Use of humanized mice to study the pathogenesis of autoimmune and inflammatory diseases

Inflammatory Bowel Diseases

Volumn 21, Issue 7, 2015, Pages 1652-1673

  Koboziev, Iurii ^a   Jones Hall, Yava ^b   Valentine, John F ^c   Reinoso Webb, Cynthia ^a   Furr, Kathryn L ^a   Grisham, Matthew B ^a  

^a TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER SCHOOL OF MEDICINE   (United States)

^b PURDUE UNIVERSITY   (United States)

^c UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

allograft rejection; diabetes; fetal liver; fetal thymus; graft versus host disease; hematopoietic stem cells; human immune system; interleukin 2 common gamma receptor; NK cells; NOD mice; rheumatoid arthritis; SCID mice

Indexed keywords

INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR GAMMA;

ADAPTIVE IMMUNITY; ARTICLE; AUTOIMMUNE DISEASE; AUTOINFLAMMATORY DISEASE; DRUG EFFICACY; ENGRAFTMENT; GENE ACTIVATION; GENE MUTATION; GRAFT RECIPIENT; GRAFT VERSUS HOST REACTION; HEMATOPOIETIC CELL; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; INTERVENTION STUDY; MOUSE; MOUSE MODEL; MULTIPLE SCLEROSIS; NOD SCID GAMMA MOUSE; NONHUMAN; NUDE MOUSE; PATHOGENESIS; PRIORITY JOURNAL; RHEUMATIC DISEASE; RHEUMATOID ARTHRITIS; SCID MOUSE; SJOEGREN SYNDROME; SYSTEMIC LUPUS ERYTHEMATOSUS; ANIMAL; DISEASE MODEL; HUMAN; IMMUNOLOGY; INTESTINE MUCOSA; PATHOLOGY;

ADAPTIVE IMMUNITY; ANIMALS; AUTOIMMUNE DISEASES; DISEASE MODELS, ANIMAL; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; MICE;

EID: 84932149475     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1097/MIB.0000000000000446     Document Type: Article

References (215)

1. Koboziev I, Karlsson F, Zhang S, Grisham MB. Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies. Inflamm Bowel Dis. 2011;17:1229-1245.
2. DeVoss J, Diehl L. Murine models of inflammatory bowel disease (IBD): challenges of modeling human disease. Toxicol Pathol. 2014; 42:99-110.
3. Hackam DG, Redelmeier DA. Translation of research evidence from animals to humans. JAMA. 2006;296:1731-1732.
4. Hackam DG. Translating animal research into clinical benefit. BMJ. 2007;334:163-164.
5. Sena ES, van der Worp HB, Bath PM, et al. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol. 2010;8:e1000344.
6. Sena ES, Currie GL, McCann SK, et al. Systematic reviews and metaanalysis of preclinical studies: why perform them and how to appraise them critically. J Cereb Blood Flow Metab. 2014;34:737-742.
7. van der Worp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies?. PLoS Med. 2010;7:e1000245.
8. Valatas V, VakasM, Kolios G. The value of experimental models of colitis in predicting efficacy of biological therapies for inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol. 2013;305:G763-G785.
9. Rongvaux A, Takizawa H, Strowig T, et al. Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol. 2013;31:635-674.
10. Receptive to replication. Nat Biotechnol. 2013;31:943.
11. Arrowsmith J. Trial watch: phase II failures: 2008-2010. Nat Rev Drug Discov. 2011;10:328-329.
12. Arrowsmith J. Trial watch: phase III and submission failures: 2007-2010. Nat Rev Drug Discov. 2011;10:87.
13. Begley CG, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature. 2012;483:531-533.
14. Couzin-Frankel J. When mice mislead. Science. 2013;342:922-923, 925.
15. Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets?. Nat Rev Drug Discov. 2011;10:712.
16. Haley PJ. Species differences in the structure and function of the immune system. Toxicology. 2003;188:49-71.
17. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731-2738.
18. Ariffin JK, Sweet MJ. Differences in the repertoire, regulation and function of toll-like receptors and inflammasome-forming NOD-like receptors between human and mouse. Curr Opin Microbiol. 2013;16: 303-310.
19. Brehm MA, Powers AC, Shultz LD, Greiner DL. Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice. Cold Spring Harb Perspect Med. 2012; 2:a007757.
20. Gibbons DL, Spencer J. Mouse and human intestinal immunity: same ballpark, different players; different rules, same score. Mucosal Immunol. 2011;4:148-157.
21. Mann ER, Landy JD, Bernardo D, et al. Intestinal dendritic cells: their role in intestinal inflammation, manipulation by the gut microbiota and differences between mice and men. Immunol Lett. 2013;150:30-40.
22. Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110:3507-3512.
23. Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2014; 112:1167-1172.
24. Brehm MA, Jouvet N, Greiner DL, Shultz LD. Humanized mice for the study of infectious diseases. Curr Opin Immunol. 2013;25:428-435.
25. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118-130.
26. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12:786-798.
27. Brehm MA, Shultz LD, Greiner DL. Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes. 2010; 17:120-125.
28. Brehm MA, Wiles MV, Greiner DL, Shultz LD. Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods. 2014;410:3-17.
29. Pearson T, Greiner DL, Shultz LD. Creation of humanized mice to study human immunity. Curr Protoc Immunol. 2008. Chapter 15:Unit 21.
30. Shultz LD, Brehm MA, Bavari S, Greiner DL. Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann N Y Acad Sci. 2011;1245:50-54.
31. Zhou Q, Facciponte J, Jin M, et al. Humanized NOD-SCID IL2rg2/2 mice as a preclinical model for cancer research and its potential use for individualized cancer therapies. Cancer Lett. 2014;344:13-19.
32. Ishikawa F, Yasukawa M, Lyons B, et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood. 2005;106:1565-1573.
33. Ito M, Hiramatsu H, Kobayashi K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100:3175-3182.
34. Shultz LD, Lyons BL, Burzenski LM, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174:6477-6489.
35. Traggiai E, Chicha L, Mazzucchelli L, et al. Development of a human adaptive immune system in cord blood cell-Transplanted mice. Science. 2004;304:104-107.
36. Spranger S, Frankenberger B, Schendel DJ. NOD/scid IL-2Rg(null) mice: a preclinical model system to evaluate human dendritic cellbased vaccine strategies in vivo. J Transl Med. 2012;10:30.
37. Vudattu NK, Waldron-Lynch F, Truman LA, et al. Humanized mice as a model for aberrant responses in human T cell immunotherapy. J Immunol. 2014;193:587-596.
38. Flanagan SP. Nude, a new hairless gene with pleiotropic effects in the mouse. Genet Res. 1966;8:295-309.
39. Pantelouris EM. Absence of thymus in a mouse mutant. Nature. 1968; 217:370-371.
40. Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000;14:142-146.
41. Nehls M, Pfeifer D, Schorpp M, et al. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994; 372:103-107.
42. Ganick DJ, Sarnwick RD, Shahidi NT, Manning DD. Inability of intravenously injected monocellular suspensions of human bone marrow to establish in the nude mouse. Int Arch Allergy Appl Immunol. 1980;62: 330-333.
43. Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983;301:527-530.
44. Jeggo PA, Jackson SP, Taccioli GE. Identification of the catalytic subunit of DNA dependent protein kinase as the product of the mouse scid gene. Curr Top Microbiol Immunol. 1996;217:79-89.
45. Kirchgessner CU, Patil CK, Evans JW, et al. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science. 1995; 267:1178-1183.
46. Blunt T, Gell D, Fox M, et al. 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 U S A. 1996;93: 10285-10290.
47. Bosma MJ, Carroll AM. The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol. 1991;9:323-350.
48. Finnie NJ, Gottlieb TM, Blunt T, et al. DNA-dependent protein kinase defects are linked to deficiencies in DNA repair and V(D)J recombination. Philos Trans R Soc Lond B Biol Sci. 1996;351:173-179.
49. Taccioli GE, Amatucci AG, Beamish HJ, et al. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity. 1998;9:355-366.
50. Lieber MR, Hesse JE, Lewis S, et al. The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell. 1988;55:7-16.
51. Malynn BA, Blackwell TK, Fulop GM, et al. The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell. 1988;54:453-460.
52. Greiner DL, Hesselton RA, Shultz LD. SCID mouse models of human stem cell engraftment. Stem Cells. 1998;16:166-177.
53. Bosma GC, Fried M, Custer RP, et al. Evidence of functional lymphocytes in some (leaky) scid mice. J Exp Med. 1988;167:1016-1033.
54. Nonoyama S, Smith FO, Bernstein ID, Ochs HD. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol. 1993;150:3817-3824.
55. Shultz LD, Schweitzer PA, Christianson SW, et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995;154:180-191.
56. Custer RP, Bosma GC, Bosma MJ. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985;120:464-477.
57. Martin A, Valentine M, Unger P, et al. Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration. J Clin Endocrinol Metab. 1994;79: 716-723.
58. Mombaerts P, Iacomini J, Johnson RS, et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68:869-877.
59. Shinkai Y, Rathbun G, Lam KP, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68:855-867.
60. Bock TA, Orlic D, Dunbar CE, et al. Improved engraftment of human hematopoietic cells in severe combined immunodeficient (SCID) mice carrying human cytokine transgenes. J Exp Med. 1995;182:2037-2043.
61. Makino S, Kunimoto K, Muraoka Y, et al. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980;29:1-13.
62. Ogasawara K, Hamerman JA, Hsin H, et al. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity. 2003;18: 41-51.
63. Kataoka S, Satoh J, Fujiya H, et al. Immunologic aspects of the nonobese diabetic (NOD) mouse. Abnormalities of cellular immunity. Diabetes. 1983;32:247-253.
64. Kikutani H, Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol. 1992;51:285-322.
65. Takenaka K, Prasolava TK, Wang JC, et al. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol. 2007;8:1313-1323.
66. Takizawa H, Manz MG. Macrophage tolerance: CD47-SIRP-Alphamediated signals matter. Nat Immunol. 2007;8:1287-1289.
67. Shultz LD, Lang PA, Christianson SW, et al. NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. J Immunol. 2000;164:2496-2507.
68. Hogenes M, Huibers M, Kroone C, de Weger R. Humanized mouse models in transplantation research. Transplant Rev (Orlando). 2014; 28:103-110.
69. Prochazka M, Gaskins HR, Shultz LD, Leiter EH. The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. Proc Natl Acad Sci U S A. 1992;89:3290-3294.
70. DiSanto JP, Muller W, Guy-Grand D, et al. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995;92:377-381.
71. Sugamura K, Asao H, Kondo M, et al. The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol. 1996;14:179-205.
72. Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev. 2004;202:67-83.
73. Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol. 2001;1:200-208.
74. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009;9:480-490.
75. Brehm MA, Cuthbert A, Yang C, et al. 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. 2010;135:84-98.
76. McDermott SP, Eppert K, Lechman ER, et al. Comparison of human cord blood engraftment between immunocompromised mouse strains. Blood. 2010;116:193-200.
77. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335:256-259.
78. King M, Pearson T, Shultz LD, et al. A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin Immunol. 2008; 126:303-314.
79. Brehm MA, Shultz LD, Luban J, Greiner DL. Overcoming current limitations in humanized mouse research. J Infect Dis. 2013;208(suppl 2): S125-S130.
80. King MA, Covassin L, Brehm MA, et al. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol. 2009;157:104-118.
81. McCune JM, Namikawa R, Kaneshima H, et al. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988;241:1632-1639.
82. Lapidot T, Pflumio F, Doedens M, et al. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science. 1992;255:1137-1141.
83. Lepus CM, Gibson TF, Gerber SA, et al. Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac2/2, Balb/c-Rag12/2gammac2/2, and C.B-17-scid/bg immunodeficient mice. Hum Immunol. 2009;70: 790-802.
84. Matsumura T, Kametani Y, Ando K, et al. Functional CD5+ B cells develop predominantly in the spleen of NOD/SCID/gammac(null) (NOG) mice transplanted either with human umbilical cord blood, bone marrow, or mobilized peripheral blood CD34+ cells. Exp Hematol. 2003; 31:789-797.
85. Choi B, Chun E, Kim M, et al. Human T cell development in the liver of humanized NOD/SCID/IL-2Rgamma(null)(NSG) mice generated by intrahepatic injection of CD34(+) human (h) cord blood (CB) cells. Clin Immunol. 2011;139:321-335.
86. Misharin AV, Haines GK III, Rose S, et al. Development of a new humanized mouse model to study acute inflammatory arthritis. J Transl Med. 2012;10:190.
87. Shultz LD, Pearson T, King M, et al. Humanized NOD/LtSz-scid IL2 receptor common gamma chain knockout mice in diabetes research. Ann N Y Acad Sci. 2007;1103:77-89.
88. Yahata T, Ando K, Nakamura Y, et al. Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic/Shi-scid, IL-2 receptor gamma null mice. J Immunol. 2002;169:204-209.
89. Tanaka S, Saito Y, Kunisawa J, et al. Development of mature and functional human myeloid subsets in hematopoietic stem cell-engrafted NOD/SCID/IL2rgammaKO mice. J Immunol. 2012;188:6145-6155.
90. Watanabe Y, Takahashi T, Okajima A, et al. 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. 2009;21:843-858.
91. Lan P, Tonomura N, Shimizu A, et al. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood. 2006; 108:487-492.
92. Melkus MW, Estes JD, Padgett-Thomas A, et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12:1316-1322.
93. Covassin L, Jangalwe S, Jouvet N, et al. Human immune system development and survival of NOD-scid IL2rgamma (NSG) mice engrafted with human thymus and autologous hematopoietic stem cells. Clin Exp Immunol. 2013;174:372-388.
94. Tonomura N, Habiro K, Shimizu A, et al. Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. Blood. 2008;111:4293-4296.
95. Brainard DM, Seung E, Frahm N, et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol. 2009;83:7305-7321.
96. Denton PW, Nochi T, Lim A, et al. IL-2 receptor gamma-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol. 2012;5:555-566.
97. Strowig T, Rongvaux A, Rathinam C, et al. Transgenic expression of human signal regulatory protein alpha in Rag22/2gamma(c)2/2 mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci U S A. 2011;108:13218-13223.
98. Stoddart CA, Maidji E, Galkina SA, et al. Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2Rgamma(2/2) (NSG) BLT mice. Virology. 2011; 417:154-160.
99. Nochi T, Denton PW, Wahl A, Garcia JV. Cryptopatches are essential for the development of human GALT. Cell Rep. 2013;3:1874-1884.
100. Rajesh D, Zhou Y, Jankowska-Gan E, et al. Th1 and Th17 immunocompetence in humanized NOD/SCID/IL2rgammanull mice. Hum Immunol. 2010;71:551-559.
101. Villaudy J, Schotte R, Legrand N, Spits H. Critical assessment of human antibody generation in humanized mouse models. J Immunol Methods. 2014;410:18-27.
102. Ali N, Flutter B, Sanchez RR, et al. Xenogeneic graft-versus-hostdisease in NOD-scid IL-2Rgammanull mice display a T-effector memory phenotype. PLoS One. 2012;7:e44219.
103. Greenblatt MB, Vrbanac V, Tivey T, et al. Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. 2012;7: e44664.
104. Lockridge JL, Zhou Y, Becker YA, et al. Mice engrafted with human fetal thymic tissue and hematopoietic stem cells develop pathology resembling chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19:1310-1322.
105. Lavender KJ, Pang WW, Messer RJ, et al. BLT-humanized C57BL/6 Rag22/2gammac2/2CD472/2 mice are resistant to GVHD and develop B-And T-cell immunity to HIV infection. Blood. 2013;122: 4013-4020.
106. Lavender KJ, Messer RJ, Race B, Hasenkrug KJ. Production of bone marrow, liver, thymus (BLT) humanized mice on the C57BL/6 Rag2 (2/2)gammac(2/2)CD47(2/2) background. J Immunol Methods. 2014;407:127-134.
107. Wang H, Madariaga ML, Wang S, et al. Lack of CD47 on nonhematopoietic cells induces split macrophage tolerance to CD47null cells. Proc Natl Acad Sci U S A. 2007;104:13744-13749.
108. Li Y, Chen Q, Zheng D, et al. Induction of functional human macrophages from bone marrow promonocytes by M-CSF in humanized mice. J Immunol. 2013;191:3192-3199.
109. Gille C, Orlikowsky TW, Spring B, et al. Monocytes derived from humanized neonatal NOD/SCID/IL2Rgnull mice are phenotypically immature and exhibit functional impairments. 2012;73:346-354.
110. Huntington ND, Legrand N, Alves NL, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009;206:25-34.
111. Willinger T, Rongvaux A, Takizawa H, et al. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci U S A. 2011;108:2390-2395.
112. Rongvaux A, Willinger T, Takizawa H, et al. Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci U S A. 2011;108:2378-2383.
113. Rathinam C, Poueymirou WT, Rojas J, et al. Efficient differentiation and function of human macrophages in humanized CSF-1 mice. Blood. 2011; 118:3119-3128.
114. Rongvaux A, Willinger T, Martinek J, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32:364-372.
115. Chen Q, Khoury M, Chen J. Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci U S A. 2009;106:21783-21788.
116. Billerbeck E, Barry WT, Mu K, et al. 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. 2011;117:3076-3086.
117. Takagi S, Saito Y, Hijikata A, et al. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood. 2012;119:2768-2777.
118. Marodon G, Desjardins D, Mercey L, et al. High diversity of the immune repertoire in humanized NOD.SCID.gamma c2/2 mice. Eur J Immunol. 2009;39:2136-2145.
119. Biswas S, Chang H, Sarkis T, et al. Humoral immune responses in humanized BLT mice immunized with West Nile virus and HIV-1 envelope proteins are largely mediated via human CD5+ B cells. Immunology. 2011;134:419-433.
120. Unsinger J, McDonough JS, Shultz LD, et al. Sepsis-induced human lymphocyte apoptosis and cytokine production in humanized mice. J Leukoc Biol. 2009;86:219-227.
121. Huntington ND, Alves NL, Legrand N, et al. IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo. Proc Natl Acad Sci U S A. 2011;108:6217-6222.
122. Danner R, Chaudhari SN, Rosenberger J, et al. Expression of HLA class II molecules in humanized NOD.Rag1KO.IL2RgcKO mice is critical for development and function of human T and B cells. PLoS One. 2011;6:e19826.
123. Jaiswal S, Pearson T, Friberg H, et al. Dengue virus infection and virusspecific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PLoS One. 2009;4:e7251.
124. Jaiswal S, Pazoles P, Woda M, et al. Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. Immunology. 2012;136:334-343.
125. Shultz LD, Saito Y, Najima Y, et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci U S A. 2010;107:13022-13027.
126. Strowig T, Gurer C, Ploss A, et al. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 2009;206:1423-1434.
127. Suzuki M, Takahashi T, Katano I, et al. Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shiscid/ gammacnull mouse. Int Immunol. 2012;24:243-252.
128. Serra-Hassoun M, Bourgine M, Boniotto M, et al. Human hematopoietic reconstitution and HLA-restricted responses in nonpermissive alymphoid mice. J Immunol. 2014;193:1504-1511.
129. Gorantla S, Sneller H, Walters L, et al. Human immunodeficiency virus type 1 pathobiology studied in humanized BALB/c-Rag22/2gammac2/2 mice. J Virol. 2007;81:2700-2712.
130. Vuyyuru R, Patton J, Manser T. Human immune system mice: current potential and limitations for translational research on human antibody responses. Immunol Res. 2011;51:257-266.
131. Seung E, Tager AM. Humoral immunity in humanized mice: a work in progress. J Infect Dis. 2013;208(suppl 2):S155-S159.
132. Schmidt MR, Appel MC, Giassi LJ, et al. Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice. PLoS One. 2008;3:e3192.
133. Chen Q, He F, Kwang J, et al. GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation. J Immunol. 2012;189:5223-5229.
134. Chappaz S, Finke D. The IL-7 signaling pathway regulates lymph node development independent of peripheral lymphocytes. J Immunol. 2010; 184:3562-3569.
135. Payne KJ, Su RJ, Francis OL, et al. A human-mouse xenogaft model to study the role of TSLP in CRLF2d-ALL. 2012;72:1347.
136. Chung H, Pamp SJ, Hill JA, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell. 2012;149: 1578-1593.
137. Legrand N, Huntington ND, Nagasawa M, et al. Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T-And natural killer-(NK) cell homeostasis in vivo. 2011;108: 13224-13229.
138. Hu Z, Van Rooijen N, Yang YG. Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood. 2011;118: 5938-5946.
139. Daley JM, Thomay AA, Connolly MD, et al. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol. 2008;83:64-70.
140. Thayer TC, Delano M, Liu C, et al. Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes. Diabetes. 2011;60:2144-2151.
141. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell. 2013;153:812-827.
142. Wells JM, Rossi O, Meijerink M, van Baarlen P. Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci U S A. 2011;108: 4607-4614.
143. Nauseef WM. Biological roles for the NOX family NADPH oxidases. J Biol Chem. 2008;283:16961-16965.
144. Holtan SG, Pasquini M, Weisdorf DJ. Acute graft-versus-host disease: a bench-To-bedside update. Blood. 2014;124:363-373.
145. Markey KA, MacDonald KP, Hill GR. The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood. 2014; 124:354-362.
146. Abraham S, Choi JG, Ye C, et al. IL-10 exacerbates xenogeneic GVHD by inducing massive human T cell expansion. Clin Immunol. 2015;156: 58-64.
147. Ito R, Katano I, Kawai K, et al. Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation. 2009;87:1654-1658.
148. van Rijn RS, Simonetti ER, Hagenbeek A, et al. A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2-/-gammac2/2 double-mutant mice. Blood. 2003;102:2522-2531.
149. Covassin L, Laning J, Abdi R, et al. Human peripheral blood CD4 T cellengrafted non-obese diabetic-scid IL2rgamma(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol. 2011; 166:269-280.
150. Hogenes MC, van DS, van KJ, et al. Histological assessment of the sclerotic graft-versus-host response in the humanized RAG22/2gammac2/2 mouse model. Biol Blood Marrow Transplant. 2012;18:1023-1035.
151. Hannon M, Lechanteur C, Lucas S, et al. Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graftversus-host disease. Transfusion. 2014;54:353-363.
152. Hippen KL, Merkel SC, Schirm DK, et al. Generation and large-scale expansion of human inducible regulatory T cells that suppress graftversus-host disease. Am J Transplant. 2011;11:1148-1157.
153. Tobin LM, Healy ME, English K, Mahon BP. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013;172:333-348.
154. Zheng J, Liu Y, Liu Y, et al. Human CD8+ regulatory T cells inhibit GVHD and preserve general immunity in humanized mice. Sci Transl Med. 2013;5:168ra9.
155. Nakauchi Y, Yamazaki S, Napier SC, et al. Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized-mouse model. Exp Hematol. 2015;43:79-88.
156. Brehm MA, Shultz LD. Human allograft rejection in humanized mice: a historical perspective. Cell Mol Immunol. 2012;9:225-231.
157. Abele-Ohl S, Leis M, Mahmoudian S, et al. Rag22/2 gamma-chain2/2 mice as hosts for human vessel transplantation and allogeneic human leukocyte reconstitution. Transpl Immunol. 2010;23:59-64.
158. Feng G, Nadig SN, Backdahl L, et al. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection. Sci Transl Med. 2011;3:83ra40.
159. Nadig SN, Wieckiewicz J, Wu DC, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010;16:809-813.
160. Lee WP, Yaremchuk MJ, Pan YC, et al. Relative antigenicity of components of a vascularized limb allograft. Plast Reconstr Surg. 1991;87: 401-411.
161. Racki WJ, Covassin L, Brehm M, et al. NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection. Transplantation. 2010;89:527-536.
162. Issa F, Hester J, Goto R, et al. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation. 2010;90:1321-1327.
163. Sagoo P, Ali N, Garg G, et al. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med. 2011;3:83ra42.
164. Todd JA. Etiology of type 1 diabetes. Immunity. 2010;32:457-467.
165. Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med. 2015;42:42-60.
166. Reed JC, Herold KC. Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol. 2015.
167. King M, Pearson T, Rossini AA, et al. Humanized mice for the study of type 1 diabetes and beta cell function. Ann N Y Acad Sci. 2008; 1150:46-53.
168. Zhao Y, Guo C, Hwang D, et al. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model. Biochem Biophys Res Commun. 2010;399:629-636.
169. Brehm MA, Bortell R, Diiorio P, et al. Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice. Diabetes. 2010;59: 2265-2270.
170. Mathews CE, Langley SH, Leiter EH. New mouse model to study islet transplantation in insulin-dependent diabetes mellitus. Transplantation. 2002;73:1333-1336.
171. Yoshioka M, Kayo T, Ikeda T, Koizumi A. A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes. 1997;46:887-894.
172. Izumi T, Yokota-Hashimoto H, Zhao S, et al. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes. 2003;52:409-416.
173. Ron D. Proteotoxicity in the endoplasmic reticulum: lessons from the Akita diabetic mouse. J Clin Invest. 2002;109:443-445.
174. Jacobson S, Heuts F, Juarez J, et al. Alloreactivity but failure to reject human islet transplants by humanized Balb/c/Rag2gc mice. Scand J Immunol. 2010;71:83-90.
175. Wu DC, Hester J, Nadig SN, et al. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. Transplantation. 2013;96:707-716.
176. Wu H, Wen D, Mahato RI. Third-party mesenchymal stem cells improved human islet transplantation in a humanized diabetic mouse model. Mol Ther. 2013;21:1778-1786.
177. Yi S, Ji M, Wu J, et al. Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes. 2012;61:1180-1191.
178. Viehmann Milam AA, Maher SE, Gibson JA, et al. A humanized mouse model of autoimmune insulitis. Diabetes. 2014;63:1712-1724.
179. Whitfield-Larry F, Young EF, Talmage G, et al. HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/gammac(null)/ HLA-A2 transgenic mice concurrent with the expansion of isletspecific CD8+ T cells. Diabetes. 2011;60:1726-1733.
180. Unger WW, Pearson T, Abreu JR, et al. 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. 2012;7:e49213.
181. Ben-Nun A, Kaushansky N, Kawakami N, et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J Autoimmun. 2014;54: 33-50.
182. Ota K, Matsui M, Milford EL, et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990;346:183-187.
183. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683-747.
184. Lill CM. Recent advances and future challenges in the genetics of multiple sclerosis. Front Neurol. 2014;5:130.
185. Zayoud M, El Malki K, Frauenknecht K, et al. Subclinical CNS inflammation as response to a myelin antigen in humanized mice. J Neuroimmune Pharmacol. 2013;8:1037-1047.
186. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25.
187. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.
188. Shapira Y, Agmon-Levin N, Shoenfeld Y. Geoepidemiology of autoimmune rheumatic diseases. Nat Rev Rheumatol. 2010;6:468-476.
189. Kobezda T, Ghassemi-Nejad S, Mikecz K, et al. Of mice and men: how animal models advance our understanding of T-cell function in RA. Nat Rev Rheumatol. 2014;10:160-170.
190. Andersson EC, Hansen BE, Jacobsen H, et al. Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice. Proc Natl Acad Sci U S A. 1998;95:7574-7579.
191. Rosloniec EF, Brand DD, Myers LK, et al. An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen. J Exp Med. 1997;185:1113-1122.
192. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205-2219.
193. Toussirot E, Roudier J. Pathophysiological links between rheumatoid arthritis and the Epstein-Barr virus: an update. Joint Bone Spine. 2007; 74:418-426.
194. Kuwana Y, Takei M, Yajima M, et al. Epstein-Barr virus induces erosive arthritis in humanized mice. PLoS One. 2011;6:e26630.
195. Andrade D, Redecha PB, Vukelic M, et al. Engraftment of peripheral blood mononuclear cells from systemic lupus erythematosus and antiphospholipid syndrome patient donors into BALB-RAG-22/2 IL-2Rgamma2/2 mice: a promising model for studying human disease. Arthritis Rheum. 2011;63:2764-2773.
196. Crampton SP, Morawski PA, Bolland S. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus. Dis Model Mech. 2014;7:1033-1046.
197. Singh N, Cohen PL. The T cell in Sjogren's syndrome: force majeure, not spectateur. J Autoimmun. 2012;39:229-233.
198. Young NA, Wu LC, Bruss M, et al. A chimeric human-mouse model of Sjogren's syndrome. Clin Immunol. 2015;156:1-8.
199. Longobardi T, Jacobs P, Bernstein CN. Work losses related to inflammatory bowel disease in the United States: results from the National Health Interview Survey. Am J Gastroenterol. 2003;98:1064-1072.
200. Koboziev I, Reinoso WC, Furr KL, Grisham MB. Role of the enteric microbiota in intestinal homeostasis and inflammation. Free Radic Biol Med. 2014;68:122-133.
201. Mathis D, Benoist C. Microbiota and autoimmune disease: the hosted self. Cell Host Microbe. 2011;10:297-301.
202. Nolte T, Zadeh-Khorasani M, Safarov O, et al. Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rg null mice engrafted with human peripheral blood mononuclear cells. Clin Exp Immunol. 2013;172:349-362.
203. Nolte T, Zadeh-Khorasani M, Safarov O, et al. Induction of oxazolonemediated features of atopic dermatitis in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells. Dis Model Mech. 2013;6:125-134.
204. Goettel JA, Shouval DS, Lexmond W, et al. 134 development of novel humanized murine models to assess mucosal homeostasis: human anti-CD3 antibody or TNBS administration leads to small and large bowel inflammation respectively in immunodeficient mice transferred with human T cells. Inflamm Bowel Dis. 2013;144:S-32.
205. Goettel JA, Biswas S, Lexmond WS, et al. Human hematopoietic stem cells with a defined immunodeficiency and enteropathy transfer clinical phenotype to a novel humanized mouse strain. Inflamm Bowel Dis. 2014;146:S-81.
206. Weigmann B, Schughart N, Wiebe C, et al. Allergen-induced IgEdependent gut inflammation in a human PBMC-engrafted murine model of allergy. J Allergy Clin Immunol. 2012;129:1126-1135.
207. Jess T, Riis L, Jespersgaard C, et al. Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease. Am J Gastroenterol. 2005; 100:2486-2492.
208. Bernstein CN, Shanahan F. Disorders of a modern lifestyle: reconciling the epidemiology of inflammatory bowel diseases. Gut. 2008;57:1185-1191.
209. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011; 140:1785-1794.
210. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307-317.
211. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46-54.
212. Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of Epigenetics. Gastroenterology. 2013;145:293-308.
213. Hintze KJ, Cox JE, Rompato G, et al. Broad scope method for creating humanized animal models for animal health and disease research through antibiotic treatment and human fecal transfer. 2014;5:183-191.
214. Berg DJ, Zhang J, Weinstock JV, et al. Rapid development of colitis in NSAID-Treated IL-10-deficient mice. Gastroenterology. 2002;123:1527-1542.
215. Hale LP, Gottfried MR, Swidsinski A. Piroxicam treatment of IL-10-deficient mice enhances colonic epithelial apoptosis and mucosal exposure to intestinal bacteria. Inflamm Bowel Dis. 2005;11:1060-1069.