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Autoimmune Diabetes: An Overview of Experimental Models and Novel Therapeutics

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Suppression and Regulation of Immune Responses

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1371))

Abstract

Type 1 diabetes (T1D) results from a chronic and selective destruction of insulin-secreting β-cells within the islets of Langerhans of the pancreas by autoreactive CD4+ and CD8+ T lymphocytes. The use of animal models of T1D was instrumental for deciphering the steps of the autoimmune process leading to T1D. The non-obese diabetic (NOD) mouse and the bio-breeding (BB) rat spontaneously develop the disease similar to the human pathology in terms of the immune responses triggering autoimmune diabetes and of the genetic and environmental factors influencing disease susceptibility. The generation of genetically modified models allowed refining our understanding of the etiology and the pathogenesis of the disease. In the present review, we provide an overview of the experimental models generated and used to gain knowledge on the molecular and cellular mechanisms underlying the breakdown of self-tolerance in T1D and the progression of the autoimmune response. Immunotherapeutic interventions designed in these animal models and translated into the clinical arena in T1D patients will also be discussed.

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References

  1. Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920

    Article  PubMed  Google Scholar 

  2. Harjutsalo V, Sjoberg L, Tuomilehto J (2008) Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 371:1777–1782

    Article  PubMed  Google Scholar 

  3. Bach JF (1994) Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516–542

    Article  CAS  PubMed  Google Scholar 

  4. Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485

    Article  CAS  PubMed  Google Scholar 

  5. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y (1980) Breeding of a non-obese, diabetic strain of mice. Exp Anim 29:1–13

    CAS  Google Scholar 

  6. Markle JG, Frank DN, Mortin-Toth S et al (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088

    Article  CAS  PubMed  Google Scholar 

  7. Pozzilli P, Signore A, Williams AJ, Beales PE (1993) NOD mouse colonies around the world: recent facts and figures. Immunol Today 14:193–196

    Article  CAS  PubMed  Google Scholar 

  8. Garchon HJ, Bedossa P, Eloy L, Bach JF (1991) Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature 353:260–262

    Article  CAS  PubMed  Google Scholar 

  9. Many MC, Maniratunga S, Denef JF (1996) The non-obese diabetic (NOD) mouse: an animal model for autoimmune thyroiditis. Exp Clin Endocrinol Diabetes 104:17–20

    Article  CAS  PubMed  Google Scholar 

  10. Many MC, Maniratunga S, Varis I, Dardenne M, Drexhage HA, Denef JF (1995) Two-step development of Hashimoto-like thyroiditis in genetically autoimmune prone non-obese diabetic mice: effects of iodine-induced cell necrosis. J Endocrinol 147:311–320

    Article  CAS  PubMed  Google Scholar 

  11. Baxter AG, Mandel TE (1991) Hemolytic anemia in non-obese diabetic mice. Eur J Immunol 21:2051–2055

    Article  CAS  PubMed  Google Scholar 

  12. Baxter AG, Horsfall AC, Healey D et al (1994) Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice. Immunology 83:227–231

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Wicker LS, Todd JA, Peterson LB (1995) Genetic control of autoimmune diabetes in the NOD mouse. Annu Rev Immunol 13:179–200

    Article  CAS  PubMed  Google Scholar 

  14. Steward CA, Gonzalez JM, Trevanion S et al (2013) The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes. Database (Oxford) 2013:bat032

    Article  CAS  Google Scholar 

  15. Hattori M, Buse JB, Jackson RA et al (1986) The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231:733–735

    Article  CAS  PubMed  Google Scholar 

  16. Acha-orbea H, Mcdevitt HO (1987) The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc Natl Acad Sci U S A 84:2435–2439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Todd JA, Bell JI, Mcdevitt HO (1987) HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329:599–604

    Article  CAS  PubMed  Google Scholar 

  18. Ridgway WM, Peterson LB, Todd JA et al (2008) Gene-gene interactions in the NOD mouse model of type 1 diabetes. Adv Immunol 100:151–175

    Article  PubMed  CAS  Google Scholar 

  19. Todd JA, Walker NM, Cooper JD et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Denny P, Lord CJ, Hill NJ et al (1997) Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes 46:695–700

    Article  CAS  PubMed  Google Scholar 

  21. Hill NJ, Lyons PA, Armitage N, Todd JA, Wicker LS, Peterson LB (2000) NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans. Diabetes 49:1744–1747

    Article  CAS  PubMed  Google Scholar 

  22. Lyons PA, Hancock WW, Denny P et al (2000) The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity 13:107–115

    Article  CAS  PubMed  Google Scholar 

  23. Yamanouchi J, Puertas MC, Verdaguer J et al (2010) Idd9.1 locus controls the suppressive activity of FoxP3 + CD4 + CD25+ regulatory T-cells. Diabetes 59:272–281

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Ghosh S, Palmer SM, Rodrigues NR et al (1993) Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet 4:404–409

    Article  CAS  PubMed  Google Scholar 

  25. Fraser HI, Dendrou CA, Healy B et al (2010) Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene. J Immunol 184:5075–5084

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Katz JD, Wang B, Haskins K, Benoist C, Mathis D (1993) Following a diabetogenic T cell from genesis through pathogenesis. Cell 74:1089–1100

    Article  CAS  PubMed  Google Scholar 

  27. Wenzlau JM, Juhl K, Yu L et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Daniel D, Gill RG, Schloot N, Wegmann D (1995) Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur J Immunol 25:1056–1062

    Article  CAS  PubMed  Google Scholar 

  29. Wegmann DR, Norbury-glaser M, Daniel D (1994) Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol 24:1853–1857

    Article  CAS  PubMed  Google Scholar 

  30. Baekkeskov S, Aanstoot HJ, Christgau S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156

    Article  CAS  PubMed  Google Scholar 

  31. Honeyman MC, Cram DS, Harrison LC (1993) Glutamic acid decarboxylase 67-reactive T cells: a marker of insulin-dependent diabetes. J Exp Med 177:535–540

    Article  CAS  PubMed  Google Scholar 

  32. Dotta F, Dionisi S, Viglietta V et al (1999) T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus. Eur J Endocrinol 141:272–278

    Article  CAS  PubMed  Google Scholar 

  33. Elias D, Reshef T, Birk OS, Van Der Zee R, Walker MD, Cohen IR (1991) Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A 88:3088–3091

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Lieberman SM, Evans AM, Han B et al (2003) Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A 100:8384–8388

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med 166:823–832

    Article  CAS  PubMed  Google Scholar 

  36. Yagi H, Matsumoto M, Kunimoto K, Kawaguchi J, Makino S, Harada M (1992) Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice. Eur J Immunol 22:2387–2393

    Article  CAS  PubMed  Google Scholar 

  37. Christianson SW, Shultz LD, Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42:44–55

    Article  CAS  PubMed  Google Scholar 

  38. Amrani A, Verdaguer J, Serra P, Tafuro S, Tan R, Santamaria P (2000) Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 406:739–742

    Article  CAS  PubMed  Google Scholar 

  39. Han B, Serra P, Yamanouchi J et al (2005) Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes. J Clin Invest 115:1879–1887

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Gagnerault MC, Luan JJ, Lotton C, Lepault F (2002) Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice. J Exp Med 196:369–377

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Zhang Y, O’Brien B, Trudeau J, Tan R, Santamaria P, Dutz JP (2002) In situ beta cell death promotes priming of diabetogenic CD8 T lymphocytes. J Immunol 168:1466–1472

    Article  CAS  PubMed  Google Scholar 

  42. Trudeau JD, Dutz JP, Arany E, Hill DJ, Fieldus WE, Finegood DT (2000) Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49:1–7

    Article  CAS  PubMed  Google Scholar 

  43. Kim HS, Han MS, Chung KW et al (2007) Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27:321–333

    Article  CAS  PubMed  Google Scholar 

  44. Diana J, Simoni Y, Furio L et al (2013) Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 19:65–73

    Article  CAS  PubMed  Google Scholar 

  45. Serreze DV, Chapman HD, Varnum DS et al (1996) B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu(null) mice. J Exp Med 184:2049–2053

    Article  CAS  PubMed  Google Scholar 

  46. Noorchashm H, Noorchashm N, Kern J, Rostami SY, Barker CF, Naji A (1997) B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice. Diabetes 46:941–946

    Article  CAS  PubMed  Google Scholar 

  47. Herbelin A, Gombert JM, Lepault F, Bach JF, Chatenoud L (1998) Mature mainstream TCR alpha beta + CD4+ thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J Immunol 161:2620–2628

    CAS  PubMed  Google Scholar 

  48. Lepault F, Gagnerault MC (2000) Characterization of peripheral regulatory CD4(+) T cells that prevent diabetes onset in nonobese diabetic mice. J Immunol 164:240–247

    Article  CAS  PubMed  Google Scholar 

  49. You S, Slehoffer G, Barriot S, Bach JF, Chatenoud L (2004) Unique role of CD4 + CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice. Proc Natl Acad Sci U S A 101(Suppl 2):14580–14585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. You S, Belghith M, Cobbold S et al (2005) Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54:1415–1422

    Article  CAS  PubMed  Google Scholar 

  51. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  CAS  PubMed  Google Scholar 

  52. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341

    Article  CAS  PubMed  Google Scholar 

  53. Dardenne M, Lepault F, Bendelac A, Bach JF (1989) Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning. Eur J Immunol 19:889–895

    Article  CAS  PubMed  Google Scholar 

  54. Salomon B, Lenschow DJ, Rhee L et al (2000) B7/CD28 Costimulation is essential for the homeostasis of the CD4 + CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440

    Article  CAS  PubMed  Google Scholar 

  55. Billiard F, Litvinova E, Saadoun D et al (2006) Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J Immunol 177:2167–2174

    Article  CAS  PubMed  Google Scholar 

  56. You S, Leforban B, Garcia C, Bach JF, Bluestone JA, Chatenoud L (2007) Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci U S A 104:6335–6340

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Tang Q, Adams JY, Penaranda C et al (2008) Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28:687–697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Korn T, Reddy J, Gao W et al (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 13:423–431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB (1977) The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26:100–112

    Article  CAS  PubMed  Google Scholar 

  60. Jacob HJ, Pettersson A, Wilson D, Mao Y, Lernmark A, Lander ES (1992) Genetic dissection of autoimmune type I diabetes in the BB rat. Nat Genet 2:56–60

    Article  CAS  PubMed  Google Scholar 

  61. Ellerman KE, Like AA (2000) Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43:890–898

    Article  CAS  PubMed  Google Scholar 

  62. Chen XL, Serrano D, Mayhue M et al (2013) GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation. Biochem J 449:353–364

    Article  CAS  PubMed  Google Scholar 

  63. Hornum L, Romer J, Markholst H (2002) The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 51:1972–1979

    Article  CAS  PubMed  Google Scholar 

  64. Wallis RH, Wang K, Marandi L et al (2009) Type 1 diabetes in the BB rat: a polygenic disease. Diabetes 58:1007–1017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Crisa L, Mordes JP, Rossini AA (1992) Autoimmune diabetes mellitus in the BB rat. Diabetes Metab Rev 8:4–37

    Article  CAS  PubMed  Google Scholar 

  66. Greiner DL, Handler ES, Nakano K, Mordes JP, Rossini AA (1986) Absence of the RT-6 T cell subset in diabetes-prone BB/W rats. J Immunol 136:148–151

    CAS  PubMed  Google Scholar 

  67. Iwakoshi NN, Goldschneider I, Tausche F, Mordes JP, Rossini AA, Greiner DL (1998) High frequency apoptosis of recent thymic emigrants in the liver of lymphopenic diabetes-prone BioBreeding rats. J Immunol 160:5838–5850

    CAS  PubMed  Google Scholar 

  68. Zipris D, Leif J, Deluca D et al (2001) Fetal thymi from diabetes-prone but not diabetes-resistant BB/Wor rats fail to generate mature ART2+ T-cells in organ culture. Cell Mol Biol (Noisy-le-Grand) 47:65–74

    CAS  Google Scholar 

  69. Markholst H, Eastman S, Wilson D, Andreasen BE, Lernmark A (1991) Diabetes segregates as a single locus in crosses between inbred BB rats prone or resistant to diabetes. J Exp Med 174:297–300

    Article  CAS  PubMed  Google Scholar 

  70. Greiner DL, Mordes JP, Handler ES, Angelillo M, Nakamura N, Rossini AA (1987) Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. J Exp Med 166:461–475

    Article  CAS  PubMed  Google Scholar 

  71. Rossini AA, Mordes JP, Greiner DL, Nakano K, Appel MC, Handler ES (1986) Spleen cell transfusion in the Bio-Breeding/Worcester rat. Prevention of diabetes, major histocompatibility complex restriction, and long-term persistence of transfused cells. J Clin Invest 77:1399–1401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Burstein D, Mordes JP, Greiner DL et al (1989) Prevention of diabetes in BB/Wor rat by single transfusion of spleen cells. Parameters that affect degree of protection. Diabetes 38:24–30

    Article  CAS  PubMed  Google Scholar 

  73. Hillebrands JL, Whalen B, Visser JT et al (2006) A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3. J Immunol 177:7820–7832

    Article  CAS  PubMed  Google Scholar 

  74. Fowell D, Mason D (1993) Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med 177:627–636

    Article  CAS  PubMed  Google Scholar 

  75. Lenzen S, Tiedge M, Elsner M et al (2001) The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 44:1189–1196

    Article  CAS  PubMed  Google Scholar 

  76. Adams TE, Alpert S, Hanahan D (1987) Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature 325:223–228

    Article  CAS  PubMed  Google Scholar 

  77. Ohashi PS, Oehen S, Buerki K et al (1991) Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65:305–317

    Article  CAS  PubMed  Google Scholar 

  78. Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H (1991) Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65:319–331

    Article  CAS  PubMed  Google Scholar 

  79. Von Herrath MG, Dockter J, Oldstone MB (1994) How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1:231–242

    Article  Google Scholar 

  80. Lo D, Freedman J, Hesse S, Palmiter RD, Brinster RL, Sherman LA (1992) Peripheral tolerance to an islet cell-specific hemagglutinin transgene affects both CD4+ and CD8+ T cells. Eur J Immunol 22:1013–1022

    Article  CAS  PubMed  Google Scholar 

  81. Socha L, Silva D, Lesage S, Goodnow C, Petrovsky N (2003) The role of endoplasmic reticulum stress in nonimmune diabetes: NOD.k iHEL, a novel model of beta cell death. Ann N Y Acad Sci 1005:178–183

    Article  CAS  PubMed  Google Scholar 

  82. Blanas E, Carbone FR, Allison J, Miller JF, Heath WR (1996) Induction of autoimmune diabetes by oral administration of autoantigen. Science 274:1707–1709

    Article  CAS  PubMed  Google Scholar 

  83. Morgan DJ, Liblau R, Scott B et al (1996) CD8(+) T cell-mediated spontaneous diabetes in neonatal mice. J Immunol 157:978–983

    CAS  PubMed  Google Scholar 

  84. Von Herrath MG, Guerder S, Lewicki H, Flavell RA, Oldstone MB (1995) Coexpression of B7-1 and viral (“self”) transgenes in pancreatic beta cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes. Immunity 3:727–738

    Article  Google Scholar 

  85. Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA (1988) Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52:773–782

    Article  CAS  PubMed  Google Scholar 

  86. Stewart TA, Hultgren B, Huang X, Pitts-meek S, Hully J, Maclachlan NJ (1993) Induction of type I diabetes by interferon-alpha in transgenic mice. Science 260:1942–1946

    Article  CAS  PubMed  Google Scholar 

  87. Elliott EA, Flavell RA (1994) Transgenic mice expressing constitutive levels of IL-2 in islet beta cells develop diabetes. Int Immunol 6:1629–1637

    Article  CAS  PubMed  Google Scholar 

  88. Guerder S, Picarella DE, Linsley PS, Flavell RA (1994) Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc Natl Acad Sci U S A 91:5138–5142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Allison J, Stephens LA, Kay TW et al (1998) The threshold for autoimmune T cell killing is influenced by B7-1. Eur J Immunol 28:949–960

    Article  CAS  PubMed  Google Scholar 

  90. Bohme J, Haskins K, Stecha P et al (1989) Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. Science 244:1179–1183

    Article  CAS  PubMed  Google Scholar 

  91. Gotz J, Eibel H, Kohler G (1990) Non-tolerance and differential susceptibility to diabetes in transgenic mice expressing major histocompatibility class II genes on pancreatic beta cells. Eur J Immunol 20:1677–1683

    Article  CAS  PubMed  Google Scholar 

  92. Verdaguer J, Schmidt D, Amrani A, Anderson B, Averill N, Santamaria P (1997) Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J Exp Med 186:1663–1676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Jasinski JM, Yu L, Nakayama M et al (2006) Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. Diabetes 55:1978–1984

    Article  CAS  PubMed  Google Scholar 

  94. Delong T, Baker RL, He J, Barbour G, Bradley B, Haskins K (2012) Diabetogenic T-cell clones recognize an altered peptide of chromogranin A. Diabetes 61:3239–3246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D (1998) Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 187:427–432

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Chen Z, Herman AE, Matos M, Mathis D, Benoist C (2005) Where CD4 + CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med 202:1387–1397

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Martinic MM, Juedes AE, Bresson D et al (2007) Minimal impact of a de novo-expressed beta-cell autoantigen on spontaneous diabetes development in NOD mice. Diabetes 56:1059–1068

    Article  CAS  PubMed  Google Scholar 

  98. Diana J, Brezar V, Beaudoin L et al (2011) Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. J Exp Med 208:729–745

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Wong S, Guerder S, Visintin I et al (1995) Expression of the co-stimulator molecule B7-1 in pancreatic beta-cells accelerates diabetes in the NOD mouse. Diabetes 44:326–329

    Article  CAS  PubMed  Google Scholar 

  100. Wogensen L, Lee MS, Sarvetnick N (1994) Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice. J Exp Med 179:1379–1384

    Article  CAS  PubMed  Google Scholar 

  101. Bohme J, Schuhbaur B, Kanagawa O, Benoist C, Mathis D (1990) MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science 249:293–295

    Article  CAS  PubMed  Google Scholar 

  102. Lund T, O’reilly L, Hutchings P et al (1990) Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature 345:727–729

    Article  CAS  PubMed  Google Scholar 

  103. Chervonsky AV, Wang Y, Wong FS et al (1997) The role of Fas in autoimmune diabetes. Cell 89:17–24

    Article  CAS  PubMed  Google Scholar 

  104. Mueller R, Krahl T, Sarvetnick N (1996) Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 184:1093–1099

    Article  CAS  PubMed  Google Scholar 

  105. Moritani M, Yoshimoto K, Wong SF et al (1998) Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1. J Clin Invest 102:499–506

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Thebault-Baumont K, Dubois-Laforgue D, Krief P et al (2003) Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest 111:851–857

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Hultgren B, Huang XJ, Dybdal N, Stewart TA (1996) Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes 45:812–817

    Article  CAS  PubMed  Google Scholar 

  108. Trembleau S, Penna G, Gregori S et al (1999) Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice. J Immunol 163:2960–2968

    CAS  PubMed  Google Scholar 

  109. Wang B, Gonzalez A, Hoglund P, Katz JD, Benoist C, Mathis D (1998) Interleukin-4 deficiency does not exacerbate disease in NOD mice. Diabetes 47:1207–1211

    Article  CAS  PubMed  Google Scholar 

  110. Balasa B, Van Gunst K, Jung N, Katz JD, Sarvetnick N (2000) IL-10 deficiency does not inhibit insulitis and accelerates cyclophosphamide-induced diabetes in the nonobese diabetic mouse. Cell Immunol 202:97–102

    Article  CAS  PubMed  Google Scholar 

  111. Lenschow DJ, Herold KC, Rhee L et al (1996) CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5:285–293

    Article  CAS  PubMed  Google Scholar 

  112. Congia M, Patel S, Cope AP, De Virgiliis S, Sonderstrup G (1998) T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. Proc Natl Acad Sci U S A 95:3833–3838

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Di Lorenzo TP, Peakman M, Roep BO (2007) Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 148:1–16

    Article  PubMed Central  PubMed  Google Scholar 

  114. Takaki T, Marron MP, Mathews CE et al (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257–3265

    Article  CAS  PubMed  Google Scholar 

  115. Enee E, Martinuzzi E, Blancou P, Bach JM, Mallone R, van Endert P (2008) Equivalent specificity of peripheral blood and islet-infiltrating CD8+ T lymphocytes in spontaneously diabetic HLA-A2 transgenic NOD mice. J Immunol 180:5430–5438

    Article  CAS  PubMed  Google Scholar 

  116. Jarchum I, Baker JC, Yamada T et al (2007) In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice. Diabetes 56:2551–2560

    Article  CAS  PubMed  Google Scholar 

  117. Jarchum I, DiLorenzo TP (2010) Ins2 deficiency augments spontaneous HLA-A*0201-restricted T cell responses to insulin. J Immunol 184:658–665

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Antal Z, Baker JC, Smith C et al (2012) Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. J Immunol 188:5766–5775

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Kuhn C, You S, Valette F et al (2011) Human CD3 transgenic mice: preclinical testing of antibodies promoting immune tolerance. Sci Transl Med 3:68ra10

    Article  PubMed  CAS  Google Scholar 

  120. Hu CY, Rodriguez-Pinto D, Du W et al (2007) Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Invest 117:3857–3867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Herold KC, Vignali DA, Cooke A, Bluestone JA (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243–256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Elias D, Meilin A, Ablamunits V et al (1997) Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens. Diabetes 46:758–764

    Article  CAS  PubMed  Google Scholar 

  123. Tian J, Atkinson MA, Clare Salzler M et al (1996) Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med 183:1561–1567

    Article  CAS  PubMed  Google Scholar 

  124. Tisch R, Wang B, Serreze DV (1999) Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent. J Immunol 163:1178–1187

    CAS  PubMed  Google Scholar 

  125. Harrison LC, Dempseycollier M, Kramer DR, Takahashi K (1996) Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167–2174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL (1991) Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A 88:10252–10256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Bach JF, Chatenoud L (2001) Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol 19:131–161

    Article  CAS  PubMed  Google Scholar 

  128. Maron R, Melican NS, Weiner HL (1999) Regulatory Th2-type T cell lines against insulin and GAD peptides derived from orally- and nasally-treated NOD mice suppress diabetes. J Autoimmun 12:251–258

    Article  CAS  PubMed  Google Scholar 

  129. Weiner HL, da Cunha AP, Quintana F, Wu H (2011) Oral tolerance. Immunol Rev 241:241–259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Al-sabbagh A, Miller A, Santos LM, Weiner HL (1994) Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. Eur J Immunol 24:2104–2109

    Article  CAS  PubMed  Google Scholar 

  131. Tian JD, Claresalzler M, Herschenfeld A et al (1996) Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med 2:1348–1353

    Article  CAS  PubMed  Google Scholar 

  132. Elias D, Cohen IR (1994) Peptide therapy for diabetes in NOD mice. Lancet 343:704–706

    Article  CAS  PubMed  Google Scholar 

  133. Diabetes Prevention Trial-Type 1 Diabetes Study Group (2002) Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346:1685–1691

    Article  Google Scholar 

  134. Chaillous L, Lefevre H, Thivolet C et al (2000) Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 356:545–549

    Article  CAS  PubMed  Google Scholar 

  135. Pozzilli P, Pitocco D, Visalli N et al (2000) No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43:1000–1004

    Article  CAS  PubMed  Google Scholar 

  136. Ludvigsson J, Faresjo M, Hjorth M et al (2008) GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 359:1909–1920

    Article  CAS  PubMed  Google Scholar 

  137. Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR (2001) Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358:1749–1753

    Article  CAS  PubMed  Google Scholar 

  138. Raz I, Avron A, Tamir M et al (2007) Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 23:292–298

    Article  CAS  PubMed  Google Scholar 

  139. Raz I, Ziegler AG, Linn T et al (2014) Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-controlled, randomized phase 3 trial. Diabetes Care 37:1392–1400

    Article  CAS  PubMed  Google Scholar 

  140. Prasad S, Kohm AP, McMahon JS, Luo X, Miller SD (2012) Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading. J Autoimmun 39:347–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Fife BT, Guleria I, Gubbels Bupp M et al (2006) Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203:2737–2747

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  142. Niens M, Grier AE, Marron M, Kay TW, Greiner DL, Serreze DV (2011) Prevention of “Humanized” diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes 60:1229–1236

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. Prasad S, Xu D, Miller SD (2012) Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes. Rev Diabet Stud 9:319–327

    Article  PubMed Central  PubMed  Google Scholar 

  144. Kasagi S, Zhang P, Che L et al (2014) In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Sci Transl Med 6:241ra278

    Article  CAS  Google Scholar 

  145. Chatenoud L (2014) Immunology. Teaching the immune system “self” respect and tolerance. Science 344:1343–1344

    Article  CAS  PubMed  Google Scholar 

  146. Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, Chen W (2008) CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14:528–535

    Article  CAS  PubMed  Google Scholar 

  147. Mandrup-Poulsen T, Pickersgill L, Donath MY (2010) Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol 6:158–166

    Article  CAS  PubMed  Google Scholar 

  148. Ablamunits V, Henegariu O, Hansen JB et al (2012) Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation. Diabetes 61:145–154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  149. Sumpter KM, Adhikari S, Grishman EK, White PC (2011) Preliminary studies related to anti-interleukin-1beta therapy in children with newly diagnosed type 1 diabetes. Pediatr Diabetes 12:656–667

    Article  CAS  PubMed  Google Scholar 

  150. Moran A, Bundy B, Becker DJ et al (2013) Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381:1905–1915

    Article  CAS  PubMed  Google Scholar 

  151. Mastrandrea L, Yu J, Behrens T et al (2009) Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32:1244–1249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. Boitard C, Bendelac A, Richard MF, Carnaud C, Bach JF (1988) Prevention of diabetes in nonobese diabetic mice by anti-I-A monoclonal antibodies: transfer of protection by splenic T cells. Proc Natl Acad Sci U S A 85:9719–9723

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Shizuru JA, Taylor-edwards C, Banks BA, Gregory AK, Fathman CG (1988) Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science 240:659–662

    Article  CAS  PubMed  Google Scholar 

  154. Sempe P, Bedossa P, Richard MF, Villa MC, Bach JF, Boitard C (1991) Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in nonobese diabetic (NOD) mice. Eur J Immunol 21:1163–1169

    Article  CAS  PubMed  Google Scholar 

  155. Moriyama H, Yokono K, Amano K et al (1996) Induction of tolerance in murine autoimmune diabetes by transient blockade of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 pathway. J Immunol 157:3737–3743

    CAS  PubMed  Google Scholar 

  156. Orban T, Bundy B, Becker DJ et al (2011) Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378:412–419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Chatenoud L, Bluestone JA (2007) CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7:622–632

    Article  CAS  PubMed  Google Scholar 

  158. Chatenoud L, Thervet E, Primo J, Bach JF (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A 91:123–127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Penaranda C, Tang Q, Bluestone JA (2011) Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol 187:2015–2022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. You S, Zuber J, Kuhn C et al (2012) Induction of allograft tolerance by monoclonal CD3 antibodies: a matter of timing. Am J Transplant 12:2909–2919

    Article  CAS  PubMed  Google Scholar 

  161. Goto R, You S, Zaitsu M, Chatenoud L, Wood KJ (2013) Delayed anti-CD3 therapy results in depletion of alloreactive T cells and the dominance of Foxp3(+)CD4(+) graft infiltrating cells. Am J Transplant 13:1655–1664

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  162. Chatenoud L (2003) CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3:123–132

    Article  CAS  PubMed  Google Scholar 

  163. Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L (2003) TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9:1202–1208

    Article  CAS  PubMed  Google Scholar 

  164. You S, Candon S, Kuhn C, Bach JF, Chatenoud L (2008) CD3 antibodies as unique tools to restore self-tolerance in established autoimmunity their mode of action and clinical application in type 1 diabetes. Adv Immunol 100:13–37

    Article  CAS  PubMed  Google Scholar 

  165. You S, Thieblemont N, Alyanakian MA, Bach JF, Chatenoud L (2006) Transforming growth factor-beta and T-cell-mediated immunoregulation in the control of autoimmune diabetes. Immunol Rev 212:185–202

    Article  CAS  PubMed  Google Scholar 

  166. Herold KC, Hagopian W, Auger JA et al (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698

    Article  CAS  PubMed  Google Scholar 

  167. Keymeulen B, Vandemeulebroucke E, Ziegler AG et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352:2598–2608

    Article  CAS  PubMed  Google Scholar 

  168. Keymeulen B, Walter M, Mathieu C et al (2010) Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53:614–623

    Article  CAS  PubMed  Google Scholar 

  169. Keymeulen B, Candon S, Fafi-Kremer S et al (2010) Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients. Blood 115:1145–1155

    Article  CAS  PubMed  Google Scholar 

  170. Sherry N, Hagopian W, Ludvigsson J et al (2011) Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 6736:60931–60938

    Google Scholar 

  171. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361:2143–2152

    Article  CAS  PubMed  Google Scholar 

  172. Hu C, Ding H, Zhang X, Wong FS, Wen L (2013) Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes. Diabetes 62:2849–2858

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Grinberg-Bleyer Y, Baeyens A, You S et al (2010) IL-2 reverses established type one diabetes by local effect on pancreatic regulatory T cells. J Exp Med 207:1871–1878

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R (2002) Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes 51:638–645

    Article  CAS  PubMed  Google Scholar 

  175. Long SA, Rieck M, Sanda S et al (2012) Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 61:2340–2348

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  176. Hartemann A, Bensimon G, Payan CA et al (2013) Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 1:295–305

    Article  CAS  PubMed  Google Scholar 

  177. Lemire JM, Archer DC, Beck L, Spiegelberg HL (1995) Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 125:1704S–1708S

    CAS  PubMed  Google Scholar 

  178. Giulietti A, Gysemans C, Stoffels K et al (2004) Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia 47:451–462

    Article  CAS  PubMed  Google Scholar 

  179. Mathieu C, Waer M, Laureys J, Rutgeerts O, Bouillon R (1994) Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia 37:552–558

    Article  CAS  PubMed  Google Scholar 

  180. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L (2002) A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 51:1367–1374

    Article  CAS  PubMed  Google Scholar 

  181. Adorini L, Penna G, Giarratana N, Uskokovic M (2003) Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J Cell Biochem 88:227–233

    Article  CAS  PubMed  Google Scholar 

  182. The EURODIAB Substudy 2 Study Group (1999) Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. Diabetologia 42:51–54

    Article  Google Scholar 

  183. Bizzarri C, Pitocco D, Napoli N et al (2010) No protective effect of calcitriol on beta-cell function in recent-onset type 1 diabetes: the IMDIAB XIII trial. Diabetes Care 33:1962–1963

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  184. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG (2010) No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 33:1443–1448

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  185. Tang Q, Henriksen KJ, Bi M et al (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  186. Bluestone JA, Tang Q (2004) Therapeutic vaccination using CD4 + CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci U S A 101(Suppl 2):14622–14626

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  187. Putnam AL, Brusko TM, Lee MR et al (2009) Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58:652–662

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  188. Kared H, Masson A, Adle-Biassette H, Bach JF, Chatenoud L, Zavala F (2005) Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. Diabetes 54:78–84

    Article  CAS  PubMed  Google Scholar 

  189. Kared H, Adle-Biassette H, Fois E et al (2006) Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. Immunity 25:823–834

    Article  CAS  PubMed  Google Scholar 

  190. Voltarelli JC, Couri CE, Stracieri AB et al (2007) Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297:1568–1576

    Article  CAS  PubMed  Google Scholar 

  191. Couri CE, Oliveira MC, Stracieri AB et al (2009) C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 301:1573–1579

    Article  CAS  PubMed  Google Scholar 

  192. Leal AM, Oliveira MC, Couri CE et al (2012) Testicular function in patients with type 1 diabetes treated with high-dose CY and autologous hematopoietic SCT. Bone Marrow Transplant 47:467–468

    Article  CAS  PubMed  Google Scholar 

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You, S., Chatenoud, L. (2016). Autoimmune Diabetes: An Overview of Experimental Models and Novel Therapeutics. In: Cuturi, M., Anegon, I. (eds) Suppression and Regulation of Immune Responses. Methods in Molecular Biology, vol 1371. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3139-2_8

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