem-cell transplantation with CCR5 Δ32 mutation. N. Engl. J. Med. 371:880–82 [Google Scholar]
  30. Burke BP, Levin BR, Zhang J, Sahakyan A, Boyer J. 30.  et al. 2015. Engineering cellular resistance to HIV-1 infection in vivo using a dual therapeutic lentiviral vector. Mol. Ther. Nucleic Acids 4:e236 [Google Scholar]
  31. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S. 31.  et al. 2014. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989–99 [Google Scholar]
  32. Hur EM, Patel SN, Shimizu S, Rao DS, Gnanapragasam PN. 32.  et al. 2012. Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood 120:4571–82 [Google Scholar]
  33. Palmer BE, Neff CP, Lecureux J, Ehler A, Dsouza M. 33.  et al. 2013. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice. J. Immunol. 190:211–19 [Google Scholar]
  34. Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM. 34.  2013. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLOS ONE 8:e77780 [Google Scholar]
  35. Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. 35.  2012. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481:81–84 [Google Scholar]
  36. Cox J, Mota J, Sukupolvi-Petty S, Diamond MS, Rico-Hesse R. 36.  2012. Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice. J. Virol. 86:7637–49 [Google Scholar]
  37. Frias-Staheli N, Dorner M, Marukian S, Billerbeck E, Labitt RN. 37.  et al. 2014. Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing. J. Virol. 88:2205–18 [Google Scholar]
  38. Jaiswal S, Pazoles P, Woda M, Shultz LD, Greiner DL. 38.  et al. 2012. Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. Immunology 136:334–43 [Google Scholar]
  39. Jaiswal S, Pearson T, Friberg H, Shultz LD, Greiner DL. 39.  et al. 2009. Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rγnull mice. PLOS ONE 4:e7251 [Google Scholar]
  40. Jaiswal S, Smith K, Ramirez A, Woda M, Pazoles P. 40.  et al. 2015. Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp. Biol. Med. 240:67–78 [Google Scholar]
  41. Kuruvilla JG, Troyer RM, Devi S, Akkina R. 41.  2007. Dengue virus infection and immune response in humanized RAG2−/−γc−/− (RAG-hu) mice. Virology 369:143–52 [Google Scholar]
  42. McCarthy M. 42.  2016. WHO sets out $56m Zika virus response plan. BMJ 352:i1042 [Google Scholar]
  43. Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD. 43.  2015. The immunology of Epstein-Barr virus–induced disease. Annu. Rev. Immunol. 33:787–821 [Google Scholar]
  44. Fujiwara S, Imadome K, Takei M. 44.  2015. Modeling EBV infection and pathogenesis in new-generation humanized mice. Exp. Mol. Med. 47:e135 [Google Scholar]
  45. Gujer C, Chatterjee B, Landtwing V, Raykova A, McHugh D, Munz C. 45.  2015. Animal models of Epstein Barr virus infection. Curr. Opin. Virol. 13:6–10 [Google Scholar]
  46. Strowig T, Gurer C, Ploss A, Liu YF, Arrey F. 46.  et al. 2009. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J. Exp. Med. 206:1423–34 [Google Scholar]
  47. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T. 47.  et al. 2010. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγnull humanized mice. PNAS 107:13022–27 [Google Scholar]
  48. Chijioke O, Muller A, Feederle R, Barros MH, Krieg C. 48.  et al. 2013. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep 5:1489–98 [Google Scholar]
  49. Yu CI, Becker C, Wang Y, Marches F, Helft J. 49.  et al. 2013. Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-β.. Immunity 38:818–30 [Google Scholar]
  50. Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM. 50.  et al. 2011. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. PNAS 108:2390–95 [Google Scholar]
  51. Li Y, Chen Q, Zheng D, Yin L, Chionh YH. 51.  et al. 2013. Induction of functional human macrophages from bone marrow promonocytes by M-CSF in humanized mice. J. Immunol. 191:3192–99 [Google Scholar]
  52. Wang LX, Kang G, Kumar P, Lu W, Li Y. 52.  et al. 2014. Humanized-BLT mouse model of Kaposi's sarcoma-associated herpesvirus infection. PNAS 111:3146–51 [Google Scholar]
  53. Libby SJ, Brehm MA, Greiner DL, Shultz LD, McClelland M. 53.  et al. 2010. Humanized nonobese diabetic-scid IL2rγnull mice are susceptible to lethal Salmonella Typhi infection. PNAS 107:15589–9453, 54, and 55. Represent the first animal models for Salmonella typhi infection that have been described. [Google Scholar]
  54. Firoz MM, Pek EA, Chenoweth MJ, Ashkar AA. 54.  2011. Humanized mice are susceptible to Salmonella typhi infection. Cell Mol. Immunol. 8:83–8753, 54, and 55. Represent the first animal models for Salmonella typhi infection that have been described. [Google Scholar]
  55. Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S. 55.  et al. 2010. A mouse model for the human pathogen Salmonella Typhi. Cell Host. Microbe 8369–7653, 54, and 55. Represent the first animal models for Salmonella typhi infection that have been described. [Google Scholar]
  56. Heuts F, Gavier-Widen D, Carow B, Juarez J, Wigzell H, Rottenberg ME. 56.  2013. CD4+ cell-dependent granuloma formation in humanized mice infected with mycobacteria. PNAS 110:6482–87 [Google Scholar]
  57. Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB. 57.  et al. 2013. A humanized mouse model of tuberculosis. PLOS ONE 8:e63331 [Google Scholar]
  58. Lee J, Brehm MA, Greiner D, Shultz LD, Kornfeld H. 58.  2013. Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice. BMC Immunol 14:53 [Google Scholar]
  59. Ludtke A, Oestereich L, Ruibal P, Wurr S, Pallasch E. 59.  et al. 2015. Ebola virus disease in mice with transplanted human hematopoietic stem cells. J. Virol. 89:4700–459 and 60. Describe the development of highly needed small animal models for Ebola virus that will permit rapid evaluation of therapies for Ebola infection. [Google Scholar]
  60. Bird BH, Spengler JR, Chakrabarti AK, Khristova ML, Sealy TK. 60.  et al. 2015. Humanized mouse model of ebola virus disease mimics the immune responses in human disease. J. Infect. Dis. 213:703–1159 and 60. Describe the development of highly needed small animal models for Ebola virus that will permit rapid evaluation of therapies for Ebola infection. [Google Scholar]
  61. Kobak L, Raftery MJ, Voigt S, Kuhl AA, Kilic E. 61.  et al. 2015. Hantavirus-induced pathogenesis in mice with a humanized immune system. J. Gen. Virol. 96:1258–63 [Google Scholar]
  62. Siu E, Ploss A. 62.  2015. Modeling malaria in humanized mice: opportunities and challenges. Ann. N.Y. Acad. Sci. 1342:29–36 [Google Scholar]
  63. Good MF, Hawkes MT, Yanow SK. 63.  2015. Humanized mouse models to study cell-mediated immune responses to liver-stage malaria vaccines. Trends Parasitol 31:583–94 [Google Scholar]
  64. Jimenez-Diaz MB, Mulet T, Viera S, Gomez V, Garuti H. 64.  et al. 2009. Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rγnull mice engrafted with human erythrocytes. Antimicrob. Agents Chemother. 53:4533–36 [Google Scholar]
  65. Soulard V, Bosson-Vanga H, Lorthiois A, Roucher C, Franetich JF. 65.  et al. 2015. Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice. Nat. Commun. 6:7690 [Google Scholar]
  66. Vaughan AM, Mikolajczak SA, Wilson EM, Grompe M, Kaushansky A. 66.  et al. 2012. Complete Plasmodium falciparum liver-stage development in liver-chimeric mice. J. Clin. Investig 122:3618–28 [Google Scholar]
  67. Vaughan AM, Pinapati RS, Cheeseman IH, Camargo N, Fishbaugher M. 67.  et al. 2015. Plasmodium falciparum genetic crosses in a humanized mouse model. Nat. Methods 12:631–33 [Google Scholar]
  68. Foquet L, Meuleman P, Hermsen CC, Sauerwein R, Leroux-Roels G. 68.  2015. Assessment of parasite liver-stage burden in human-liver chimeric mice. Methods Mol. Biol. 1325:59–68 [Google Scholar]
  69. Ernst W, Zimara N, Hanses F, Mannel DN, Seelbach-Gobel B, Wege AK. 69.  2013. Humanized mice, a new model to study the influence of drug treatment on neonatal sepsis. Infect. Immun. 81:1520–31 [Google Scholar]
  70. Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS. 70.  2009. Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. J. Leukoc. Biol. 86:219–27 [Google Scholar]
  71. Skirecki T, Kawiak J, Machaj E, Pojda Z, Wasilewska D. 71.  et al. 2015. Early severe impairment of hematopoietic stem and progenitor cells from the bone marrow caused by CLP sepsis and endotoxemia in a humanized mice model. Stem Cell Res. Ther. 6:142 [Google Scholar]
  72. Ye C, Choi JG, Abraham S, Wu H, Diaz D. 72.  et al. 2012. Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. PNAS 109:21052–57 [Google Scholar]
  73. Cheng L, Li F, Bility MT, Murphy CM, Su L. 73.  2015. Modeling hepatitis B virus infection, immunopathology and therapy in mice. Antiviral Res 121:1–8 [Google Scholar]
  74. von SM, Ding Q, Ploss A. 74.  2014. Visualizing hepatitis C virus infection in humanized mice. J. Immunol. Methods 410:50–59 [Google Scholar]
  75. Li S, Ling C, Zhong L, Li M, Su Q. 75.  et al. 2015. Efficient and targeted transduction of nonhuman primate liver with systemically delivered optimized AAV3B vectors. Mol. Ther. 23:1867–76 [Google Scholar]
  76. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C. 76.  et al. 2001. Hepatitis C virus replication in mice with chimeric human livers. Nat. Med. 7:927–33 [Google Scholar]
  77. Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT. 77.  et al. 2010. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J. Clin. Investig. 120:924–30 [Google Scholar]
  78. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A. 78.  et al. 2011. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140:1334–44 [Google Scholar]
  79. Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P. 79.  et al. 2015. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat. Biotechnol. 33:549–54 [Google Scholar]
  80. Vercauteren K, Van den Eede N, Mesalam AA, Belouzard S, Catanese MT. 80.  et al. 2014. Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents. Hepatology 60:1508–18 [Google Scholar]
  81. de Jong YP, Dorner M, Mommersteeg MC, Xiao JW, Balazs AB. 81.  et al. 2014. Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci. Transl. Med. 6:254ra129 [Google Scholar]
  82. Wang Z, Wu N, Tesfaye A, Feinstone S, Kumar A. 82.  2015. HCV infection-associated hepatocellular carcinoma in humanized mice. Infect. Agent. Cancer 10:24 [Google Scholar]
  83. Allweiss L, Volz T, Lutgehetmann M, Giersch K, Bornscheuer T. 83.  et al. 2014. Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-α administration. J. Hepatol. 60:500–7 [Google Scholar]
  84. Bility MT, Cheng L, Zhang Z, Luan Y, Li F. 84.  et al. 2014. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLOS Pathog 10:e1004032 [Google Scholar]
  85. Giersch K, Allweiss L, Volz T, Helbig M, Bierwolf J. 85.  et al. 2015. Hepatitis delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J. Hepatol. 63:346–53 [Google Scholar]
  86. Allweiss L, Gass S, Giersch K, Groth A, Kah J. 86.  et al. 2016. Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation. J. Hepatol. 64:1033–40 [Google Scholar]
  87. Zhang RR, Zheng YW, Li B, Tsuchida T, Ueno Y. 87.  et al. 2015. Human hepatic stem cells transplanted into a fulminant hepatic failure Alb-TRECK/SCID mouse model exhibit liver reconstitution and drug metabolism capabilities. Stem Cell Res. Ther. 6:49 [Google Scholar]
  88. Xu D, Michie SA, Zheng M, Takeda S, Wu M, Peltz G. 88.  2015. Humanized thymidine kinase–NOG mice can be used to identify drugs that cause animal-specific hepatotoxicity: a case study with furosemide. J. Pharmacol. Exp. Ther. 354:73–78 [Google Scholar]
  89. Xu D, Wu M, Nishimura S, Nishimura T, Michie SA. 89.  et al. 2015. Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity. J. Pharmacol. Exp. Ther. 352:274–80 [Google Scholar]
  90. Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL. 90.  2014. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb. Protoc. 2014:694–708 [Google Scholar]
  91. Cassidy JW, Caldas C, Bruna A. 91.  2015. Maintaining tumor heterogeneity in patient-derived tumor xenografts. Cancer Res 75:2963–68 [Google Scholar]
  92. Shankavaram UT, Bredel M, Burgan WE, Carter D, Tofilon P, Camphausen K. 92.  2012. Molecular profiling indicates orthotopic xenograft of glioma cell lines simulate a subclass of human glioblastoma. J. Cell Mol. Med. 16:545–54 [Google Scholar]
  93. Rosfjord E, Lucas J, Li G, Gerber HP. 93.  2014. Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem. Pharmacol. 91:135–43 [Google Scholar]
  94. Maykel J, Liu JH, Li H, Shultz LD, Greiner DL, Houghton J. 94.  2014. NOD-scidIl2rgtm1Wjl and NOD-Rag1nullIl2rgtm1Wjl: a model for stromal cell–tumor cell interaction for human colon cancer. Dig. Dis. Sci. 59:1169–79 [Google Scholar]
  95. Wege AK, Ernst W, Eckl J, Frankenberger B, Vollmann-Zwerenz A. 95.  et al. 2011. Humanized tumor mice—a new model to study and manipulate the immune response in advanced cancer therapy. Int. J. Cancer 129:2194–206 [Google Scholar]
  96. Roth MD, Harui A. 96.  2015. Human tumor infiltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model. J. Immunother. Cancer 3:12 [Google Scholar]
  97. Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV. 97.  et al. 2014. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32:364–72Describes a humanized mouse model that permits study of the interaction of the human innate immune system with tumors. [Google Scholar]
  98. Rezvani K, Rouce RH. 98.  2015. The application of natural killer cell immunotherapy for the treatment of cancer. Front. Immunol. 6:578 [Google Scholar]
  99. Liu D, Song L, Wei J, Courtney AN, Gao X. 99.  et al. 2012. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. J. Clin. Investig. 122:2221–33 [Google Scholar]
  100. Cany J, van der Waart AB, Tordoir M, Franssen GM, Hangalapura BN. 100.  et al. 2013. Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rgnull mice. PLOS ONE 8:e64384 [Google Scholar]
  101. Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X. 101.  et al. 2010. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 70:9053–61 [Google Scholar]
  102. Schilbach K, Alkhaled M, Welker C, Eckert F, Blank G. 102.  et al. 2015. Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation. Oncoimmunology 4:e1014760 [Google Scholar]
  103. Morton JJ, Bird G, Keysar SB, Astling DP, Lyons TR. 103.  et al. 2016. XactMice: Humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene 35:290–300Describes a potential breakthrough for ex vivo expansion of human HSCs for engraftment into immunodeficient mice. [Google Scholar]
  104. Varga J, Lopatin M, Boden G. 104.  1990. Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus. J. Rheumatol. 17:1226–29 [Google Scholar]
  105. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. 105.  2008. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer 8:299–308 [Google Scholar]
  106. Provasi E, Genovese P, Lombardo A, Magnani Z, Liu PQ. 106.  et al. 2012. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18:807–15 [Google Scholar]
  107. Hudecek M, Lupo-Stanghellini MT, Kosasih PL, Sommermeyer D, Jensen MC. 107.  et al. 2013. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19:3153–64 [Google Scholar]
  108. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M. 108.  et al. 2013. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood 122:3461–72 [Google Scholar]
  109. Song DG, Powell DJ. 109.  2012. Pro-survival signaling via CD27 costimulation drives effective CAR T-cell therapy. Oncoimmunology 1:547–49 [Google Scholar]
  110. Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE. 110.  et al. 2014. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124:1070–80 [Google Scholar]
  111. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. 111.  2013. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31:71–75 [Google Scholar]
  112. 112.  Deleted in proof
  113. Chu Y, Hochberg J, Yahr A, Ayello J, van de Ven C. 113.  et al. 2014. Targeting CD20+ aggressive B-cell non–Hodgkin lymphoma by anti-CD20 CAR mRNA modified expanded natural killer cells in vitro and in NSG mice. Cancer Immunol. Res. 3:333–44 [Google Scholar]
  114. Urbanska K, Lanitis E, Poussin M, Lynn RC, Gavin BP. 114.  et al. 2012. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res 72:1844–52 [Google Scholar]
  115. Horvath C, Andrews L, Baumann A, Black L, Blanset D. 115.  et al. 2012. Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial. Nat. Rev. Immunol. 12:740 [Google Scholar]
  116. Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe T, Ono R. 116.  et al. 2016. Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rγKO mice. Blood 127:722–34 [Google Scholar]
  117. Fisher TS, Kamperschroer C, Oliphant T, Love VA, Lira PD. 117.  et al. 2012. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol. Immunother. 61:1721–33 [Google Scholar]
  118. Mullard A. 118.  2013. New checkpoint inhibitors ride the immunotherapy tsunami. Nat. Rev. Drug Discov. 12:489–92 [Google Scholar]
  119. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ. 118a.  2013. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369:134–44 [Google Scholar]
  120. Sanmamed MF, Rodriguez I, Schalper KA, Onate C, Azpilikueta A. 119.  et al. 2015. Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2−/−IL2Rγnull immunodeficient mice. Cancer Res 75:3466–78 [Google Scholar]
  121. Brady JL, Harrison LC, Goodman DJ, Cowan PJ, Hawthorne WJ. 120.  et al. 2014. Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model. Clin. Transl. Immunol. 3:e29120 and 121. Describe humanized mouse models for evaluation of a cytokine release syndrome critical for evaluating new drugs prior to their advance into the clinic. [Google Scholar]
  122. Weissmuller S, Kronhart S, Kreuz D, Schnierle B, Kalinke U. 121.  et al. 2016. TGN1412 induces lymphopenia and human cytokine release in a humanized mouse model. PLOS ONE 11:e0149093120 and 121. Describe humanized mouse models for evaluation of a cytokine release syndrome critical for evaluating new drugs prior to their advance into the clinic. [Google Scholar]
  123. Brehm MA, Shultz LD. 122.  2012. Human allograft rejection in humanized mice: a historical perspective. Cell Mol. Immunol. 9:225–31 [Google Scholar]
  124. Hogenes M, Huibers M, Kroone C, de Weger R. 123.  2014. Humanized mouse models in transplantation research. Transplant. Rev. 28:103–10 [Google Scholar]
  125. Kenney LL, Shultz LD, Greiner DL, Brehm MA. 124.  2016. Humanized mouse models for transplant immunology. Am. J. Transplant. 16:389–97 [Google Scholar]
  126. Jacobson S, Heuts F, Juarez J, Hultcrantz M, Korsgren O. 125.  et al. 2010. Alloreactivity but failure to reject human islet transplants by humanized Balb/c/Rag2−/−gc−/− mice. Scand. J. Immunol. 71:83–90 [Google Scholar]
  127. Brehm MA, Bortell R, DiIorio P, Leif J, Laning J. 126.  et al. 2010. Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1nullIL2rγnullIns2Akita mice. Diabetes 59:2265–70 [Google Scholar]
  128. Xiao F, Ma L, Zhao M, Huang G, Mirenda V. 127.  et al. 2014. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice. PLOS ONE 9:e90387 [Google Scholar]
  129. Kirkiles-Smith NC, Harding MJ, Shepherd BR, Fader SA, Yi T. 128.  et al. 2009. Development of a humanized mouse model to study the role of macrophages in allograft injury. Transplantation 87:189–97 [Google Scholar]
  130. Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L. 129.  et al. 2014. A humanized mouse model of autoimmune insulitis. Diabetes 63:1712–24 [Google Scholar]
  131. Babad J, Mukherjee G, Follenzi A, Ali R, Roep BO. 130.  et al. 2015. Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin. Exp. Immunol. 179:398–413 [Google Scholar]
  132. Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR. 131.  et al. 2012. Islet-specific CTL cloned from a type 1 diabetes patient cause β-cell destruction after engraftment into HLA-A2 transgenic NOD/SCID/IL2RG null mice. PLOS ONE 7:e49213 [Google Scholar]
  133. Gallagher GR, Brehm MA, Finberg RW, Barton BA, Shultz LD. 132.  et al. 2015. Viral infection of engrafted human islets leads to diabetes. Diabetes 64:1358–69 [Google Scholar]
  134. Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A. 133.  et al. 2014. Generation of functional human pancreatic β cells in vitro. Cell 159:428–39Describes the first in vitro maturation of human pluripotent stem cells into fully functional β cells and their ability to regulate glucose homeostasis in hyperglycemic, immunodeficient mice. [Google Scholar]
  135. Zhao T, Zhang ZN, Westenskow PD, Todorova D, Hu Z. 134.  et al. 2015. Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17:353–59 [Google Scholar]
  136. Andrade D, Redecha PB, Vukelic M, Qing X, Perino G. 135.  et al. 2011. Engraftment of peripheral blood mononuclear cells from systemic lupus erythematosus and antiphospholipid syndrome patient donors into BALB-RAG-2−/− IL-2Rγ−/− mice: a promising model for studying human disease. Arthritis Rheumatol 63:2764–73 [Google Scholar]
  137. Ratliff ML, Ward JM, Merrill JT, James JA, Webb CF. 136.  2015. Differential expression of the transcription factor ARID3a in lupus patient hematopoietic progenitor cells. J. Immunol. 194:940–49 [Google Scholar]
  138. Kuwana Y, Takei M, Yajima M, Imadome K, Inomata H. 137.  et al. 2011. Epstein-Barr virus induces erosive arthritis in humanized mice. PLOS ONE 6:e26630 [Google Scholar]
  139. Misharin AV, Haines GK III, Rose S, Gierut AK, Hotchkiss RS, Perlman H. 138.  2012. Development of a new humanized mouse model to study acute inflammatory arthritis. J. Transl. Med. 10:190 [Google Scholar]
  140. Nolte T, Zadeh-Khorasani M, Safarov O, Rueff F, Gulberg V. 139.  et al. 2013. Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγnull mice engrafted with human peripheral blood mononuclear cells. Clin. Exp. Immunol. 172:349–62 [Google Scholar]
  141. Eschborn M, Weigmann B, Reissig S, Waisman A, Saloga J, Bellinghausen I. 140.  2015. Activated glycoprotein A repetitions predominant (GARP)–expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice. J. Allergy Clin. Immunol. 136:159–68 [Google Scholar]
  142. Martin H, Reuter S, Dehzad N, Heinz A, Bellinghausen I. 141.  et al. 2012. CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease. J. Allergy Clin. Immunol. 129:521–28.E7 [Google Scholar]
  143. Ito R, Takahashi T, Katano I, Kawai K, Kamisako T. 142.  et al. 2013. Establishment of a human allergy model using human IL-3/GM-CSF-transgenic NOG mice. J. Immunol. 191:2890–99142 and 143. Describe the first humanized mouse models for human anaphylaxis responses. [Google Scholar]
  144. Bryce PJ, Falahati R, Kenney L, Leung J, Bebbington C. 143.  et al. 2016. Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. J. Allergy Clin. Immunol. 138:769–79142 and 143. Describe the first humanized mouse models for human anaphylaxis responses. [Google Scholar]
  145. Goettel JA, Biswas S, Lexmond WS, Yeste A, Passerini L. 144.  et al. 2015. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886–95 [Google Scholar]
  146. Tezuka K, Xun R, Tei M, Ueno T, Tanaka M. 145.  et al. 2014. An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity. Blood 123:346–55 [Google Scholar]
  147. Melican K, Aubey F, Dumenil G. 146.  2014. Humanized mouse model to study bacterial infections targeting the microvasculature. J. Vis. Exp. 2014:51134 [Google Scholar]
  148. Kwant-Mitchell A, Ashkar AA, Rosenthal KL. 147.  2009. Mucosal innate and adaptive immune responses against herpes simplex virus type 2 in a humanized mouse model. J. Virol. 83:10664–76 [Google Scholar]
  149. Tanner A, Carlson SA, Nukui M, Murphy EA, Berges BK. 148.  2013. Human herpesvirus 6A infection and immunopathogenesis in humanized Rag2−/−γc−/− mice. J. Virol. 87:12020–28 [Google Scholar]
  150. Hakki M, Goldman DC, Streblow DN, Hamlin KL, Krekylwich CN. 149.  et al. 2014. HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors. Biol. Blood Marrow Transplant. 20:132–35 [Google Scholar]
  151. Tan CS, Broge TA Jr., Seung E, Vrbanac V, Viscidi R. 150.  et al. 2013. Detection of JC virus-specific immune responses in a novel humanized mouse model. PLOS ONE 8:e64313 [Google Scholar]
  152. Wege AK, Florian C, Ernst W, Zimara N, Schleicher U. 151.  et al. 2012. Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response. PLOS Negl. Trop. Dis. 6:e1741 [Google Scholar]
  153. Arvin AM, Moffat JF, Sommer M, Oliver S, Che X. 152.  et al. 2010. Varicella-zoster virus T cell tropism and the pathogenesis of skin infection. Curr. Top. Microbiol. Immunol. 342:189–209 [Google Scholar]
  154. Valbuena G, Halliday H, Borisevich V, Goez Y, Rockx B. 153.  2014. A human lung xenograft mouse model of Nipah virus infection. PLOS Pathog 10:e1004063 [Google Scholar]
  155. Stary G, Olive A, Radovic-Moreno AF, Gondek D, Alvarez D. 154.  et al. 2015. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205 [Google Scholar]
/content/journals/10.1146/annurev-pathol-052016-100332
Loading
/content/journals/10.1146/annurev-pathol-052016-100332
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error