Seminars in Immunopathology

, Volume 33, Issue 1, pp 67–87

Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease

  • John P. Driver
  • David V. Serreze
  • Yi-Guang Chen


For almost 30 years, the non-obese diabetic (NOD) mouse has served as the primary model for dissecting the genetic and pathogenic basis for T-lymphocyte-mediated autoimmune type 1 diabetes (T1D). However, while sharing many similarities, it is becoming increasingly appreciated that there are also some differences in the immunopathogenic basis of T1D development between humans and NOD mice. This review will focus on aspects of T1D development in NOD mice that are similar and different from that in humans.


Type 1 diabetes NOD mice Immunological tolerance Genetics 


  1. 1.
    Mordes JP, Serreze DV, Greiner DL, Rossini AA (2004) Animal models of autoimmune diabetes mellitus. In: LeRoith D, Taylor SI, Olefsky JM (eds) Diabetes mellitus: a fundamental and clinical text. Lippincott Williams and Wilkins, Philadelphia, pp 591–610Google Scholar
  2. 2.
    Tanaguchi H, Makino S, Ikegami H (2007) The NOD mouse and its related strains. In: Shafrir E (ed) Animal models of diabetes frontiers in research, 2nd edn. CRC, Boca Raton, pp 41–60Google Scholar
  3. 3.
    Delovitch TL, Singh B (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:291–297CrossRefGoogle Scholar
  4. 4.
    Prochazka M, Leiter EH, Serreze DV, Coleman DL (1987) Three recessive loci required for insulin-dependent diabetes in NOD mice. Science 237:286–289PubMedCrossRefGoogle Scholar
  5. 5.
    Wicker LS, Todd JA, Peterson LB (1995) Genetic control of autoimmune diabetes in the NOD mouse. Ann Rev Immunol 13:179–200CrossRefGoogle Scholar
  6. 6.
    Prochazka M, Serreze DV, Worthen SM, Leiter EH (1989) Genetic control of diabetogenesis in NOD/Lt mice: development and analysis of congenic stocks. Diabetes 38:1446–1455PubMedCrossRefGoogle Scholar
  7. 7.
    Acha-Orbea H, McDevitt HO (1987) The first external domain of the nonobese diabetic mouse class II I-Aβ chain is unique. Proc Natl Acad Sci USA 84:2435–2439PubMedCrossRefGoogle Scholar
  8. 8.
    Miyazaki T, Uno M, Uehira M, Kikutani H, Kishimoto T, Kimoto M, Nishimoto H, Miyazaki J, Yamamura K (1990) Direct evidence for the contribution of the unique I-Anod to the development of insulitis in non-obese diabetic mice. Nature 345:722–724PubMedCrossRefGoogle Scholar
  9. 9.
    Lund T, O'Reilly L, Hutchings P, Kanagawa O, Simpson E, Gravely R, Chandler P, Dyson J, Picard JK, Edwards A, Kioussis D, Cooke A (1990) Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain. Nature 345:727–729PubMedCrossRefGoogle Scholar
  10. 10.
    Slattery RM, Kjer-Nielsen L, Allison J, Charlton B, Mandel T, Miller JFAP (1990) Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature 345:724–726PubMedCrossRefGoogle Scholar
  11. 11.
    Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, McDermott M, Sinha AA, Timmerman L, Steinman L, McDevitt HO (1988) A molecular basis for MHC class II—associated autoimmunity. Science 240:1003–1009PubMedCrossRefGoogle Scholar
  12. 12.
    Ikegami H, Makino S, Yamato E, Kawaguchi Y, Ueda H, Sakamoto T, Takekawa K, Ogihara T (1995) Identification of a new susceptibility locus for insulin-dependent diabetes mellitus by ancestral haplotype congenic mapping. J Clin Invest 96:1936–1942PubMedCrossRefGoogle Scholar
  13. 13.
    Serreze DV, Chapman HD, Varnum DS, Gerling I, Leiter EH, Shultz LD (1997) Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent. J Immunol 158:3978–3986PubMedGoogle Scholar
  14. 14.
    Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC (1994) MHC class I deficient NOD-B2m null mice are diabetes and insulitis resistant. Diabetes 43:505–509PubMedCrossRefGoogle Scholar
  15. 15.
    Serreze DV, Bridgett M, Chapman HD, Chen E, Richard SD, Leiter EH (1998) Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for β2-microglobulin. J Immunol 160:1472–1478PubMedGoogle Scholar
  16. 16.
    Hamilton-Williams EE, Serreze DV, Charlton B, Johnson EA, Marron MP, Mullbacher A, Slattery RM (2001) Transgenic rescue implicates β2-microglobulin as a diabetes susceptibility gene in NOD mice. Proc Natl Acad Sci USA 98:11533–11538PubMedCrossRefGoogle Scholar
  17. 17.
    Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, Hulme J, Maier LM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Consortium TWTCC, Clayton DG, Todd JA (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892PubMedCrossRefGoogle Scholar
  18. 18.
    Marron MP, Graser RT, Chapman HD, Serreze DV (2002) Functional evidence for the mediation of diabetogenic T cell responses by human HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc Natl Acad Sci USA 99:13753–13758PubMedCrossRefGoogle Scholar
  19. 19.
    Wicker LS, Todd JA, Prins J-B, Podolin PL, Renjilian RJ, Peterson LB (1994) Resistance alleles at two non-MHC-linked insulin dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect NOD mice from diabetes. J Exp Med 180:1705–1713PubMedCrossRefGoogle Scholar
  20. 20.
    McGuire HM, Vogelzang A, Hill N, Flodstrom-Tullberg M, Sprent J, King C (2009) Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus. Proc Natl Acad Sci U S A 106:19438–19443PubMedCrossRefGoogle Scholar
  21. 21.
    Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P (2007) Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 39:329–337PubMedCrossRefGoogle Scholar
  22. 22.
    Lyons PA, Armitage N, Argentina F, Denny P, Hill NJ, Lord CJ, Wilusz MB, Peterson LB, Wicker LS, Todd JA (2000) Congenic mapping of the type 1 diabetes locus, ldd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping. Genome Res 10:446–453PubMedCrossRefGoogle Scholar
  23. 23.
    King C, Ilic A, Koelsch K, Sarvetnick N (2004) Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117:265–277PubMedCrossRefGoogle Scholar
  24. 24.
    Serreze DV, Leiter EH (1988) Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol 140:3801–3807PubMedGoogle Scholar
  25. 25.
    Serreze DV, Hamaguchi K, Leiter EH (1989) Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmunity 2:759–776CrossRefGoogle Scholar
  26. 26.
    Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ (2008) IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci U S A 105:14028–14033PubMedCrossRefGoogle Scholar
  27. 27.
    Sutherland AP, Van Belle T, Wurster AL, Suto A, Michaud M, Zhang D, Grusby MJ, von Herrath M (2009) Interleukin-21 is required for the development of type 1 diabetes in NOD mice. Diabetes 58:1144–1155PubMedCrossRefGoogle Scholar
  28. 28.
    Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA (2008) Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28:687–697PubMedCrossRefGoogle Scholar
  29. 29.
    Podolin PL, Wilusz MB, Cubbon RM, Pajvani U, Lord CJ, Todd JA, Peterson LB, Wicker LS, Lyons PA (2000) Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene? Cytokine 12:477–482PubMedCrossRefGoogle Scholar
  30. 30.
    Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–779PubMedCrossRefGoogle Scholar
  31. 31.
    Asano K, Ikegami H, Fujisawa T, Nishino M, Nojima K, Kawabata Y, Noso S, Hiromine Y, Fukai A, Ogihara T (2007) Molecular scanning of interleukin-21 gene and genetic susceptibility to type 1 diabetes. Hum Immunol 68:384–391PubMedCrossRefGoogle Scholar
  32. 32.
    Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707PubMedCrossRefGoogle Scholar
  33. 33.
    Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511PubMedCrossRefGoogle Scholar
  34. 34.
    Vijayakrishnan L, Slavik JM, Illes Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK (2004) An autoimmune disease associated CTLa-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20:563–575PubMedCrossRefGoogle Scholar
  35. 35.
    Sansom DM, Walker LS (2006) The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev 212:131–148PubMedCrossRefGoogle Scholar
  36. 36.
    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275PubMedCrossRefGoogle Scholar
  37. 37.
    Araki M, Chung D, Liu S, Rainbow DB, Chamberlain G, Garner V, Hunter KM, Vijayakrishnan L, Peterson LB, Oukka M, Sharpe AH, Sobel R, Kuchroo VK, Wicker LS (2009) Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. J Immunol 183:5146–5157PubMedCrossRefGoogle Scholar
  38. 38.
    McAleer MA, Reifsnyder P, Palmer SM, Prochazka M, Love JM, Copeman JB, Powell EE, Rodrigues NR, Prins JB, Serreze DV et al (1995) Crosses of NOD mice with the related NON strain. A polygenic model for IDDM. Diabetes 44:1186–1195PubMedCrossRefGoogle Scholar
  39. 39.
    Ghosh S, Palmer SM, Rodrigues NR, Cordell HJ, Hearne CM, Cornall RJ, Prins JB, McShane P, Lathrop GM, Peterson LB et al (1993) Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet 4:404–409PubMedCrossRefGoogle Scholar
  40. 40.
    DiLorenzo TP, Lieberman SM, Takaki T, Honda S, Chapman HD, Santamaria P, Serreze DV, Nathenson SG (2002) During the early prediabetic period in NOD Mice, the pathogenic CD8+ T cell population comprises multiple antigenic specificities. Clin Immunol 105:332–341PubMedCrossRefGoogle Scholar
  41. 41.
    Serreze DV, Choisy-Rossi CM, Grier AE, Holl TM, Chapman HD, Gahagan JR, Osborne MA, Zhang W, King BL, Brown A, Roopenian D, Marron MP (2008) Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in nonobese diabetic mice. J Immunol 180:3250–3259PubMedGoogle Scholar
  42. 42.
    Choisy-Rossi CM, Holl TM, Pierce MA, Chapman HD, Serreze DV (2004) Enhanced pathogenicity of diabetogenic T cells escaping a non-MHC gene-controlled near death experience. J Immunol 173:3791–3800PubMedGoogle Scholar
  43. 43.
    Lyons PA, Hancock WW, Denny P, Lord CJ, Hill NJ, Armitage N, Siegmund T, Todd JA, Phillipps MS, Hess JF, Chen S-L, Fischer PA, Peterson LB, Wicker LS (2000) The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137. Immunity 13:107–115PubMedCrossRefGoogle Scholar
  44. 44.
    Waldner H, Sobel RA, Price N, Kuchroo VK (2006) The autoimmune diabetes locus Idd9 regulates development of type 1 diabetes by affecting the homing of islet-specific T cells. J Immunol 176:5455–5462PubMedGoogle Scholar
  45. 45.
    Ueno A, Wang J, Cheng L, Im JS, Shi Y, Porcelli SA, Yang Y (2008) Enhanced early expansion and maturation of semi-invariant NK T cells inhibited autoimmune pathogenesis in congenic nonobese diabetic mice. J Immunol 181:6789–6796PubMedGoogle Scholar
  46. 46.
    Yamanouchi J, Puertas MC, Verdaguer J, Lyons PA, Rainbow DB, Chamberlain G, Hunter KM, Peterson LB, Wicker LS, Santamaria P (2010) The Idd9.1 locus controls the suppressive activity of FoxP3 + CD4 + CD25+ regulatory T-cells. Diabetes 59:272–281PubMedCrossRefGoogle Scholar
  47. 47.
    Hill NJ, Stotland A, Solomon M, Secrest P, Getzoff E, Sarvetnick N (2007) Resistance of the target islet tissue to autoimmune destruction contributes to genetic susceptibility in type 1 diabetes. Biol Direct 2:5PubMedCrossRefGoogle Scholar
  48. 48.
    Silveira PA, Chapman HD, Stolp J, Johnson E, Cox SL, Hunter K, Wicker LS, Serreze DV (2006) Genes within the Idd5 and Idd9/11 diabetes susceptibility loci affect the pathogenic activity of B cells in nonobese diabetic mice. J Immunol 177:7033–7041PubMedGoogle Scholar
  49. 49.
    Brodnicki TC, Fletcher AL, Pellicci DG, Berzins SP, McClive P, Quirk F, Webster KE, Scott HS, Boyd RL, Godfrey DI, Morahan G (2005) Localization of Idd11 is not associated with thymus and nkt cell abnormalities in NOD mice. Diabetes 54:3453–3457PubMedCrossRefGoogle Scholar
  50. 50.
    Reifsnyder PC, Li R, Silveira P, Churchill GA, Serreze DV, Leiter EH (2005) Conditioning the genome identifies additional diabetes resistance loci in type 1 diabetes resistant NOR/Lt mice. Genes Immun 6:528–538PubMedCrossRefGoogle Scholar
  51. 51.
    Mao HZ, Roussos ET, Peterfy M (2006) Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains. Biochim Biophys Acta 1762:440–446PubMedGoogle Scholar
  52. 52.
    McClive PJ, Huang D, Morahan G (1994) C57BL/6 and C57BL/10 inbred mouse strains differ at multiple loci on chromosome 4. Immunogenetics 39:286–288PubMedCrossRefGoogle Scholar
  53. 53.
    Rolf J, Motta V, Duarte N, Lundholm M, Berntman E, Bergman ML, Sorokin L, Cardell SL, Holmberg D (2005) The enlarged population of marginal zone/CD1d(high) B lymphocytes in nonobese diabetic mice maps to diabetes susceptibility region Idd11. J Immunol 174:4821–4827PubMedGoogle Scholar
  54. 54.
    Marino E, Batten M, Groom J, Walters S, Liuwantara D, Mackay F, Grey ST (2008) Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells. Diabetes 57:395–404PubMedCrossRefGoogle Scholar
  55. 55.
    Chen YG, Scheuplein F, Osborne MA, Tsaih SW, Chapman HD, Serreze DV (2008) Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes 57:3273–3280PubMedCrossRefGoogle Scholar
  56. 56.
    Martin AM, Blankenhorn EP, Maxson MN, Zhao M, Leif J, Mordes JP, Greiner DL (1999) Non-major histocompatibility complex-linked diabetes susceptibility loci on chromosomes 4 and 13 in a backcross of the DP-BB/Wor rat to the WF rat. Diabetes 48:50–58PubMedCrossRefGoogle Scholar
  57. 57.
    Field LL, Tobias R, Magnus T (1994) A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin dependent diabetes mellitus. Nat Genet 8:189–194PubMedCrossRefGoogle Scholar
  58. 58.
    Zamani M, Pociot F, Raeymaekers P, Nerup J, Cassiman JJ (1996) Linkage of type I diabetes to 15q26 (IDDM3) in the Danish population. Hum Genet 98:491–496PubMedCrossRefGoogle Scholar
  59. 59.
    Serreze DV, Prochazka M, Reifsnyder PC, Bridgett M, Leiter EH (1994) Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin dependent diabetes resistance gene. J Exp Med 180:1553–1558PubMedCrossRefGoogle Scholar
  60. 60.
    Esteban LM, Tsoutsman T, Jordan MA, Roach D, Poulton LD, Brooks A, Naidenko OV, Sidobre S, Godfrey DI, Baxter AG (2003) Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol 171:2873–2878PubMedGoogle Scholar
  61. 61.
    Chen YG, Driver JP, Silveira PA, Serreze DV (2007) Subcongenic analysis of genetic basis for impaired development of invariant NKT cells in NOD mice. Immunogenetics 59:705–712PubMedCrossRefGoogle Scholar
  62. 62.
    Fletcher JM, Jordan MA, Snelgrove SL, Slattery RM, Dufour FD, Kyparissoudis K, Besra GS, Godfrey DI, Baxter AG (2008) Congenic analysis of the NKT cell control gene Nkt2 implicates the peroxisomal protein Pxmp4. J Immunol 181:3400–3412PubMedGoogle Scholar
  63. 63.
    Fox CJ, Paterson AD, Mortin-Toth SM, Danska JS (2000) Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Am J Hum Genet 67:67–81PubMedCrossRefGoogle Scholar
  64. 64.
    Serreze DV, Leiter EH (2001) Genes and pathways underlying autoimmune diabetes in NOD mice. In: von Herrath MG (ed) Molecular pathology of insulin dependent diabetes mellitus. Karger, New York, pp 31–67CrossRefGoogle Scholar
  65. 65.
    Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2:11–19PubMedCrossRefGoogle Scholar
  66. 66.
    Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606PubMedCrossRefGoogle Scholar
  67. 67.
    Moser M (2003) Dendritic cells in immunity and tolerance-do they display opposite functions? Immunity 19:5–8PubMedCrossRefGoogle Scholar
  68. 68.
    Reis e Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6:476–483PubMedCrossRefGoogle Scholar
  69. 69.
    Dahlen E, Hedlund G, Dawe K (2000) Low CD86 expression in the nonobese diabetic mouse results in the impairment of both T cell activation and CTLA-4 up-regulation. J Immunol 164:2444–2456PubMedGoogle Scholar
  70. 70.
    Lee M, Kim AY, Kang Y (2000) Defects in the differentiation and function of bone marrow-derived dendritic cells in non-obese diabetic mice. J Korean Med Sci 15:217–223PubMedGoogle Scholar
  71. 71.
    Strid J, Lopes L, Marcinkiewicz J, Petrovska L, Nowak B, Chain BM, Lund T (2001) A defect in bone marrow derived dendritic cell maturation in the nonobese diabetic mouse. Clin Exp Immunol 123:375–381PubMedCrossRefGoogle Scholar
  72. 72.
    Boudaly S, Morin J, Berthier R, Marche P, Boitard C (2002) Altered dendritic cells (DC) might be responsible for regulatory T cell imbalance and autoimmunity in nonobese diabetic (NOD) mice. Eur Cytokine Netw 13:29–37PubMedGoogle Scholar
  73. 73.
    Pearson T, Markees TG, Serreze DV, Pierce MA, Marron MP, Wicker LS, Peterson LB, Shultz LD, Mordes JP, Rossini AA, Greiner DL (2003) Genetic dissociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice. J Immunol 171:185–195PubMedGoogle Scholar
  74. 74.
    Ucker DS, Meyers J, Obermiller PS (1992) Activation-driven T cell death. II. Quantitative differences alone distinguish stimuli triggering nontransformed T cell proliferation or death. J Immunol 149:1583–1592PubMedGoogle Scholar
  75. 75.
    Chen YG, Choisy-Rossi CM, Holl TM, Chapman HD, Besra GS, Porcelli SA, Shaffer DJ, Roopenian D, Wilson SB, Serreze DV (2005) Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes. J Immunol 174:1196–1204PubMedGoogle Scholar
  76. 76.
    Kurts C, Cannarile M, Klebba I, Brocker T (2001) Dendritic cells are sufficient to cross-present self-antigens to CD8 T cells in vivo. J Immunol 166:1439–1442PubMedGoogle Scholar
  77. 77.
    Kurts C, Kosaka H, Carbone FR, Miller JF, Heath WR (1997) Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. J Exp Med 186:239–245PubMedCrossRefGoogle Scholar
  78. 78.
    Kreuwel HT, Biggs JA, Pilip IM, Pamer EG, Lo D, Sherman LA (2001) Defective CD8 T cell peripheral tolerance in nonobese diabetic mice. J Immunol 167:1112–1117PubMedGoogle Scholar
  79. 79.
    Clare-Salzler MJ, Brooks J, Chai A, Herle KV, Anderson C (1992) Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer. J Clin Invest 90:741–748PubMedCrossRefGoogle Scholar
  80. 80.
    Hamilton-Williams EE, Martinez X, Clark J, Howlett S, Hunter KM, Rainbow DB, Wen L, Shlomchik MJ, Katz JD, Beilhack GF, Wicker LS, Sherman LA (2009) Expression of diabetes-associated genes by dendritic cells and CD4 T cells drives the loss of tolerance in nonobese diabetic mice. J Immunol 183:1533–1541PubMedCrossRefGoogle Scholar
  81. 81.
    Dai YD, Marrero IG, Gros P, Zaghouani H, Wicker LS, Sercarz EE (2009) Slc11a1 enhances the autoimmune diabetogenic T-cell response by altering processing and presentation of pancreatic islet antigens. Diabetes 58:156–164PubMedCrossRefGoogle Scholar
  82. 82.
    Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC, Richard SD, Fleming SA, Leiter EH, Shultz LD (1996) B lymphocytes are essential for the initiation of T cell mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Igµ null mice. J Exp Med 184:2049–2053PubMedCrossRefGoogle Scholar
  83. 83.
    Akashi T, Nagafuchi S, Anzai K, Kondo S, Kitamura D, Wakana S, Ono J, Kikuchi M, Niho Y, Watanabe T (1997) Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice. Int Immunol 9:1159–1164PubMedCrossRefGoogle Scholar
  84. 84.
    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 46:941–946PubMedCrossRefGoogle Scholar
  85. 85.
    Yang M, Charlton B, Gautam AM (1997) Development of insulitis and diabetes in B cell-deficient NOD mice. J Autoimmunity 10:257–260CrossRefGoogle Scholar
  86. 86.
    Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L (2007) Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Invest 117:3857–3867PubMedCrossRefGoogle Scholar
  87. 87.
    Fiorina P, Vergani A, Dada S, Jurewicz M, Wong M, Law K, Wu E, Tian Z, Abdi R, Guleria I, Rodig S, Dunussi-Joannopoulos K, Bluestone J, Sayegh MH (2008) Targeting CD22 reprograms B-cells and reverses autoimmune diabetes. Diabetes 57:3013–3024PubMedCrossRefGoogle Scholar
  88. 88.
    Xiu Y, Wong CP, Bouaziz JD, Hamaguchi Y, Wang Y, Pop SM, Tisch RM, Tedder TF (2008) B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions. J Immunol 180:2863–2875PubMedGoogle Scholar
  89. 89.
    Zekavat G, Rostami SY, Badkerhanian A, Parsons RF, Koeberlein B, Yu M, Ward CD, Migone TS, Yu L, Eisenbarth GS, Cancro MP, Naji A, Noorchashm H (2008) In vivo BLyS/BAFF neutralization ameliorates islet-directed autoimmunity in nonobese diabetic mice. J Immunol 181:8133–8144PubMedGoogle Scholar
  90. 90.
    Marino E, Villanueva J, Walters S, Liuwantara D, Mackay F, Grey ST (2009) CD4(+)CD25(+) T-cells control autoimmunity in the absence of B-cells. Diabetes 58:1568–1577PubMedCrossRefGoogle Scholar
  91. 91.
    Melanitou E, Devendra D, Liu E, Miao D, Eisenbarth GS (2004) Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset. J Immunol 173:6603–6610PubMedGoogle Scholar
  92. 92.
    Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM (1998) B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol 161:3912–3918PubMedGoogle Scholar
  93. 93.
    Greeley SA, Katsumata M, Yu L, Eisenbarth GS, Moore DJ, Goodarzi H, Barker CF, Naji A, Noorchashm H (2002) Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 8:399–402PubMedCrossRefGoogle Scholar
  94. 94.
    Wong FS, Wen L, Tang M, Ramanathan M, Visintin I, Daugherty J, Hannum LG, Janeway CA Jr, Shlomchik MJ (2004) Investigation of the role of B-cells in type 1 diabetes in the NOD mouse. Diabetes 53:2581–2587PubMedCrossRefGoogle Scholar
  95. 95.
    Falcone M, Lee J, Patstone G, Yeung B, Sarvetnick N (1998) B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice. J Immunol 161:1163–1168PubMedGoogle Scholar
  96. 96.
    Greeley SA, Moore DJ, Noorchashm H, Noto LE, Rostami SY, Schlachterman A, Song HK, Koeberlein B, Barker CF, Naji A (2001) Impaired activation of islet reactive CD4 T cells in pancreatic lymph nodes of B cell deficient nonobese diabetic mice. J Immunol 167:4351–4357PubMedGoogle Scholar
  97. 97.
    Tian J, Zekzer D, Lu Y, Dang H, Kaufman DL (2006) B cells are crucial for determinant spreading of T cell autoimmunity among beta cell antigens in diabetes-prone nonobese diabetic mice. J Immunol 176:2654–2661PubMedGoogle Scholar
  98. 98.
    Noorchashm H, Lieu YK, Noorchashm N, Rostami SY, Greeley SA, Schlachterman A, Song HK, Noto LE, Jevnikar AM, Barker CF, Naji A (1999) I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice. J Immunol 163:743–750PubMedGoogle Scholar
  99. 99.
    Silveira P, Johnson EA, Chapman HD, Tisch RM, Serreze DV (2002) The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen specific immunoglobulin receptors. Eur J Immunol 32:3657–3666PubMedCrossRefGoogle Scholar
  100. 100.
    Hulbert C, Riseili B, Rojas M, Thomas JW (2001) B cell specificity contributes to the outcome of diabetes in nonobese diabetic mice. J Immunol 167:5535–5538PubMedGoogle Scholar
  101. 101.
    Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG (2000) BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin dependent lymphoid neogenesis. Immunity 12:471–481PubMedCrossRefGoogle Scholar
  102. 102.
    Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6:205–217PubMedCrossRefGoogle Scholar
  103. 103.
    Wu Q, Saloman B, Chen M, Wang Y, Hoffman LM, Bluestone JA, Fu YX (2001) Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J Exp Med 193:1327–1332PubMedCrossRefGoogle Scholar
  104. 104.
    Lee Y, Chin RK, Christiansen P, Sun Y, Tumanov AV, Wang J, Chervonsky AV, Fu YX (2006) Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure. Immunity 25:499–509PubMedCrossRefGoogle Scholar
  105. 105.
    Guleria I, Gubbels Bupp M, Dada S, Fife B, Tang Q, Ansari MJ, Trikudanathan S, Vadivel N, Fiorina P, Yagita H, Azuma M, Atkinson M, Bluestone JA, Sayegh MH (2007) Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clin Immunol 125:16–25PubMedCrossRefGoogle Scholar
  106. 106.
    Chiu PP, Serreze DV, Danska JS (2001) Development and function of diabetogenic T-cells in B-cell-deficient nonobese diabetic mice. Diabetes 50:763–770PubMedCrossRefGoogle Scholar
  107. 107.
    Silveira PA, Dombrowsky J, Johnson E, Chapman HD, Nemazee D, Serreze DV (2004) B-cell selection defects underlie the development of diabetogenic antigen presenting cells in NOD mice. J Immunol 172:5086–5094PubMedGoogle Scholar
  108. 108.
    Serreze DV, Gaedeke JW, Leiter EH (1993) Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C. Proc Natl Acad Sci U S A 90:9625–9629PubMedCrossRefGoogle Scholar
  109. 109.
    Serreze DV, Gaskins HR, Leiter EH (1993) Defects in the differentiation and function of antigen presenting cells in NOD/Lt mice. J Immunol 150:2534–2543PubMedGoogle Scholar
  110. 110.
    Anderson AC, Chandwaskar R, Lee DH, Kuchroo VK (2008) Cutting edge: the Idd3 genetic interval determines regulatory T cell function through CD11b + CD11c- APC. J Immunol 181:7449–7452PubMedGoogle Scholar
  111. 111.
    Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME (2008) The consequences of apoptosis in autoimmunity. J Autoimmun 31:257–262PubMedCrossRefGoogle Scholar
  112. 112.
    O'Brien BA, Huang Y, Geng X, Dutz JP, Finegood DT (2002) Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced. Diabetes 51:2481–2488PubMedCrossRefGoogle Scholar
  113. 113.
    Stoffels K, Overbergh L, Giulietti A, Kasran A, Bouillon R, Gysemans C, Mathieu C (2004) NOD macrophages produce high levels of inflammatory cytokines upon encounter of apoptotic or necrotic cells. J Autoimmun 23:9–15PubMedCrossRefGoogle Scholar
  114. 114.
    O'Brien BA, Geng X, Orteu CH, Huang Y, Ghoreishi M, Zhang Y, Bush JA, Li G, Finegood DT, Dutz JP (2006) A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse. J Autoimmun 26:104–115PubMedCrossRefGoogle Scholar
  115. 115.
    Trudeau JD, Dutz JP, Arany E, Hill DJ, Fieldus WE, Finegood DT (2000) Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49:1–7PubMedCrossRefGoogle Scholar
  116. 116.
    Litherland SA, Grebe KM, Belkin NS, Paek E, Elf J, Atkinson M, Morel L, Clare-Salzler MJ, McDuffie M (2005) Nonobese diabetic mouse congenic analysis reveals chromosome 11 locus contributing to diabetes susceptibility, macrophage STAT5 dysfunction, and granulocyte-macrophage colony-stimulating factor overproduction. J Immunol 175:4561–4565PubMedGoogle Scholar
  117. 117.
    Leiter EH (2005) Nonobese diabetic mice and the genetics of diabetes susceptibility. Curr Diab Rep 5:141–148PubMedCrossRefGoogle Scholar
  118. 118.
    Rapaport MJ, Zipris D, Lazarus AH, Jaramillo A, Serreze DV, Leiter EH, Cyopick P, Delovitch TL (1993) Thymic T cell proliferative unresponsiveness in autoimmune NOD mice. II. IL-4 reverses NOD thymic T cell anergy and prevents the onset of diabetes. J Exp Med 178:87–99CrossRefGoogle Scholar
  119. 119.
    Rapoport MJ, Lazurus AH, Jaramillo A, Speck E, Delovitch TL (1993) Thymic T cell anergy in autoimmune nonobese diabetic mice is mediated by deficient T cell receptor regulation in the pathway of p21ras activation. J Exp Med 177:1221–1226PubMedCrossRefGoogle Scholar
  120. 120.
    Decallonne B, van Etten E, Giulietti A, Casteels K, Overbergh L, Bouillon R, Mathieu C (2003) Defect in activation-induced cell death in non-obese diabetic (NOD) T lymphocytes. J Autoimmun 20:219–226PubMedCrossRefGoogle Scholar
  121. 121.
    Arreaza G, Salojin K, Yang W, Zhang J, Gill B, Mi QS, Gao JX, Meagher C, Cameron M, Delovitch TL (2003) Deficient activation and resistance to activation-induced apoptosis of CD8+ T cells is associated with defective peripheral tolerance in nonobese diabetic mice. Clin Immunol 107:103–115PubMedCrossRefGoogle Scholar
  122. 122.
    Piccirillo CA, Tritt M, Sgouroudis E, Albanese A, Pyzik M, Hay V (2005) Control of type 1 autoimmune diabetes by naturally occurring CD4 + CD25+ regulatory T lymphocytes in neonatal NOD mice. Ann N Y Acad Sci 1051:72–87PubMedCrossRefGoogle Scholar
  123. 123.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114:1379–1388PubMedGoogle Scholar
  124. 124.
    Zipris D, Lazarus AH, Crow AR, Hadazija M, Delovitch TL (1991) Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice: evidence of thymic T cell anergy that correlates with the onset of insulitis. J Immunol 146:3763–3771PubMedGoogle Scholar
  125. 125.
    Sebzda E, Wallace VA, Mayer J, Yeung RSM, Mak T, Ohashi PS (1994) Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263:1615–1618PubMedCrossRefGoogle Scholar
  126. 126.
    Ashton-Rickardt PG, Bandeira A, Delany JR, Kaer LV, Pircher H-B, Zinkernagel RM, Tonegawa S (1994) Evidence for a differential avidity model of T cell selection in the thymus. Cell 76:651–663PubMedCrossRefGoogle Scholar
  127. 127.
    Liston A, Lesage S, Gray DH, O'Reilly LA, Strasser A, Fahrer AM, Boyd RL, Wilson J, Baxter AG, Gallo EM, Crabtree GR, Peng K, Wilson SR, Goodnow CC (2004) Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. Immunity 21:817–830PubMedGoogle Scholar
  128. 128.
    Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D (2005) Defective central tolerance induction in NOD mice: genomics and genetics. Immunity 22:385–396PubMedCrossRefGoogle Scholar
  129. 129.
    Rocha B, Von Boehmer H (1991) Peripheral selection of the T cell repertoire. Science 251:1225–1231PubMedCrossRefGoogle Scholar
  130. 130.
    Zhang L, Martin DR, Fung-Leung W-P, Teh H-S, Miller RG (1992) Peripheral deletion of mature CD8+ antigen specific T cells after in vivo exposure to male antigen. J Immunol 148:3740–3745PubMedGoogle Scholar
  131. 131.
    Critchfield JM, Racke MK, Zuniga-Pflucker JC, Cannella B, Raine CS, Goverman J, Lenardo MJ (1994) T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263:1139–1143PubMedCrossRefGoogle Scholar
  132. 132.
    Pelfry CM, Tranquill LR, Boehme SA, McFarland HF, Lenardo MJ (1995) Two mechanisms of antigen-specific apoptosis of myelin basic protein (MBP)-specific T lymphocytes derived from multiple sclerosis patients and normal individuals. J Immunol 154:6191–6202Google Scholar
  133. 133.
    Cameron MJ, Arreaza GA, Zucker P, Chensue SW, Strieter RM, Chakrabarti S, Delovitch TL (1997) IL-4 prevents insulitis and insulin dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 159:4686–4692PubMedGoogle Scholar
  134. 134.
    Chandy KG, Charles AM, Kershnar A, Buckingham B, Waldeck N, Gupta S (1984) Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus. J Clin Immunol 4:424–428PubMedCrossRefGoogle Scholar
  135. 135.
    Rasanen L, Hyoty H, Lehto M, Kallioniemi OP, Antonen J, Huupponen T, Karjalainen J, Leinikki P (1988) Defective autologous mixed leukocyte reaction in newly diagnosed type 1 diabetes mellitus. Clin Exp Immunol 71:470–474PubMedGoogle Scholar
  136. 136.
    Giordano C, Panto F, Caruso C, Modica MA, Zambito AM, Sapienza N, Amato MP, Galluzzo A (1989) Interleukin 2 and soluble interleukin 2-receptor secretion defect in vitro in newly diagnosed type I diabetic patients. Diabetes 38:310–315PubMedCrossRefGoogle Scholar
  137. 137.
    De Maria R, Todaro M, Stassi G, Di Blasi F, Giordano M, Galluzzo A, Giordano C (1994) Defective T cell receptor/CD3 complex signaling in human type I diabetes. Eur J Immunol 24:999–1002PubMedCrossRefGoogle Scholar
  138. 138.
    Giordano C, De Maria R, Stassi G, Todaro M, Richiusa P, Giordano M, Testi R, Galluzzo A (1995) Defective expression of the apoptosis-inducing CD95 (Fas/APO-1) molecule on T and B cells in IDDM. Diabetologia 38:1449–1454PubMedCrossRefGoogle Scholar
  139. 139.
    Dosch H, Cheung RK, Karges W, Pietropaolo M, Becker DJ (1999) Persistent T cell anergy in human type 1 diabetes. J Immunol 163:6933–6940PubMedGoogle Scholar
  140. 140.
    Nervi S, Atlan-Gepner C, Kahn-Perles B, Lecine P, Vialettes B, Imbert J, Naquet P (2000) Specific deficiency of p56lck expression in T lymphocytes from type 1 diabetic patients. J Immunol 165:5874–5883PubMedGoogle Scholar
  141. 141.
    Dendrou CA, Plagnol V, Fung E, Yang JH, Downes K, Cooper JD, Nutland S, Coleman G, Himsworth M, Hardy M, Burren O, Healy B, Walker NM, Koch K, Ouwehand WH, Bradley JR, Wareham NJ, Todd JA, Wicker LS (2009) Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet 41:1011–1015PubMedCrossRefGoogle Scholar
  142. 142.
    Li XC, Demirci G, Ferrari-Lacraz S, Groves C, Coyle A, Malek TR, Strom TB (2001) IL-15 and IL-2: a matter of life and death for T cells in vivo. Nat Med 7:114–118PubMedCrossRefGoogle Scholar
  143. 143.
    Lenardo MJ (1991) Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353:858–861PubMedCrossRefGoogle Scholar
  144. 144.
    You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach JF, Chatenoud L (2005) Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54:1415–1422PubMedCrossRefGoogle Scholar
  145. 145.
    Gregori S, Giarratana N, Smiroldo S, Adorini L (2003) Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 171:4040–4047PubMedGoogle Scholar
  146. 146.
    Vandenbark AA, Culbertson NE, Bartholomew RM, Huan J, Agotsch M, LaTocha D, Yadav V, Mass M, Whitham R, Lovera J, Milano J, Theofan G, Chou YK, Offner H, Bourdette DN (2008) Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology 123:66–78PubMedCrossRefGoogle Scholar
  147. 147.
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440PubMedCrossRefGoogle Scholar
  148. 148.
    Bour-Jordan H, Salomon BL, Thompson HL, Szot GL, Bernhard MR, Bluestone JA (2004) Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells. J Clin Invest 114:979–987PubMedGoogle Scholar
  149. 149.
    Mellanby RJ, Thomas D, Phillips JM, Cooke A (2007) Diabetes in non-obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells. Immunology 121:15–28PubMedCrossRefGoogle Scholar
  150. 150.
    Tritt M, Sgouroudis E (2008) d'Hennezel E, Albanese A, Piccirillo CA: Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes 57:113–123PubMedCrossRefGoogle Scholar
  151. 151.
    D'Alise AM, Auyeung V, Feuerer M, Nishio J, Fontenot J, Benoist C, Mathis D (2008) The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc Natl Acad Sci U S A 105:19857–19862PubMedCrossRefGoogle Scholar
  152. 152.
    Gregg RK, Jain R, Schoenleber SJ, Divekar R, Bell JJ, Lee HH, Yu P, Zaghouani H (2004) A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes. J Immunol 173:7308–7316PubMedGoogle Scholar
  153. 153.
    Sgouroudis E, Albanese A, Piccirillo CA (2008) Impact of protective IL-2 allelic variants on CD4+ Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice. J Immunol 181:6283–6292PubMedGoogle Scholar
  154. 154.
    Krishnamurthy B, Dudek NL, McKenzie MD, Purcell AW, Brooks AG, Gellert S, Colman PG, Harrison LC, Lew AM, Thomas HE, Kay TW (2006) Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 116:3258–3265PubMedCrossRefGoogle Scholar
  155. 155.
    Sgouroudis E, Piccirillo CA (2009) Control of type 1 diabetes by CD4 + Foxp3+ regulatory T cells: lessons from mouse models and implications for human disease. Diabetes Metab Res Rev 25:208–218PubMedCrossRefGoogle Scholar
  156. 156.
    Brigl M, Brenner MB (2004) CD1: antigen presentation and T cell function. Annu Rev Immunol 22:817–890PubMedCrossRefGoogle Scholar
  157. 157.
    Jordan MA, Fletcher JM, Pellicci D, Baxter AG (2007) Slamf1, the NKT cell control gene Nkt1. J Immunol 178:1618–1627PubMedGoogle Scholar
  158. 158.
    Falcone M, Yeung B, Tucker L, Rodriguez E, Sarvetnick N (1999) A defect in interleukin 12-induced activation and interferon γ secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus. J Exp Med 190:963–972PubMedCrossRefGoogle Scholar
  159. 159.
    Hammond KJ, Pellicci DG, Poulton LD, Naidenko OV, Scalzo AA, Baxter AG, Godfrey DI (2001) CD1d-restricted NKT cells: an interstrain comparison. J Immunol 167:1164–1173PubMedGoogle Scholar
  160. 160.
    Wang B, Geng YB, Wang CR (2001) CD1-restricted NK T cells protect nonobese diabetic mice from developing diabetes. J Exp Med 194:313–320PubMedCrossRefGoogle Scholar
  161. 161.
    Sharif S, Arreaza GA, Zucker P, Mi Q-S, Sondhi J, Naidenko OV, Kronenberg M, Koezuka Y, Delovitch TL, Gombert J-M, Leite-de-Moraes M, Gouarin C, Zhu R, Hameg A, Nakayama T, Taniguchi M, Lepault F, Lehuen A, Bach J-F, Herbelin A (2001) Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrance of autoimmune type 1 diabetes. Nat Med 7:1057–1062PubMedCrossRefGoogle Scholar
  162. 162.
    Naumov YN, Bahjat KS, Gausling R, Abraham R, Exley MA, Koezuka Y, Balk SB, Strominger JL, Clare-Salzer M, Wilson SB (2001) Activation of CD1d restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc Natl Acad Sci USA 98:13838–13843PubMedCrossRefGoogle Scholar
  163. 163.
    Hong S, Wilson MT, Serizawa I, Wu L, Singh N, Naidenko OV, Miura T, Haba T, Scherer DC, Wei J, Kronenberg M, Koezuka Y, Van Kaer L (2001) The natural killer T cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat Med 7:1052–1056PubMedCrossRefGoogle Scholar
  164. 164.
    Hammond KJL, Poulton LD, Palmisano L, Silveira P, Godfrey DI, Baxter AG (1998) α/ß T cell receptor (TCR) CD4-CD8- (NKT) thymocytes prevent insulin dependent diabetes mellitus in non-obese diabetic (NOD) mice by influence of interleukin (IL)-4 and/or IL-10. J Exp Med 187:1047–1056PubMedCrossRefGoogle Scholar
  165. 165.
    Lehuen A, Lantz O, Beaudoin L, Laloux V, Carnaud C, Bendelac A, Bach JF, Monteiro RC (1998) Overexpression of natural killer T cells protects Valpha14- Jalpha281 transgenic nonobese diabetic mice against diabetes. J Exp Med 188:1831–1839PubMedCrossRefGoogle Scholar
  166. 166.
    Shi FD, Flodstrom M, Balasa B, Kim SH, Van Gunst K, Strominger JL, Wilson SB, Sarvetnick N (2001) Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc Natl Acad Sci U S A 98:6777–6782PubMedCrossRefGoogle Scholar
  167. 167.
    Pillai AB, George TI, Dutt S, Strober S (2009) Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4 + CD25 + Foxp3+ T regulatory cells that protects against graft-versus-host disease. Blood 113:4458–4467PubMedCrossRefGoogle Scholar
  168. 168.
    Wang J, Cho S, Ueno A, Cheng L, Xu BY, Desrosiers MD, Shi Y, Yang Y (2008) Ligand-dependent induction of noninflammatory dendritic cells by anergic invariant NKT cells minimizes autoimmune inflammation. J Immunol 181:2438–2445PubMedGoogle Scholar
  169. 169.
    Driver JP, Scheuplein F, Chen YG, Grier AE, Wilson SB, Serreze DV (2010) iNKT-cell control of type-1 diabetes: a dendritic cell genetic decision of a silver bullet or Russian roulette. Diabetes 59:423–432PubMedCrossRefGoogle Scholar
  170. 170.
    Jahng AW, Maricic I, Pedersen B, Burdin N, Naidenko O, Kronenberg M, Koezuka Y, Kumar V (2001) Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J Exp Med 194:1789–1799PubMedCrossRefGoogle Scholar
  171. 171.
    Singh AK, Wilson MT, Hong S, Olivares-Villagomez D, Du C, Stanic AK, Joyce S, Sriram S, Koezuka Y, Van Kaer L (2001) Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med 194:1801–1811PubMedCrossRefGoogle Scholar
  172. 172.
    Zeng D, Liu Y, Sidobre S, Kronenberg M, Strober S (2003) Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. J Clin Invest 112:1211–1222PubMedGoogle Scholar
  173. 173.
    Forestier C, Molano A, Im JS, Dutronc Y, Diamond B, Davidson A, Illarionov PA, Besra GS, Porcelli SA (2005) Expansion and hyperactivity of CD1d-restricted NKT cells during the progression of systemic lupus erythematosus in (New Zealand Black x New Zealand White)F1 mice. J Immunol 175:763–770PubMedGoogle Scholar
  174. 174.
    Mukherjee R, Chaturvedi P, Qin HY, Singh B (2003) CD4+CD25+ regulatory T cells generated in response to insulin B:9-23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. J Autoimmun 21:221–237PubMedCrossRefGoogle Scholar
  175. 175.
    Feili-Hariri M, Morel PA (2001) Phenotypic and functional characteristics of BM-derived DC from NOD and non-diabetes prone strains. Clin Immunol 98:133–142PubMedCrossRefGoogle Scholar
  176. 176.
    Tian J, Kaufman DL (2009) Antigen-based therapy for the treatment of type 1 diabetes. Diabetes 58:1939–1946PubMedCrossRefGoogle Scholar
  177. 177.
    Atkinson MA, Maclaren NK, Luchetta R (1990) Insulitis and diabetes in NOD mice reduced by prohylactic insulin therapy. Diabetes 39:933–937PubMedCrossRefGoogle Scholar
  178. 178.
    Gotfredsen CF, Buschard K, Frandsen E (1985) Reduction of diabetes incidence of BB rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia 28:933–935PubMedCrossRefGoogle Scholar
  179. 179.
    Gottlieb PA, Handler ES, Appel MC, Greiner DL, Mordes JP, Rossini AA (1991) Insulin treatment prevents diabetes mellitus but not thyroiditis in RT6-depleted diabetes resistant BB/Wor rats. Diabetologia 34:296–300PubMedCrossRefGoogle Scholar
  180. 180.
    Group DPT-TS (2002) Effects of insulin in relatives of patients with type 1 diabetes mellitus. New Eng J Med 346:1685–1691CrossRefGoogle Scholar
  181. 181.
    Group TDPT-TS (2005) Effects of oral insulin in relatives of patients with type 1 diabetes: The diabetes prevention trial-type 1. Diabetes Care 28:1068–1076CrossRefGoogle Scholar
  182. 182.
    Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, Korhonen S, Erkkola R, Sipila JI, Haavisto L, Siltala M, Tuominen J, Hakalax J, Hyoty H, Ilonen J, Veijola R, Simell T, Knip M, Simell O (2008) Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372:1746–1755PubMedCrossRefGoogle Scholar
  183. 183.
    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 148:1–16PubMedCrossRefGoogle Scholar
  184. 184.
    Tisch R, Yang X-D, Singer SM, Liblau RS, Fugger L, McDevitt HO (1993) Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366:72–75PubMedCrossRefGoogle Scholar
  185. 185.
    Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GSP, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366:69–72PubMedCrossRefGoogle Scholar
  186. 186.
    Nakayama T, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS (2005) Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220–223PubMedCrossRefGoogle Scholar
  187. 187.
    Ott PA, Dittrich MT, Herzog BA, Guerkov R, Gottlieb PA, Putnam AL, Durinovic-Bello I, Boehm BO, Tary-Lehmann M, Lehmann PV (2004) T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading. J Clin Immunol 24:327–339PubMedCrossRefGoogle Scholar
  188. 188.
    Ott PA, Herzog BA, Quast S, Hofstetter HH, Boehm BO, Tary-Lehmann M, Durinovic-Bello I, Berner BR, Lehmann PV (2005) Islet-cell antigen-reactive T cells show different expansion rates and Th1/Th2 differentiation in type 1 diabetic patients and healthy controls. Clin Immunol 115:102–114PubMedCrossRefGoogle Scholar
  189. 189.
    Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, Roep BO, Peakman M (2004) Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 113:451–463PubMedGoogle Scholar
  190. 190.
    Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C, Bouhanick B, Mogenet A, Nicolino M, Carel JC, Lecomte P, Marechaud R, Bougneres P, Charbonnel B, Sai P (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 356:545–549PubMedCrossRefGoogle Scholar
  191. 191.
    Pozzilli P, Pitocco D, Visalli N, Cavallo MG, Buzzetti R, Crino A, Spera S, Suraci C, Multari G, Cervoni M, Manca Bitti ML, Matteoli MC, Marietti G, Ferrazzoli F, Cassone Faldetta MR, Giordano C, Sbriglia M, Sarugeri E, Ghirlanda G (2000) No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43:1000–1004PubMedCrossRefGoogle Scholar
  192. 192.
    Monetini L, Cavallo MG, Sarugeri E, Sentinelli F, Stefanini L, Bosi E, Thorpe R, Pozzilli P (2004) Cytokine profile and insulin antibody IgG subclasses in patients with recent onset type 1 diabetes treated with oral insulin. Diabetologia 47:1795–1802PubMedCrossRefGoogle Scholar
  193. 193.
    Ergun-Longmire B, Marker J, Zeidler A, Rapaport R, Raskin P, Bode B, Schatz D, Vargas A, Rogers D, Schwartz S, Malone J, Krischer J, Maclaren NK (2004) Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann N Y Acad Sci 1029:260–277PubMedCrossRefGoogle Scholar
  194. 194.
    Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, Roep BO (2008) Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol 152:488–497PubMedCrossRefGoogle Scholar
  195. 195.
    Agardh CD, Lynch KF, Palmer M, Link K, Lernmark A (2009) GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia 52:1363–1368PubMedCrossRefGoogle Scholar
  196. 196.
    Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R (2008) GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 359:1909–1920PubMedCrossRefGoogle Scholar
  197. 197.
    Jenkins MK, Ashwell JD, Schwartz RH (1988) Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol 140:3324–3330PubMedGoogle Scholar
  198. 198.
    Turley DM, Miller SD (2007) Peripheral tolerance induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis. J Immunol 178:2212–2220PubMedGoogle Scholar
  199. 199.
    Luo X, Pothoven KL, McCarthy D, DeGutes M, Martin A, Getts DR, Xia G, He J, Zhang X, Kaufman DB, Miller SD (2008) ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms. Proc Natl Acad Sci U S A 105:14527–14532PubMedCrossRefGoogle Scholar
  200. 200.
    Serreze DV, Osborne MA, Chen YG, Chapman HD, Pearson T, Brehm MA, Greiner DL (2006) Partial versus full allogeneic hemopoietic chimerization is a preferential means to inhibit type 1 diabetes as the latter induces generalized immunosuppression. J Immunol 177:6675–6684PubMedGoogle Scholar
  201. 201.
    Johnson EA, Silveira P, Chapman HD, Leiter EH, Serreze DV (2001) Inhibition of autoimmune diabetes in nonobese diabetic mice by transgenic restoration of H2-E MHC class II expression: additive, but unequal, involvement of multiple APC subtypes. J Immunol 167:2404–2410PubMedGoogle Scholar
  202. 202.
    Serreze DV, Leiter EH (1991) Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium. J Immunol 147:1222–1229PubMedGoogle Scholar
  203. 203.
    Nikolic B, Takeuchi Y, Leykin I, Fudaba Y, Smith RN, Sykes M (2004) Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 53:376–383PubMedCrossRefGoogle Scholar
  204. 204.
    Seung E, Iwakoshi N, Woda BA, Markees TG, Mordes JP, Rossini AA, Greiner DL (2000) Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 95:2175–2182PubMedGoogle Scholar
  205. 205.
    Seung E, Mordes JP, Rossini AA, Greiner DL (2003) Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning. J Clin Invest 112:795–808PubMedGoogle Scholar
  206. 206.
    Beilhack GF, Scheffold YC, Weismann IL, Taylor C, Jerabeck L, Burge MJ, Masek MA, Shizuru JA (2003) Purified allogeneic hematopoietic stem cell transplantation blocks diabetes pathogenesis in NOD mice. Diabetes 52:59–68PubMedCrossRefGoogle Scholar
  207. 207.
    Beilhack GF, Landa RR, Masek MA, Shizuru JA (2005) Prevention of type 1 diabetes with major histocompatibility complex-compatible and nonmarrow ablative hematopoietic stem cell transplants. Diabetes 54:1770–1779PubMedCrossRefGoogle Scholar
  208. 208.
    Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, Raskin P, Rodriguez H, Schatz DA, Wherrett D, Wilson DM, Lachin JM, Skyler JS (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361:2143–2152PubMedCrossRefGoogle Scholar
  209. 209.
    Feili-Hariri M, Flores RR, Vasquez AC, Morel PA (2006) Dendritic cell immunotherapy for autoimmune diabetes. Immunol Res 36:167–173PubMedCrossRefGoogle Scholar
  210. 210.
    Rutella S, Bonanno G, Pierelli L, Mariotti A, Capoluongo E, Contemi AM, Ameglio F, Curti A, De Ritis DG, Voso MT, Perillo A, Mancuso S, Scambia G, Lemoli RM, Leone G (2004) Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha. Eur J Immunol 34:1291–1302PubMedCrossRefGoogle Scholar
  211. 211.
    Gaudreau S, Guindi C, Menard M, Besin G, Dupuis G, Amrani A (2007) Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4 + CD25+ regulatory T cells. J Immunol 179:3638–3647PubMedGoogle Scholar
  212. 212.
    Cheatem D, Ganesh BB, Gangi E, Vasu C, Prabhakar BS (2009) Modulation of dendritic cells using granulocyte-macrophage colony-stimulating factor (GM-CSF) delays type 1 diabetes by enhancing CD4 + CD25+ regulatory T cell function. Clin Immunol 131:260–270PubMedCrossRefGoogle Scholar
  213. 213.
    Morin J, Faideau B, Gagnerault MC, Lepault F, Boitard C, Boudaly S (2003) Passive transfer of flt-3 L-derived dendritic cells delays diabetes development in NOD mice and associates with early production of interleukin (IL)-4 and IL-10 in the spleen of recipient mice. Clin Exp Immunol 134:388–395PubMedCrossRefGoogle Scholar
  214. 214.
    Chatenoud L, Primo J, Bach JF (1997) CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158:2947–2954PubMedGoogle Scholar
  215. 215.
    Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA (2005) A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763–1769PubMedCrossRefGoogle Scholar
  216. 216.
    Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352:2598–2608PubMedCrossRefGoogle Scholar
  217. 217.
    Chatenoud L, Bluestone JA (2007) CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7:622–632PubMedCrossRefGoogle Scholar
  218. 218.
    Parker MJ, Xue S, Alexander JJ, Wasserfall CH, Campbell-Thompson ML, Battaglia M, Gregori S, Mathews CE, Song S, Troutt M, Eisenbeis S, Williams J, Schatz DA, Haller MJ, Atkinson MA (2009) Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes 58:2277–2284PubMedCrossRefGoogle Scholar
  219. 219.
    Suarez-Pinzon WL, Power RF, Yan Y, Wasserfall C, Atkinson M, Rabinovitch A (2008) Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes 57:3281–3288PubMedCrossRefGoogle Scholar
  220. 220.
    Valle A, Jofra T, Stabilini A, Atkinson M, Roncarolo MG, Battaglia M (2009) Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice. Diabetes 58:875–881PubMedCrossRefGoogle Scholar
  221. 221.
    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):14622–14626PubMedCrossRefGoogle Scholar
  222. 222.
    Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA (2009) Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58:652–662PubMedCrossRefGoogle Scholar
  223. 223.
    Takaki T, Marron MP, Mathews CE, Guttman ST, Bottino R, Trucco M, DiLorenzo TP, Serreze DV (2006) HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176:3257–3265PubMedGoogle Scholar
  224. 224.
    Mallone R, Martinuzzi E, Blancou P, Novelli G, Afonso G, Dolz M, Bruno G, Chaillous L, Chatenoud L, Bach JM, van Endert P (2007) CD8+ T-cell responses identify beta-cell autoimmunity in human type 1 diabetes. Diabetes 56:613–621PubMedCrossRefGoogle Scholar
  225. 225.
    Kudva YC, Rajagopalan G, Raju R, Abraham RS, Smart M, Hanson J, David CS (2002) Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. Hum Immunol 63:987–999PubMedCrossRefGoogle Scholar
  226. 226.
    Elliott JF, Liu J, Yuan Z-N, Bautista-Lopez N, Wallbank SL, Suzuki K, Rayner D, Nation P, Robertson MA, Liu G, Kavanagh KM (2003) Autoimmune cardiomyopathy and heart block development develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice. Proc Natl Acad Sci USA 100:13447–13452PubMedCrossRefGoogle Scholar
  227. 227.
    Hanna J, Markoulaki S, Mitalipova M, Cheng AW, Cassady JP, Staerk J, Carey BW, Lengner CJ, Foreman R, Love J, Gao Q, Kim J, Jaenisch R (2009) Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell 4:513–524PubMedCrossRefGoogle Scholar
  228. 228.
    Nichols J, Jones K, Phillips JM, Newland SA, Roode M, Mansfield W, Smith A, Cooke A (2009) Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat Med 15:814–818PubMedCrossRefGoogle Scholar
  229. 229.
    Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130PubMedCrossRefGoogle Scholar
  230. 230.
    Mosier DE, Gulizia RJ, Baird SM, Wilson DB (1988) Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335:256–259PubMedCrossRefGoogle Scholar
  231. 231.
    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 241:1632–1639PubMedCrossRefGoogle Scholar
  232. 232.
    Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE (1992) Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255:1137–1141PubMedCrossRefGoogle Scholar
  233. 233.
    Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL et al (1995) Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154:180–191PubMedGoogle Scholar
  234. 234.
    Hesselton RM, Greiner DL, Mordes JP, Rajan TV, Sullivan JL, Shultz LD (1995) High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-scid/scid mice. J Infect Dis 172:974–982PubMedCrossRefGoogle Scholar
  235. 235.
    Lowry PA, Shultz LD, Greiner DL, Hesselton RM, Kittler EL, Tiarks CY, Rao SS, Reilly J, Leif JH, Ramshaw H, Stewart FM, Quesenberry PJ (1996) Improved engraftment of human cord blood stem cells in NOD/LtSz-scid/scid mice after irradiation or multiple-day injections into unirradiated recipients. Biol Blood Marrow Transplant 2:15–23PubMedGoogle Scholar
  236. 236.
    Pflumio F, Izac B, Katz A, Shultz LD, Vainchenker W, Coulombel L (1996) Phenotype and function of human hematopoietic cells engrafting immune-deficient CB17-severe combined immunodeficiency mice and nonobese diabetic-severe combined immunodeficiency mice after transplantation of human cord blood mononuclear cells. Blood 88:3731–3740PubMedGoogle Scholar
  237. 237.
    Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R (2005) Human lymphoid and myeloid development in NOD/LtSz-scid IL2rγ null engrafted with mobilized human hematopoietic stem cells. J Immunol 174:6477–6489PubMedGoogle Scholar
  238. 238.
    Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice. Blood 106:1565–1573PubMedCrossRefGoogle Scholar
  239. 239.
    Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JRS, Hearne CM, Knight AM, Love JM, McAleer MA, Prins JB, Rodriques N, Lathrop M, Pressey A, DeLarato NH, Peterson LB, Wicker LS (1991) Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351:542–547PubMedCrossRefGoogle Scholar
  240. 240.
    Pearce RB (1998) Fine-mapping of the mouse T lymphocyte fraction (Tlf) locus on Chromosome 9: association with autoimmune diabetes. J Autoimm 10:1–15Google Scholar
  241. 241.
    Ivakine EA, Mortin-Toth SM, Gulban OM, Valova A, Canty A, Scott C, Danska JS (2006) The idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes 55:3611–3619PubMedCrossRefGoogle Scholar
  242. 242.
    Wicker LS, Chamberlain G, Hunter K, Rainbow D, Howlett S, Tiffen P, Clark J, Gonzalez-Munoz A, Cumiskey AM, Rosa RL, Howson JM, Smink LJ, Kingsnorth A, Lyons PA, Gregory S, Rogers J, Todd JA, Peterson LB (2004) Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol 173:164–173PubMedGoogle Scholar
  243. 243.
    Hunter K, Rainbow D, Plagnol V, Todd JA, Peterson LB, Wicker LS (2007) Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes. J Immunol 179:8341–8349PubMedGoogle Scholar
  244. 244.
    Hung MS, Avner P, Rogner UC (2006) Identification of the transcription factor ARNTL2 as a candidate gene for the type 1 diabetes locus Idd6. Hum Mol Genet 15:2732–2742PubMedCrossRefGoogle Scholar
  245. 245.
    Bergman ML, Duarte N, Campino S, Lundholm M, Motta V, Lejon K, Penha-Goncalves C, Holmberg D (2003) Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains. Diabetes 52:1677–1682PubMedCrossRefGoogle Scholar
  246. 246.
    Ghosh S, Palmer SM, Rodrigues NR, Cordell HJ, Hearne CM, Cornall RJ, Prins JB, McShane P, Lathrop GM, Peterson LB, Wicker LS, Todd JA (1993) Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet 4:404–409PubMedCrossRefGoogle Scholar
  247. 247.
    McAleer MA, Reifsnyder PC, Palmer SM, Prochazka M, Love JM, Copeman JB, Powell EE, Rodrigues NR, Prins J-B, Serreze DV, DeLarto NH, Wicker LS, Peterson LB, Schork NJ, Todd JA, Leiter EH (1995) Crosses of NOD mice with the related NON strain: a polygenic threshold model for type I diabetes. Diabetes 44:1186–1195PubMedCrossRefGoogle Scholar
  248. 248.
    Siegmund T, Armitage N, Wicker LS, Peterson LB, Todd JA, Lyons PA (2000) Analysis of the mouse CD30 gene: a candidate for the NOD mouse type 1 diabetes locus Idd9.2. Diabetes 49:1612–1616PubMedCrossRefGoogle Scholar
  249. 249.
    Cannons JL, Chamberlain G, Howson J, Smink LJ, Todd JA, Peterson LB, Wicker LS, Watts TH (2005) Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. J Autoimmun 25:13–20PubMedCrossRefGoogle Scholar
  250. 250.
    Penha-Goncalves C, Moule C, Smink LJ, Howson J, Gregory S, Rogers J, Lyons PA, Suttie JJ, Lord CJ, Peterson LB, Todd JA, Wicker LS (2003) Identification of a structurally distinct CD101 molecule encoded in the 950-kb Idd10 region of NOD mice. Diabetes 52:1551–1556PubMedCrossRefGoogle Scholar
  251. 251.
    Brodnicki TC, McClive P, Couper S, Morahan G (2000) Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as a candidate gene. Immunogenetics 51:37–41PubMedCrossRefGoogle Scholar
  252. 252.
    Morahan G, McClive P, Huang D, Little P, Baxter A (1994) Genetic and physiological association of diabetes susceptibility with raised Na+/H + exchange activity. Proc Natl Acad Sci U S A 91:5898–5902PubMedCrossRefGoogle Scholar
  253. 253.
    Brodnicki TC, Quirk F, Morahan G (2003) A susceptibility allele from a non-diabetes-prone mouse strain accelerates diabetes in NOD congenic mice. Diabetes 52:218–222PubMedCrossRefGoogle Scholar
  254. 254.
    Deruytter N, Boulard O, Garchon HJ (2004) Mapping non-class II H2-linked loci for type 1 diabetes in nonobese diabetic mice. Diabetes 53:3323–3327PubMedCrossRefGoogle Scholar
  255. 255.
    Podolin PL, Denny P, Lord CJ, Hill NJ, Todd JA, Peterson LB, Wicker LS, Lyons PA (1997) Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1. J Immunol 159:1835–1843PubMedGoogle Scholar
  256. 256.
    Lyons PA, Armitage N, Lord CJ, Phillips MS, Todd JA, Peterson LB, Wicker LS (2001) Mapping by genetic interaction: high-resolution congenic mapping of the type 1 diabetes loci Idd10 and Idd18 in the NOD mouse. Diabetes 50:2633–2637PubMedCrossRefGoogle Scholar
  257. 257.
    Morin J, Boitard C, Vallois D, Avner P, Rogner UC (2006) Mapping of the murine type 1 diabetes locus Idd20 by genetic interaction. Mamm Genome 17:1105–1112PubMedCrossRefGoogle Scholar
  258. 258.
    Rogner UC, Boitard C, Morin J, Melanitou E, Avner P (2001) Three loci on mouse chromosome 6 influence onset and final incidence of type I diabetes in NOD.C3H congenic strains. Genomics 74:163–171PubMedCrossRefGoogle Scholar
  259. 259.
    Hollis-Moffatt JE, Hook SM, Merriman TR (2005) Colocalization of mouse autoimmune diabetes loci Idd21.1 and Idd21.2 with IDDM6 (human) and Iddm3 (rat). Diabetes 54:2820–2825PubMedCrossRefGoogle Scholar
  260. 260.
    Mathews CE, Graser RT, Bagley RJ, Caldwell JW, Li R, Churchill GA, Serreze DV, Leiter EH (2003) Genetic analysis of resistance to type-1 diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics 55:491–496PubMedCrossRefGoogle Scholar
  261. 261.
    Chen J, Reifsnyder PC, Scheuplein F, Schott WH, Mileikovsky M, Soodeen-Karamath S, Nagy A, Dosch MH, Ellis J, Koch-Nolte F, Leiter EH (2005) “Agouti NOD”: identification of a CBA-derived Idd locus on chromosome 7 and its use for chimera production with NOD embryonic stem cells. Mamm Genome 16:775–783PubMedCrossRefGoogle Scholar
  262. 262.
    Leiter EH, Reifsnyder PC, Wallace R, Li R, King B, Churchill GC (2009) NOD × 129.H2(g7) backcross delineates 129S1/SvImJ-derived genomic regions modulating type 1 diabetes development in mice. Diabetes 58:1700–1703PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • John P. Driver
    • 1
  • David V. Serreze
    • 1
  • Yi-Guang Chen
    • 1
  1. 1.The Jackson LaboratoryBar HarborUSA

Personalised recommendations