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Humanized mouse models of immunological diseases and precision medicine

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Abstract

With the increase in knowledge resulting from the sequencing of the human genome, the genetic basis for the underlying differences in individuals, their diseases, and how they respond to therapies is starting to be understood. This has formed the foundation for the era of precision medicine in many human diseases that is beginning to be implemented in the clinic, particularly in cancer. However, preclinical testing of therapeutic approaches based on individual biology will need to be validated in animal models prior to translation into patients. Although animal models, particularly murine models, have provided significant information on the basic biology underlying immune responses in various diseases and the response to therapy, murine and human immune systems differ markedly. These fundamental differences may be the underlying reason why many of the positive therapeutic responses observed in mice have not translated directly into the clinic. There is a critical need for preclinical animal models in which human immune responses can be investigated. For this, many investigators are using humanized mice, i.e., immunodeficient mice engrafted with functional human cells, tissues, and immune systems. We will briefly review the history of humanized mice, the remaining limitations, approaches to overcome them and how humanized mouse models are being used as a preclinical bridge in precision medicine for evaluation of human therapies prior to their implementation in the clinic.

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References

  • Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143–150

    Article  CAS  PubMed  Google Scholar 

  • Akkina R, Allam A, Balazs AB, Blankson JN, Burnett JC, Casares S, Garcia JV, Hasenkrug KJ, Kashanchi F, Kitchen SG, Klein F, Kumar P, Luster AD, Poluektova LY, Rao M, Sanders-Beer BE, Shultz LD, Zack JA (2016) Improvements and limitations of humanized mouse models for HIV research: NIH/NIAID “meet the experts” 2015 workshop summary. AIDS Res Hum Retroviruses 32:109–119

    Article  PubMed  PubMed Central  Google Scholar 

  • Ali R, Babad J, Follenzi A, Gebe JA, Brehm MA, Nepom GT, Shultz LD, Greiner DL, DiLorenzo TP (2016) Genetically modified human CD4(+) T cells can be evaluated in vivo without lethal graft-versus-host disease. Immunology 148:339–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Babad J, Mukherjee G, Follenzi A, Ali R, Roep BO, Shultz LD, Santamaria P, Yang OO, Goldstein H, Greiner DL, DiLorenzo TP (2015) Generation of beta 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barclay AN, Brown MH (2006) The SIRP family of receptors and immune regulation. Nat Rev Immunol 6:457–464

    Article  CAS  PubMed  Google Scholar 

  • Bar-Ephraim YE, Mebius RE (2016) Innate lymphoid cells in secondary lymphoid organs. Immunol Rev 271:185–199

    Article  CAS  PubMed  Google Scholar 

  • Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A (2011) Development of human CD4+ FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rgamma(null) humanized mice. Blood 117:3076–3086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blunt T, Gell D, Fox M, Taccioli GE, Lehmann AR, Jackson SP, Jeggo PA (1996) Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci USA 93:10285–10290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301:527–530

    Article  CAS  PubMed  Google Scholar 

  • Brady JL, Harrison LC, Goodman DJ, Cowan PJ, Hawthorne WJ, O’Connell PJ, Sutherland RM, Lew AM (2014) Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model. Clin Transl Immunol 3:e29

    Article  CAS  Google Scholar 

  • Brehm MA, Cuthbert A, Yang C, Miller DM, DiIorio P, Laning J, Burzenski L, Gott B, Foreman O, Kavirayani A, Herlihy M, Rossini AA, Shultz LD, Greiner DL (2010) Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol 135:84–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brehm MA, Racki WJ, Leif J, Burzenski L, Hosur V, Wetmore A, Gott B, Herlihy M, Ignotz R, Dunn R, Shultz LD, Greiner DL (2012) Engraftment of human HSC in non-irradiated newborn NOD-scid IL2rgammanull mice is enhanced by transgenic expression of membrane-bound human SCF. Blood 119:2778–2788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brehm MA, Jouvet N, Greiner DL, Shultz LD (2013) Humanized mice for the study of infectious diseases. Curr Opin Immunol 25:428–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brehm MA, Wiles MV, Greiner DL, Shultz LD (2014) Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods 410:3–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brehm MA, Bortell R, Verma M, Shultz LD, Greiner DL (2016) Humanized mice in translational immunology. In: Tan SL (ed) Translational immunology: mechanisms and pharmacological approaches. Elsevier, Amsterdam, pp 285–326

    Chapter  Google Scholar 

  • Brehm MA, Kenney LL, Wiles MV, Low BE, Tisch RM, Burzenski L, Mueller C, Greiner DL, Shultz LD (2018) Lack of acute xenogeneic graft- versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J e-pub ahead of print:fj201800636R

  • Broudy VC (1997) Stem cell factor and hematopoiesis. Blood 90:1345–1364

    CAS  PubMed  Google Scholar 

  • Brown EJ, Frazier WA (2001) Integrin-associated protein (CD47) and its ligands. Trends Cell Biol 11:130–135

    Article  CAS  PubMed  Google Scholar 

  • Brown ME, Zhou Y, McIntosh BE, Norman IG, Lou HE, Biermann M, Sullivan JA, Kamp TJ, Thomson JA, Anagnostopoulos PV, Burlingham WJ (2018) A humanized mouse model generated using surplus neonatal tissue. Stem Cell Rep 10:1175–1183

    Article  CAS  Google Scholar 

  • Bryce PJ, Falahati R, Kenney LL, Leung J, Bebbington C, Tomasevic N, Krier RA, Hsu CL, Shultz LD, Greiner DL, Brehm MA (2016) Humanized mouse model of mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. J Allergy Clin Immunol 138:769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burton OT, Stranks AJ, Tamayo JM, Koleoglou KJ, Schwartz LB, Oettgen HC (2017) A humanized mouse model of anaphylactic peanut allergy. J Allergy Clin Immunol 139:314–322 e319

    Article  CAS  PubMed  Google Scholar 

  • Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET et al (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–238

    Article  CAS  PubMed  Google Scholar 

  • Carragher D, Johal R, Button A, White A, Eliopoulos A, Jenkinson E, Anderson G, Caamano J (2004) A stroma-derived defect in NF-kappaB2−/− mice causes impaired lymph node development and lymphocyte recruitment. J Immunol 173:2271–2279

    Article  CAS  PubMed  Google Scholar 

  • Chappaz S, Finke D (2010) The IL-7 signaling pathway regulates lymph node development independent of peripheral lymphocytes. J Immunol 184:3562–3569

    Article  CAS  PubMed  Google Scholar 

  • Choo JK, Seebach JD, Nickeleit V, Shimizu A, Lei H, Sachs DH, Madsen JC (1997) Species differences in the expression of major histocompatibility complex class II antigens on coronary artery endothelium: implications for cell-mediated xenoreactivity. Transplantation 64:1315–1322

    Article  CAS  PubMed  Google Scholar 

  • Couzin-Frankel J (2014) Hope in a mouse. Science 346:28–29

    Article  CAS  PubMed  Google Scholar 

  • Covassin L, Jangalwe S, Jouvet N, Laning J, Burzenski L, Shultz LD, Brehm MA (2013) Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rgamma(null) (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells. Clin Exp Immunol 174:372–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crotty S (2014) T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis MM (2012) Immunology taught by humans. Sci Transl Med 4:117fs112

    Article  CAS  Google Scholar 

  • DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denton PW, Nochi T, Lim A, Krisko JF, Martinez-Torres F, Choudhary SK, Wahl A, Olesen R, Zou W, Di Santo JP, Margolis DM, Garcia JV (2012) IL-2 receptor gamma-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol 5:555–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Y, Wilkinson A, Idris A, Fancke B, O’Keeffe M, Khalil D, Ju X, Lahoud MH, Caminschi I, Shortman K, Rodwell R, Vuckovic S, Radford KJ (2014) FLT3-ligand treatment of humanized mice results in the generation of large numbers of CD141+ and CD1c+ dendritic cells in vivo. J Immunol 192:1982–1989

    Article  CAS  PubMed  Google Scholar 

  • DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 92:377–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donini C, D’Ambrosio L, Grignani G, Aglietta M, Sangiolo D (2018) Next generation immune-checkpoints for cancer therapy. J Thorac Dis 10:S1581–S1601

    Article  PubMed  PubMed Central  Google Scholar 

  • Editorial (2017) Fantasy politics over fetal-tissue research. Nature 541:133

    Google Scholar 

  • Ellis LM, Reardon DA (2009) Cancer: the nuances of therapy. Nature 458:290–292

    Article  CAS  PubMed  Google Scholar 

  • Gaffen SL, Jain R, Garg AV, Cua DJ (2014) The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenblatt MB, Vbranac V, Tivey T, Tsang K, Tager AM, Aliprantis AO (2012) Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLoS ONE 7:e44664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greiner DL, Shultz LD (1998) Use of NOD/LtSz-scid/scid mice in biomedical research. In: Leiter EH, Atkinson MA (eds) NOD mice and related strains: research applications in diabetes, AIDS, cancer and other diseases. R.G. Landes Co., Austin, pp 173–204

    Google Scholar 

  • Hagai T, Chen X, Miragaia RJ, Rostom R, Gomes T, Kunowska N, Henriksson J, Park JE, Proserpio V, Donati G, Bossini-Castillo L, Vieira Braga FA, Naamati G, Fletcher J, Stephenson E, Vegh P, Trynka G, Kondova I, Dennis M, Haniffa M, Nourmohammad A, Lassig M, Teichmann SA (2018) Gene expression variability across cells and species shapes innate immunity. Nature 563:197–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanazawa A, Ito R, Katano I, Kawai K, Goto M, Suemizu H, Kawakami Y, Ito M, Takahashi T (2018) Generation of human immunosuppressive myeloid cell populations in human interleukin-6 transgenic NOG mice. Front Immunol 9:152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herndler-Brandstetter D, Shan L, Yao Y, Stecher C, Plajer V, Lietzenmayer M, Strowig T, de Zoete MR, Palm NW, Chen J, Blish CA, Frleta D, Gurer C, Macdonald LE, Murphy AJ, Yancopoulos GD, Montgomery RR, Flavell RA (2017) Humanized mouse model supports development, function, and tissue residency of human natural killer cells. Proc Natl Acad Sci USA 114:E9626–E9634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hidalgo M, Bruckheimer E, Rajeshkumar NV, Garrido-Laguna I, De OE, Rubio-Viqueira B, Strawn S, Wick MJ, Martell J, Sidransky D (2011) A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol Cancer Ther 10:1311–1316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosoya M (2012) Preparation of pancreatic beta-cells from human iPS cells with small molecules. Islets 4:249–252

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu Z, Yang YG (2012) Full reconstitution of human platelets in humanized mice after macrophage depletion. Blood 120:1713–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Li X, Coelho-dos-Reis JG, Wilson JM, Tsuji M (2014) An AAV vector-mediated gene delivery approach facilitates reconstitution of functional human CD8+ T cells in mice. PLoS ONE 9:e88205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP (2009) IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 206:25–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T (2002) NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100:3175–3182

    Article  CAS  PubMed  Google Scholar 

  • Ito R, Katano I, Kawai K, Hirata H, Ogura T, Kamisako T, Eto T, Ito M (2009) Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation 87:1654–1658

    Article  CAS  PubMed  Google Scholar 

  • Ito R, Takahashi T, Katano I, Kawai K, Kamisako T, Ogura T, Ida-Tanaka M, Suemizu H, Nunomura S, Ra C, Mori A, Aiso S, Ito M (2013) Establishment of a human allergy model using human IL-3/GM-CSF-transgenic NOG mice. J Immunol 191:2890–2899

    Article  CAS  PubMed  Google Scholar 

  • Iwabuchi R, Ikeno S, Kobayashi-Ishihara M, Takeyama H, Ato M, Tsunetsugu-Yokota Y, Terahara K (2018) Introduction of human Flt3-L and GM-CSF into humanized mice enhances the reconstitution and maturation of myeloid dendritic cells and the development of Foxp3(+)CD4(+) T cells. Front Immunol 9:1042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobs H, Krimpenfort P, Haks M, Allen J, Blom B, Demolliere C, Kruisbeek A, Spits H, Berns A (1999) PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chain-mutant mice and permits thymocyte maturation in Rag- but not CD3gamma-deficient mice. J Exp Med 190:1059–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jangalwe S, Shultz LD, Mathew A, Brehm MA (2016) Improved B cell development in humanized NOD-scid IL2Rgamma(null) mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3. Immun Inflamm Dis 4:427–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaiser J (2018) Too much of a good thing? Science 359:1346–1347

    Article  CAS  PubMed  Google Scholar 

  • Kalscheuer H, Danzl N, Onoe T, Faust T, Winchester R, Goland R, Greenberg E, Spitzer TR, Savage DG, Tahara H, Choi G, Yang YG, Sykes M (2012) A model for personalized in vivo analysis of human immune responsiveness. Sci Transl Med 4:125ra130

    Article  Google Scholar 

  • Kamel-Reid S, Dick JE (1988) Engraftment of immune-deficient mice with human hematopoietic stem cells. Science 242:1706–1709

    Article  CAS  PubMed  Google Scholar 

  • Kametani Y, Katano I, Miyamoto A, Kikuchi Y, Ito R, Muguruma Y, Tsuda B, Habu S, Tokuda Y, Ando K, Ito M (2017) NOG-hIL-4-Tg, a new humanized mouse model for producing tumor antigen-specific IgG antibody by peptide vaccination. PLoS ONE 12:e0179239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katano I, Nishime C, Ito R, Kamisako T, Mizusawa T, Ka Y, Ogura T, Suemizu H, Kawakami Y, Ito M, Takahashi T (2017) Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15- transgenic NOG mouse. Sci Rep 7:17230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  • Kenney LL, Shultz LD, Greiner DL, Brehm MA (2016) Humanized mouse models for transplant immunology. Am J Transpl 16:389–397

    Article  CAS  Google Scholar 

  • King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J, Laning J, Fodor W, Foreman O, Burzenski L, Chase T, Gott B, Rossini AA, Bortell R, Shultz LD, Greiner DL (2009) Hu-PBL-NOD-scid IL2rgnull mouse model of xenogeneic graft-versus-host-like disease and the role of host MHC. Clin Exp Immunol 157:104–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klausen U, Jorgensen NGD, Grauslund JH, Holmstrom MO, Andersen MH (2019) Cancer immune therapy for lymphoid malignancies: recent advances. Semin Immunopathol 41:111–124

    Article  PubMed  Google Scholar 

  • Koyanagi Y, Tanaka Y, Tanaka R, Misawa N, Kawano Y, Tanaka T, Miyasaka M, Ito M, Ueyama Y, Yamamoto N (1997) High levels of viremia in hu-PBL-NOD-scid mice with HIV-1 infection. Leukemia 11(Suppl 3):109–112

    PubMed  Google Scholar 

  • Lan P, Tonomura N, Shimizu A, Wang S, Yang YG (2006) Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108:487–492

    Article  CAS  PubMed  Google Scholar 

  • Landgraf M, McGovern JA, Friedl P, Hutmacher DW (2018) Rational design of mouse models for cancer research. Trends Biotechnol 36:242–251

    Article  CAS  PubMed  Google Scholar 

  • Lavender KJ, Pang WW, Messer RJ, Duley AK, Race B, Phillips K, Scott D, Peterson KE, Chan CK, Dittmer U, Dudek T, Allen TM, Weissman IL, Hasenkrug KJ (2013) BLT-humanized C57BL/6 Rag2−/−gammac−/−CD47−/− mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013–4020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavender KJ, Messer RJ, Race B, Hasenkrug KJ (2014) Production of bone marrow, liver, thymus (BLT) humanized mice on the C57BL/6 Rag2(−/−)gammac(−/−)CD47(−/−) background. J Immunol Methods 407:127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee J, Brehm MA, Greiner D, Shultz LD, Kornfeld H (2013) Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice. BMC Immunol 14:53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee A, Sun S, Sandler A, Hoang T (2018) Recent progress in therapeutic antibodies for cancer immunotherapy. Curr Opin Chem Biol 44:56–65

    Article  CAS  PubMed  Google Scholar 

  • Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de JY, Deng, Di Santo H, Eisenbarth JP, Eynon S, Flavell E, Guzman RA, Huntington CA, Kremsdorf ND, Manns D, Manz MP, Mention MG, Ott JJ, Rathinam M, Rice C, Rongvaux CM, Stevens A, Spits S, Strick-Marchand H, Takizawa H, van Lent H, Wang AU, Weijer C, Willinger K, Ziegler T P (2009) Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe 6:5–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Legrand N, Huntington ND, Nagasawa M, Bakker AQ, Schotte R, Strick-Marchand H, de Geus SJ, Pouw SM, Bohne M, Voordouw A, Weijer K, Di Santo JP, Spits H (2011) Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer-(NK) cell homeostasis in vivo. Proc Natl Acad Sci USA 108:13224–13229

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Y, Mention JJ, Court N, Masse-Ranson G, Toubert A, Spits H, Legrand N, Corcuff E, Strick-Marchand H, Santo JP (2016) A novel Flt3-deficient HIS mouse model with selective enhancement of human DC development. Eur J Immunol 46:1291–1299

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kok A, Strick-Marchand H, Jouvion G, Serafini N, Lim AI, Dusseaux M, Hieu T, Bourgade F, Toubert A, Finke D, Schwartz O, Bousso P, Mouquet H, Di Santo JP (2018) A human immune system mouse model with robust lymph node development. Nat Methods 15:623–630

    Article  CAS  PubMed  Google Scholar 

  • Lipson EJ, Drake CG (2011) Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res 17:6958–6962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lockridge JL, Zhou Y, Becker YA, Ma S, Kenney SC, Hematti P, Capitini CM, Burlingham WJ, Gendron-Fitzpatrick A, Gumperz JE (2013) Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease. Biol Blood Marrow Transpl 19:1310–1322

    Article  Google Scholar 

  • Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel RL, Melton DA (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 106:15768–15773

    Article  PubMed  PubMed Central  Google Scholar 

  • Malcolm SL, Smith EL, Bourne T, Shaw S (2012) A humanised mouse model of cytokine release: comparison of CD3-specific antibody fragments. J Immunol Methods 384:33–42

    Article  CAS  PubMed  Google Scholar 

  • Manz MG (2007) Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity 26:537–541

    Article  CAS  PubMed  Google Scholar 

  • Marchesi F, Martin AP, Thirunarayanan N, Devany E, Mayer L, Grisotto MG, Furtado GC, Lira SA (2009) CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol 2:486–494

    Article  CAS  PubMed  Google Scholar 

  • McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL (1988) The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241:1632–1639

    Article  CAS  PubMed  Google Scholar 

  • Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, Wege AK, Haase AT, Garcia JV (2006) Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12:1316–1322

    Article  CAS  PubMed  Google Scholar 

  • Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738

    Article  CAS  PubMed  Google Scholar 

  • Mosier DE, Gulizia RJ, Baird SM, Wilson DB (1988) Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256–259

    Article  CAS  PubMed  Google Scholar 

  • Nair G, Hebrok M (2015) Islet formation in mice and men: lessons for the generation of functional insulin-producing beta-cells from human pluripotent stem cells. Curr Opin Genet Dev 32:171–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neely HR, Flajnik MF (2015) CXCL13 responsiveness but not CXCR5 expression by late transitional B cells initiates splenic white pulp formation. J Immunol 194:2616–2623

    Article  CAS  PubMed  Google Scholar 

  • Neely HR, Flajnik MF (2016) Emergence and evolution of secondary lymphoid organs. Annu Rev Cell Dev Biol 32:693–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nostro MC, Sarangi F, Yang C, Holland A, Elefanty AG, Stanley EG, Greiner DL, Keller G (2015) Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. Stem Cell Rep 4:591–604

    Article  CAS  Google Scholar 

  • Ohbo K, Suda T, Hashiyama M, Mantani A, Ikebe M, Miyakawa K, Moriyama M, Nakamura M, Katsuki M, Takahashi K, Yamamura K, Sugamura K (1996) Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain. Blood 87:956–967

    CAS  PubMed  Google Scholar 

  • Onoe T, Kalscheuer H, Danzl N, Chittenden M, Zhao G, Yang YG, Sykes M (2011) Human natural regulatory T cell development, suppressive function, and postthymic maturation in a humanized mouse model. J Immunol 187:3895–3903

    Article  CAS  PubMed  Google Scholar 

  • Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA (2014) Generation of functional human pancreatic beta cells in vitro. Cell 159:428–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearson T, Shultz LD, Miller D, King M, Laning J, Fodor W, Cuthbert A, Burzenski L, Gott B, Lyons B, Foreman O, Rossini AA, Greiner DL (2008) Non-obese diabetic-recombination activating gene-1 (NOD-Rag1 null) interleukin (IL)-2 receptor common gamma chain (IL2r gamma null) null mice: a radioresistant model for human lymphohaematopoietic engraftment. Clin Exp Immunol 154:270–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perrin S (2014) Preclinical research: make mouse studies work. Nature 507:423–425

    Article  PubMed  Google Scholar 

  • Raghavan M, Bjorkman PJ (1996) Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol 12:181–220

    Article  CAS  PubMed  Google Scholar 

  • Rahmig S, Kronstein-Wiedemann R, Fohgrub J, Kronstein N, Nevmerzhitskaya A, Bornhauser M, Gassmann M, Platz A, Ordemann R, Tonn T, Waskow C (2016) Improved human erythropoiesis and platelet formation in humanized NSGW41 Mice. Stem Cell Rep 7:591–601

    Article  CAS  Google Scholar 

  • Rezania A, Bruin JE, Xu J, Narayan K, Fox JK, O’Neil JJ, Kieffer TJ (2013) Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells 31:2432–2442

    Article  CAS  PubMed  Google Scholar 

  • Rongvaux A, Takizawa H, Strowig T, Willinger T, Eynon EE, Flavell RA, Manz MG (2013) Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol 31:635–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK, Manz MG, Flavell RA (2014) Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32:364–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725

    Article  CAS  PubMed  Google Scholar 

  • Rosenthal N, Brown S (2007) The mouse ascending: perspectives for human-disease models. Nat Cell Biol 9:993–999

    Article  CAS  PubMed  Google Scholar 

  • Sage PT, Sharpe AH (2016) T follicular regulatory cells. Immunol Rev 271:246–259

    Article  CAS  PubMed  Google Scholar 

  • Sato K, Takeuchi JS, Misawa N, Izumi T, Kobayashi T, Kimura Y, Iwami S, Takaori-Kondo A, Hu WS, Aihara K, Ito M, An DS, Pathak VK, Koyanagi Y (2014) APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. PLoS Pathog 10:e1004453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG, Inflammation, Host Response to Injury LSCRP (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 110:3507–3512

    Article  PubMed  PubMed Central  Google Scholar 

  • Shahjalal HM, Shiraki N, Sakano D, Kikawa K, Ogaki S, Baba H, Kume K, Kume S (2014) Generation of insulin-producing beta-like cells from human iPS cells in a defined and completely xeno-free culture system. J Mol Cell Biol 6:394–408

    Article  CAS  PubMed  Google Scholar 

  • Sharma A, Wu W, Sung B, Huang J, Tsao T, Li X, Gomi R, Tsuji M, Worgall S (2016) Respiratory syncytial virus (RSV) pulmonary infection in humanized mice induces human anti-RSV immune responses and pathology. J Virol 90:5068–5074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL (1995) Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154:180–191

    CAS  PubMed  Google Scholar 

  • Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2rgnull mice engrafted with mobilized human hematopoietic stem cell. J Immunol 174:6477–6489

    Article  CAS  PubMed  Google Scholar 

  • Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130

    Article  CAS  PubMed  Google Scholar 

  • Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12:786–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL (2014) Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb Protoc 2014:694–708

    PubMed  PubMed Central  Google Scholar 

  • Strowig T, Rongvaux A, Rathinam C, Takizawa H, Borsotti C, Philbrick W, Eynon EE, Manz MG, Flavell RA (2011) Transgenic expression of human signal regulatory protein alpha in Rag2-/-γc-/- mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci USA 108:13218–13223

    Article  PubMed  PubMed Central  Google Scholar 

  • Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K, Nakamura M, Takeshita T (1996) The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 14:179–205

    Article  CAS  PubMed  Google Scholar 

  • Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, Goettel JA, Serrao E, Rowe RG, Malleshaiah M, Wong I, Sousa P, Zhu TN, Ditadi A, Keller G, Engelman AN, Snapper SB, Doulatov S, Daley GQ (2017) Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545:432–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Z, Denton PW, Estes JD, Othieno FA, Wei BL, Wege AK, Melkus MW, Padgett-Thomas A, Zupancic M, Haase AT, Garcia JV (2007) Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 204:705–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Hiramatsu H, Fukushima-Shintani M, Heike T, Nakahata T (2007) Efficient assay for evaluating human thrombopoiesis using NOD/SCID mice transplanted with cord blood CD34+ cells. Eur J Haematol 78:123–130

    CAS  PubMed  Google Scholar 

  • Takahashi T, Katano I, Ito R, Goto M, Abe H, Mizuno S, Kawai K, Sugiyama F, Ito M (2018) Enhanced antibody responses in a novel NOG transgenic mouse with restored lymph node organogenesis. Front Immunol 8:2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takao K, Miyakawa T (2014) Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci USA 112:1167–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takao K, Miyakawa T (2015) Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci USA 112:1167–1172

    Article  CAS  PubMed  Google Scholar 

  • Takao K, Hagihara H, Miyakawa T (2014) Reply to Warren et al. and Shay et al.: Commonalities across species do exist and are potentially important. Proc Natl Acad Sci USA 112:E347–E348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takao K, Hagihara H, Miyakawa T (2015) Reply to Warren et al. and Shay et al.: Commonalities across species do exist and are potentially important. Proc Natl Acad Sci USA 112:E347–E348

    Article  CAS  PubMed  Google Scholar 

  • Tan S, Li Y, Xia J, Jin CH, Hu Z, Duinkerken G, Li Y, Khosravi Maharlooei M, Chavez E, Nauman G, Danzl N, Nakayama M, Roep BO, Sykes M, Yang YG (2017) Type 1 diabetes induction in humanized mice. Proc Natl Acad Sci USA 114:10954–10959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Theocharides AP, Rongvaux A, Fritsch K, Flavell RA, Manz MG (2016) Humanized hemato-lymphoid system mice. Haematologica 101:5–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorpe SJ, Stebbings R, Findlay L, Eastwood D, Poole S, Thorpe R (2013) How predictive are in vitro assays for cytokine release syndrome in vivo? A comparison of methods reveals worrying differences in sensitivity and frequency of response. Cytokine 64:471–472

    Article  CAS  PubMed  Google Scholar 

  • Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, Manz MG (2004) Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304:104–107

    Article  CAS  PubMed  Google Scholar 

  • Ueno H, Banchereau J, Vinuesa CG (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR, der Kracht SM, Kester MG, Serreze DV, Shultz LD, Griffioen M, Drijfhout JW, Greiner DL, Roep BO (2012) Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/SCID/IL2RG null mice. PLoS ONE 7:e49213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van de Pavert SA, Olivier BJ, Goverse G, Vondenhoff MF, Greuter M, Beke P, Kusser K, Hopken UE, Lipp M, Niederreither K, Blomhoff R, Sitnik K, Agace WW, Randall TD, de Jonge WJ, Mebius RE (2009) Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat Immunol 10:1193–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viehmann Milam AA, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL (2014) A humanized mouse model of autoimmune insulitis. Diabetes 63:1712–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wadman M (2015) The truth about fetal tissue research. Nature 528:178–181

    Article  CAS  PubMed  Google Scholar 

  • Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD (2017) Humanized mouse models of clinical disease. Annu Rev Pathol 12:187–215

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Yao LC, Cheng M, Cai D, Martinek J, Pan CX, Shi W, Ma AH, De Vere White RW, Airhart S, Liu ET, Banchereau J, Brehm MA, Greiner DL, Shultz LD, Palucka K, Keck JG (2018) Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. FASEB J 32:1537–1549

    Article  CAS  PubMed  Google Scholar 

  • Warren HS, Tompkins RG, Moldawer LL, Seok J, Xu W, Mindrinos MN, Maier RV, Xiao W, Davis RW (2014) Mice are not men. Proc Natl Acad Sci USA 112:E345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe Y, Takahashi T, Okajima A, Shiokawa M, Ishii N, Katano I, Ito R, Ito M, Minegishi M, Minegishi N, Tsuchiya S, Sugamura K (2009) The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gammac(null) (NOG) mice (hu-HSC NOG mice). Int Immunol 21:843–858

    Article  CAS  PubMed  Google Scholar 

  • Weih F, Caamano J (2003) Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 195:91–105

    Article  CAS  PubMed  Google Scholar 

  • Weissmuller S, Kronhart S, Kreuz D, Schnierle B, Kalinke U, Kirberg J, Hanschmann KM, Waibler Z (2016) TGN1412 induces lymphopenia and human cytokine release in a humanized mouse model. PLoS ONE 11:e0149093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkinson RW, Leishman AJ (2018) Further advances in cancer immunotherapy: going beyond checkpoint blockade. Front Immunol 9:1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, Auerbach W, Eynon EE, Stevens S, Manz MG, Flavell RA (2011) Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci USA 108:2390–2395

    Article  PubMed  PubMed Central  Google Scholar 

  • Yaguchi T, Kobayashi A, Inozume T, Morii K, Nagumo H, Nishio H, Iwata T, Ka Y, Katano I, Ito R, Ito M, Kawakami Y (2018) Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses. Cell Mol Immunol 15:953–962

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, Iwamoto C, Nishihara M, Iwasaki H, Miyamoto T, Honma N, Nakao M, Matozaki T, Akashi K (2013) Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood 121:1316–1325

    Article  CAS  PubMed  Google Scholar 

  • Yu H, Borsotti C, Schickel JN, Zhu S, Strowig T, Eynon EE, Frleta D, Gurer C, Murphy AJ, Yancopoulos GD, Meffre E, Manz MG, Flavell RA (2017) A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood 129:959–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, Shi Y, Deng H (2009) Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res 19:429–438

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Zoe Reifsnyder for assistance in preparation of the figures. This work was supported, in part, by U.S. National Institutes of Health (NIH) Office of the Director Grant 1R24 OD018259 (M.A.B., D.L.G., and L.D.S.), and the NIH National Institute of Diabetes and Digestive and Kidney Diseases—supported Human Islet Research Network (https://hirnetwork.org) Grants and NIH UC4 DK104218 (M.A.B., D.L.G., and L.D.S.), CA034196 (to L.D.S.), 1R01 AI132963 (M.A.B. and L.D.S.), 1DP3DK111898 (M.A.B.), and 1R01 DK1035486 (M.A.B.) grants. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Correspondence to Leonard D. Shultz.

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M.A.B. and D.L.G. are consultants for The Jackson Laboratory. The remaining authors declare no conflicts of interest.

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Shultz, L.D., Keck, J., Burzenski, L. et al. Humanized mouse models of immunological diseases and precision medicine. Mamm Genome 30, 123–142 (2019). https://doi.org/10.1007/s00335-019-09796-2

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