Animal Models of Type 1 Diabetes Mellitus

  • Lucienne Chatenoud
Part of the Contemporary Endocrinology book series (COE)


Type 1 diabetes (T1D) or insulin-dependent diabetes is an autoimmune disease caused by the selective destruction of insulin secreting β cells in the pancreas by autoreactive CD4+ and CD8+ T lymphocytes. Animal models of the spontaneous disease as well as genetically modified models have contributed significantly to our understanding of both the pathogenesis and the pathophysiology of the disease. In particular, animal models have allowed a better approach to the complex problem of genetic and environmental factors that are important not only for disease predisposition but also for disease protection. The molecular characterization of triggering autoantigens has also been facilitated by the study of animal models. Although various molecules expressed by β cells are well-recognized targets of the autoimmune response, the use of particular genetically modified mouse models has recently pointed to proinsulin/insulin as the primary autoantigen. Last but not least, when used adequately, animal models of T1D have also been helpful in preclinical studies to search for new immunointervention strategies applicable to the clinic. The overall conclusion of >30 years of studies conducted using animal models of T1D is that they recapitulate quite satisfactorily the human situation. In analyzing the data, it is, however, essential to consider that each of the mouse or rat strains used is genetically identical. In fact, they represent multiple copies of a single individual which is of course not the case for the clinical situation.


Type 1 diabetes mellitus animal models insulitis NOD mouse BB rat transgenic mice. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bottazzo, G.F., A. Florin-christensen, and D. Doniach. 1974. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2: 1279–1283.PubMedGoogle Scholar
  2. 2.
    Nakhooda, A.F., A.A. Like, C.I. Chappel, F.T. Murray, and E.B. Marliss. 1977. The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26: 100–112.PubMedGoogle Scholar
  3. 3.
    Crisa, L., J.P. Mordes, and A.A. Rossini. 1992. Autoimmune diabetes mellitus in the BB rat. Diabetes Metab. Rev. 8: 4–37.PubMedGoogle Scholar
  4. 4.
    Ellerman, K.E., C.A. Richards, D.L. Guberski, W.R. Shek., and A.A. Like. 1996. Kilham rat virus triggers T-cell-dependent autoimmune diabetes in multiple strains of rat. Diabetes 45: 557–562.PubMedGoogle Scholar
  5. 5.
    Markholst, H., S. Eastman, D. Wilson, B.E. Andreasen, and A. Lernmark. 1991. Diabetes segregates as a single locus in crosses between inbred BB rats prone or resistant to diabetes. J. Exp. Med. 174: 297–300.PubMedGoogle Scholar
  6. 6.
    Jackson, R., N. Rassi, T. Crump, B. Haynes, and G.S. Eisenbarth. 1981. The BB diabetic rat. Profound T-cell lymphocytopenia. Diabetes 30: 887–889.PubMedGoogle Scholar
  7. 7.
    Greiner, D.L., E.S. Handler, K. Nakano, J.P. Mordes, and A.A. Rossini. 1986. Absence of the RT-6 T cell subset in diabetes-prone BB/W rats. J. Immunol. 136: 148–151.PubMedGoogle Scholar
  8. 8.
    Greiner, D.L., J.P. Mordes, E.S. Handler, M. Angelillo, N. Nakamura, and A.A. Rossini. 1987. Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. J. Exp. Med. 166: 461–475.PubMedGoogle Scholar
  9. 9.
    Rossini, A.A., J.P. Mordes, D.L. Greiner, K. Nakano, M.C. Appel, and E.S. Handler. 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.PubMedGoogle Scholar
  10. 10.
    Iwakoshi, N.N., I. Goldschneider, F. Tausche, J.P. Mordes, A.A. Rossini, and D.L. Greiner. 1998. High frequency apoptosis of recent thymic emigrants in the liver of lymphopenic diabetes-prone BioBreeding rats. J. Immunol. 160: 5838–5850.PubMedGoogle Scholar
  11. 11.
    Poussier, P., T. Ning, T. Murphy, D. Dabrowski, and S. Ramanathan. 2005. Impaired post-thymic development of regulatory CD4+25+ T cells contributes to diabetes pathogenesis in BB rats. J. Immunol. 174: 4081–4089.PubMedGoogle Scholar
  12. 12.
    Fowell, D., and D. Mason. 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.PubMedGoogle Scholar
  13. 13.
    Colle, E., S.J. Ono, A. Fuks, R.D. Guttmann, and T.A. Seemayer. 1988. Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex. Diabetes 37: 1438–1443.PubMedGoogle Scholar
  14. 14.
    Jacob, H.J., A. Pettersson, D. Wilson, Y. Mao, A. Lernmark, and E.S. Lander. 1992. Genetic dissection of autoimmune type I diabetes in the BB rat. Nat. Genet. 2: 56–60.PubMedGoogle Scholar
  15. 15.
    Ellerman, K.E., and A.A. Like. 2000. Susceptibility to diabetes is widely distributed in normal classIIu haplotype rats. Diabetologia 43: 890–898.PubMedGoogle Scholar
  16. 16.
    Chao, N.J., L. Timmerman, H.O. McDevitt, and C.O. Jacob. 1989. Molecular characterization of MHC class II antigens (beta 1 domain) in the BB diabetes-prone and -resistant rat. Immunogenetics 29: 231–234.PubMedGoogle Scholar
  17. 17.
    Hornum, L., J. Romer, and H. Markholst. 2002. The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 51: 1972–1979.PubMedGoogle Scholar
  18. 18.
    MacMurray, A.J., D.H. Moralejo, A.E. Kwitek, E.A. Rutledge, B. Van Yserloo, P. Gohlke, S.J. Speros, B. Snyder, J. Schaefer, S. Bieg, J. Jiang, R.A. Ettinger, J. Fuller, T.L. Daniels, A. Pettersson, K. Orlebeke, B. Birren, H.J. Jacob, E.S. Lander, and A. Lernmark. 2002. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res. 12: 1029–1039.PubMedGoogle Scholar
  19. 19.
    Martin, A.M., M.N. Maxson, J. Leif, J.P. Mordes, D.L. Greiner, and E.P. Blankenhorn. 1999. Diabetes-prone and diabetes-resistant BB rats share a common major diabetes susceptibility locus, iddm4: additional evidence for a “universal autoimmunity locus” on rat chromosome 4. Diabetes 48: 2138–2144.PubMedGoogle Scholar
  20. 20.
    Mathews, C.E. 2005. Utility of murine models for the study of spontaneous autoimmune type 1 diabetes. Pediatr. Diabetes 6: 165–177.PubMedGoogle Scholar
  21. 21.
    Kawano, K., T. Hirashima, S. Mori, Y. Saitoh, M. Kurosumi, and T. Natori. 1992. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41: 1422–1428.PubMedGoogle Scholar
  22. 22.
    Kawano, K., T. Hirashima, S. Mori, Y. Saitoh, M. Kurosumi, and T. Natori. 1991. New inbred strain of Long-Evans Tokushima lean rats with IDDM without lymphopenia. Diabetes 40: 1375–1381.PubMedGoogle Scholar
  23. 23.
    Lenzen, S., M. Tiedge, M. Elsner, S. Lortz, H. Weiss, A. Jorns, G. Kloppel, D. Wedekind, C.M. Prokop, and H.J. Hedrich. 2001. The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 44: 1189–1196.PubMedGoogle Scholar
  24. 24.
    Makino, S., K. Kunimoto, Y. Muraoka, Y. Mizushima, K. Katagiri, and Y. Tochino. 1980. Breeding of a non-obese, diabetic strain of mice. Exp. Anim. 29: 1–13.Google Scholar
  25. 25.
    Ohsugi, T., and T. Kurosawa. 1994. Increased incidence of diabetes mellitus in specific pathogen-eliminated offspring produced by embryo transfer in NOD mice with low incidence of the disease. Lab. Anim. Sci. 44: 386–388.PubMedGoogle Scholar
  26. 26.
    Bach, J.F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347: 911–920.PubMedGoogle Scholar
  27. 27.
    Garchon, H.J., P. Bedossa, L. Eloy, and J.F. Bach. 1991. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature 353: 260–262.PubMedGoogle Scholar
  28. 28.
    Many, M.C., S. Maniratunga, and J.F. Denef. 1996. The non-obese diabetic (NOD) mouse: An animal model for autoimmune thyroiditis. Exp. Clin. Endocrinol. Diabetes 104: 17–20.PubMedGoogle Scholar
  29. 29.
    Many, M.C., S. Maniratunga, I. Varis, M. Dardenne, H.A. Drexhage, and J.F. Denef. 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.PubMedGoogle Scholar
  30. 30.
    Baxter, A.G., and T.E. Mandel. 1991. Hemolytic anemia in non-obese diabetic mice. Eur. J. Immunol. 21: 2051–2055.PubMedGoogle Scholar
  31. 31.
    Humphreys Beher, M.G., L. Brinkley, K.R. Purushotham, P.L. Wang, Y. Nakagawa, D. Dusek, M. Kerr, N. Chegini, and E.K. Chan. 1993. Characterization of antinuclear autoantibodies present in the serum from nonobese diabetic (NOD) mice. Clin. Immunol. Immunopathol. 68: 350–356.PubMedGoogle Scholar
  32. 32.
    Baxter, A.G., A.C. Horsfall, D. Healey, P. Ozegbe, S. Day, D.G. Williams, and A. Cooke. 1994. Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice. Immunology 83: 227–231.PubMedGoogle Scholar
  33. 33.
    Fujino-kurihara, H., H. Fujita, A. Hakura, K. Nonaka, and S. Tarui. 1985. Morphological aspects on pancreatic islets of non-obese diabetic (NOD) mice. Virchows Arch. B. Cell. Pathol. Incl. Mol. Pathol. 49: 107–120.PubMedGoogle Scholar
  34. 34.
    Katz, J.D., B. Wang, K. Haskins, C. Benoist, and D. Mathis. 1993. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74: 1089–1100.PubMedGoogle Scholar
  35. 35.
    Bendelac, A., C. Carnaud, C. Boitard, and J.F. Bach. 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.PubMedGoogle Scholar
  36. 36.
    Rohane, P.W., A. Shimada, D.T. Kim, C.T. Edwards, B. Charlton, L.D. Shultz, and C.G. Fathman. 1995. Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice. Diabetes 44: 550–554.PubMedGoogle Scholar
  37. 37.
    Christianson, S.W., L.D. Shultz, and E.H. Leiter. 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.PubMedGoogle Scholar
  38. 38.
    Wicker, L.S., B.J. Miller, and Y. Mullen. 1986. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes 35: 855–860.PubMedGoogle Scholar
  39. 39.
    Daniel, D., R.G. Gill, N. Schloot, and D. Wegmann. 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.PubMedGoogle Scholar
  40. 40.
    Wegmann, D.R. 1996. The immune response to islets in experimental diabetes and insulin-dependent diabetes mellitus. Curr. Opin. Immunol. 8: 860–864.PubMedGoogle Scholar
  41. 41.
    Wegmann, D.R., M. Norbury-glaser, and D. Daniel. 1994. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur. J. Immunol. 24: 1853–1857.PubMedGoogle Scholar
  42. 42.
    French, M.B., J. Allison, D.S. Cram, H.E. Thomas, M. Dempsey Collier, A. Silva, H.M. Georgiou, T.W. Kay, L.C. Harrison, and A.M. Lew. 1997. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 46: 34–39.PubMedGoogle Scholar
  43. 43.
    Harrison, L.C., M.C. Honeyman, S. Trembleau, S. Gregori, F. Gallazzi, P. Augstein, V. Brusic, J. Hammer, and L. Adorini. 1997. A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice. J. Exp. Med. 185: 1013–1021.PubMedGoogle Scholar
  44. 44.
    Baekkeskov, S., H.J. Aanstoot, S. Christgau, A. Reetz, M. Solimena, M. Cascalho, F. Folli, H. Richter-olesen, and P. De Camilli. 1990. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347: 151–156.PubMedGoogle Scholar
  45. 45.
    Honeyman, M.C., D.S. Cram, and L.C. Harrison. 1993. Glutamic acid decarboxylase 67-reactive T cells: a marker of insulin-dependent diabetes. J. Exp. Med. 177: 535–540.PubMedGoogle Scholar
  46. 46.
    Panina-bordignon, P., R. Lang, P.M. Van Endert, E. Benazzi, A.M. Felix, R.M. Pastore, G.A. Spinas, and F. Sinigaglia. 1995. Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes. J. Exp. Med. 181: 1923–1927.PubMedGoogle Scholar
  47. 47.
    Tisch, R., X.D. Yang, R.S. Liblau, and H.O. Mcdevitt. 1994. Administering glutamic acid decarboxylase to NOD mice prevents diabetes. J. Autoimmun. 7: 845–850.PubMedGoogle Scholar
  48. 48.
    Trembleau, S., G. Penna, S. Gregori, M.K. Gately, and L. Adorini. 1997. Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes. Eur. J. Immunol. 27: 2330–2339.PubMedGoogle Scholar
  49. 49.
    Hawkes, C.J., C. Wasmeier, M.R. Christie, and J.C. Hutton. 1996. Identification of the 37-kDa antigen in IDDM as a tyrosine phosphatase-like protein (phogrin) related to IA-2. Diabetes 45: 1187–1192.PubMedGoogle Scholar
  50. 50.
    Dotta, F., S. Dionisi, V. Viglietta, C. Tiberti, M.C. Matteoli, M. Cervoni, C. Bizzarri, G. Marietti, M. Testi, G. Multari, L. Lucentini, and U. Di Mario. 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.PubMedGoogle Scholar
  51. 51.
    Lampasona, V., M. Bearzatto, S. Genovese, E. Bosi, M. Ferrari, and E. Bonifacio. 1996. Autoantibodies in insulin-dependent diabetes recognize distinct cytoplasmic domains of the protein tyrosine phosphatase-like IA-2 autoantigen. J. Immunol. 157: 2707–2711.PubMedGoogle Scholar
  52. 52.
    Elias, D., T. Reshef, O.S. Birk, R. Van Der Zee, M.D. Walker, and I.R. Cohen. 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.PubMedGoogle Scholar
  53. 53.
    Elias, D., and I.R. Cohen. 1994. Peptide therapy for diabetes in NOD mice. Lancet 343: 704–706.PubMedGoogle Scholar
  54. 54.
    Elias, D., A. Meilin, V. Ablamunits, O.S. Birk, P. Carmi, S. Konenwaisman, and I.R. Cohen. 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.PubMedGoogle Scholar
  55. 55.
    Lieberman, S.M., A.M. Evans, B. Han, T. Takaki, Y. Vinnitskaya, J.A. Caldwell, D.V. Serreze, J. Shabanowitz, D.F. Hunt, S.G. Nathenson, P. Santamaria, and T.P. DiLorenzo. 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.PubMedGoogle Scholar
  56. 56.
    Utsugi, T., J.W. Yoon, B.J. Park, M. Imamura, N. Averill, S. Kawazu, and P. Santamaria. 1996. Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8(+) T-cell clones in vivo. Diabetes 45: 1121–1131.PubMedGoogle Scholar
  57. 57.
    Serreze, D.V., H.D. Chapman, D.S. Varnum, M.S. Hanson, P.C. Reifsnyder, S.D. Richard, S.A. Fleming, E.H. Leiter, and L.D. Shultz. 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.PubMedGoogle Scholar
  58. 58.
    Akashi, T., S. Nagafuchi, K. Anzai, S. Kondo, D. Kitamura, S. Wakana, J. Ono, M. Kikuchi, Y. Niho, and T. Watanabe. 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: 1159–1164.PubMedGoogle Scholar
  59. 59.
    Noorchashm, H., N. Noorchashm, J. Kern, S.Y. Rostami, C.F. Barker, and A. Naji. 1997. B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice. Diabetes 46: 941–946.PubMedGoogle Scholar
  60. 60.
    Dardenne, M., F. Lepault, A. Bendelac, and J.F. Bach. 1989. Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning. Eur. J. Immunol. 19: 889–895.PubMedGoogle Scholar
  61. 61.
    Yasunami, R., and J.F. Bach. 1988. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur. J. Immunol. 18: 481–484.PubMedGoogle Scholar
  62. 62.
    Yasunami, R., M. Debray-sachs, and J.F. Bach. 1990. Ontogeny of regulatory and effector T cells in autoimmune NOD mice. In Frontiers in Diabetes Research. Lessons from animal diabetes III. E. Shafrir, editor. Smith-Gordon, London. 88–93.Google Scholar
  63. 63.
    Charlton, B., A. Bacelj, R.M. Slattery, and T.E. Mandel. 1989. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 38: 441–447.PubMedGoogle Scholar
  64. 64.
    Mahiou, J., U. Walter, F. Lepault, F. Godeau, J.F. Bach, and L. Chatenoud. 2001. In vivo blockade of the fas-fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice. J. Autoimmun. 16: 431–440.PubMedGoogle Scholar
  65. 65.
    Askenase, P.W., B.J. Hayden, and R.K. Gershon. 1975. Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which do not affect antibody responses. J. Exp. Med. 141: 697–702.PubMedGoogle Scholar
  66. 66.
    Minagawa, H., A. Takenaka, Y. Itoyama, and R. Mori. 1987. Experimental allergic encephalomyelitis in the Lewis rat. A model of predictable relapse by cyclophosphamide. J. Neurol. Sci. 78: 225–235.PubMedGoogle Scholar
  67. 67.
    Miyazaki, C., T. Nakamura, K. Kaneko, R. Mori, and H. Shibasaki. 1985. Reinduction of experimental allergic encephalomyelitis in convalescent Lewis rats with cyclophosphamide. J. Neurol. Sci. 67: 277–284.PubMedGoogle Scholar
  68. 68.
    Boitard, C., R. Yasunami, M. Dardenne, and J.F. Bach. 1989. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J. Exp. Med. 169: 1669–1680.PubMedGoogle Scholar
  69. 69.
    Herbelin, A., J.M. Gombert, F. Lepault, J.F. Bach, and L. Chatenoud. 1998. Mature mainstream TCR alpha beta(+)CD4(+) thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J. Immunol. 161: 2620–2628.PubMedGoogle Scholar
  70. 70.
    Nishizuka, Y., and T. Sakakura. 1969. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166: 753–755.PubMedGoogle Scholar
  71. 71.
    Asano, M., M. Toda, N. Sakaguchi, and S. Sakaguchi. 1996. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184: 387–396.PubMedGoogle Scholar
  72. 72.
    Lepault, F., M.C. Gagnerault, C. Faveeuw, H. Bazin, and C. Boitard. 1995. Lack of L-selectin expression by cells transferring diabetes in NOD mice: insights into the mechanisms involved in diabetes prevention by Mel-14 antibody treatment. Eur. J. Immunol. 25: 1502–1507.PubMedGoogle Scholar
  73. 73.
    You, S., M. Belghith, P. Cobbold, M.A. Alyanakian, C. Gouarin, S. Barriot, C. Garcia, H. Waldmann, L. Chatenoud, and J.F. Bach. 2005. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T cells. Diabetes 54: 1415–1422.PubMedGoogle Scholar
  74. 74.
    Lepault, F., and M.C. Gagnerault. 2000. Characterization of peripheral regulatory CD4(+) T cells that prevent diabetes onset in nonobese diabetic mice. J. Immunol. 164: 240–247.PubMedGoogle Scholar
  75. 75.
    Sreenan, S., A.J. Pick, M. Levisetti, A.C. Baldwin, W. Pugh, and K.S. Polonsky. 1999. Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. Diabetes 48: 989–996.PubMedGoogle Scholar
  76. 76.
    Strandell, E., D.L. Eizirik, and S. Sandler. 1990. Reversal of beta-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J. Clin. Invest. 85: 1944–1950.PubMedGoogle Scholar
  77. 77.
    Maki, T., T. Ichikawa, R. Blanco, and J. Porter. 1992. Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum. Proc. Natl. Acad. Sci. U. S. A. 89: 3434–3438.PubMedGoogle Scholar
  78. 78.
    Sempe, P., P. Bedossa, M.F. Richard, M.C. Villa, J.F. Bach, and C. Boitard. 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.PubMedGoogle Scholar
  79. 79.
    Chatenoud, L., E. Thervet, J. Primo, and J.F. Bach. 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.PubMedGoogle Scholar
  80. 80.
    Wicker, L.S., J.A. Todd, and L.B. Peterson. 1995. Genetic control of autoimmune diabetes in the NOD mouse. Annu. Rev. Immunol. 13: 179–200.PubMedGoogle Scholar
  81. 81.
    Wicker, L.S., J. Clark, H.I. Fraser, V.E. Garner, A. Gonzalez-Munoz, B. Healy, S. Howlett, K. Hunter, D. Rainbow, R.L. Rosa, L.J. Smink, J.A. Todd, and L.B. Peterson. 2005. Type 1 diabetes genes and pathways shared by humans and NOD mice. J. Autoimmun. 25 (Suppl):29–33.PubMedGoogle Scholar
  82. 82.
    Acha-orbea, H., and H.O. Mcdevitt. 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.PubMedGoogle Scholar
  83. 83.
    Todd, J.A., J.I. Bell, and H.O. Mcdevitt. 1987. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604.PubMedGoogle Scholar
  84. 84.
    Corper, A.L., T. Stratmann, V. Apostolopoulos, C.A. Scott, K.C. Garcia, A.S. Kang, I.A. Wilson, and L. Teyton. 2000. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288: 505–511.PubMedGoogle Scholar
  85. 85.
    Stratmann, T., V. Apostolopoulos, V. Mallet-Designe, A.L. Corper, C.A. Scott, I.A. Wilson, A.S. Kang, and L. Teyton. 2000. The I-Ag7 MHC class II molecule linked to murine diabetes is a promiscuous peptide binder. J. Immunol. 165: 3214–3225.PubMedGoogle Scholar
  86. 86.
    Carrasco-Marin, E., J. Shimizu, O. Kanagawa, and E.R. Unanue. 1996. The class II MHC I-Ag7 molecules from non-obese diabetic mice are poor peptide binders. J. Immunol. 156: 450–458.PubMedGoogle Scholar
  87. 87.
    Denny, P., C.J. Lord, N.J. Hill, J.V. Goy, E.R. Levy, P.L. Podolin, L.B. Peterson, L.S. Wicker, J.A. Todd, and P.A. Lyons. 1997. Mapping of the IDDM locus Idd3 to . 0.35-cM interval containing the interleukin-2 gene. Diabetes 46: 695–700.PubMedGoogle Scholar
  88. 88.
    Concannon, P., H.A. Erlich, C. Julier, G. Morahan, J. Nerup, F. Pociot, J.A. Todd, and S.S. Rich. 2005. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes 54: 2995–3001.PubMedGoogle Scholar
  89. 89.
    Ueda, H., J.M. Howson, L. Esposito, J. Heward, H. Snook, G. Chamberlain, D.B. Rainbow, K.M. Hunter, A.N. Smith, G. Di Genova, M.H. Herr, I. Dahlman, F. Payne, D. Smyth, C. Lowe, R.C. Twells, S. Howlett, B. Healy, S. Nutland, H.E. Rance, V. Everett, L.J. Smink, A.C. Lam, H.J. Cordell, N.M. Walker, C. Bordin, J. Hulme, C. Motzo, F. Cucca, J.F. Hess, M.L. Metzker, J. Rogers, S. Gregory, A. Allahabadia, R. Nithiyananthan, E. Tuomilehto-Wolf, J. Tuomilehto, P. Bingley, K.M. Gillespie, D.E. Undlien, K.S. Ronningen, C. Guja, C. Ionescu-Tirgoviste, D.A. Savage, A.P. Maxwell, D.J. Carson, C.C. Patterson, J.A. Franklyn, D.G. Clayton, L.B. Peterson, L.S. Wicker, J.A. Todd, and S.C. Gough. 2003. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423: 506–511.PubMedGoogle Scholar
  90. 90.
    Bain, S.C., J.B. Prins, C.M. Hearne, N.R. Rodrigues, B.R. Rowe, L.E. Pritchard, R.J. Ritchie, J.R. Hall, D.E. Undlien, K.S. Ronningen, D.B. Dunger, A.H. Barnett, and J.A. Todd. 1992. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nat. Genet. 2: 212–215.PubMedGoogle Scholar
  91. 91.
    Bennett, S.T., A.J. Wilson, F. Cucca, J. Nerup, F. Pociot, P.A. Mckinney, A.H. Barnett, S.C. Bain, and J.A. Todd. 1996. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J. Autoimmun. 9: 415–421.PubMedGoogle Scholar
  92. 92.
    Krishnamurthy, B., N.L. Dudek, M.D. McKenzie, A.W. Purcell, A.G. Brooks, S. Gellert, P.G. Colman, L.C. Harrison, A.M. Lew, H.E. Thomas, and T.W.H. Kay. 2006. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J. Clin. Inves.. 116: 3258–3265.Google Scholar
  93. 93.
    Nakayama, M., N. Abiru, H. Moriyama, N. Babaya, E. Liu, D. Miao, L. Yu, D. Wegmann, J.C. Hutton, J.F. Elliott, and G. Eisenbarth. 2005. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435: 220–223.PubMedGoogle Scholar
  94. 94.
    Luan, J.J., R.C. Monteiro, C. Sautes, G. Fluteau, L. Eloy, W.H. Fridman, J.F. Bach, and H.J. Garchon. 1996. Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum. J. Immunol. 157: 4707–4716.PubMedGoogle Scholar
  95. 95.
    Adams, T.E., S. Alpert, and D. Hanahan. 1987. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature 325: 223–228.PubMedGoogle Scholar
  96. 96.
    Oldstone, M.B., M. Nerenberg, P. Southern, J. Price, and H. Lewicki. 1991. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65: 319–331.PubMedGoogle Scholar
  97. 97.
    Von Herrath, M.G., J. Dockter, and M.B. Oldstone. 1994. How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1: 231–242.Google Scholar
  98. 98.
    Ohashi, P.S., S. Oehen, K. Buerki, H. Pircher, C.T. Ohashi, B. Odermatt, B. Malissen, R.M. Zinkernagel, and H. Hengartner. 1991. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65: 305–317.PubMedGoogle Scholar
  99. 99.
    Roman, L.M., L.F. Simons, R.E. Hammer, J.F. Sambrook, and M.J. Gething. 1990. The expression of influenza virus hemagglutinin in the pancreatic beta cells of transgenic mice results in autoimmune diabetes. Cell 61: 383–396.PubMedGoogle Scholar
  100. 100.
    Sarukhan, A., A. Lanoue, A. Franzke, N. Brousse, J. Buer, and H. Von Boehmer. 1998. Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model. EMBO J. 17: 71–80.PubMedGoogle Scholar
  101. 101.
    Von Herrath, M.G., S. Guerder, H. Lewicki, R.A. Flavell, and M.B. Oldstone. 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.Google Scholar
  102. 102.
    Lang, K.S., M. Recher, T. Junt, A.A. Navarini, N.L. Harris, S. Freigang, B. Odermatt, C. Conrad, L.M. Ittner, S. Bauer, S.A. Luther, S. Uematsu, S. Akira, H. Hengartner, and R.M. Zinkernagel. 2005. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 11: 138–145.PubMedGoogle Scholar
  103. 103.
    Lehmann, P.V., T. Forsthuber, A. Miller, and E.E. Sercarz. 1992. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358: 155–157.PubMedGoogle Scholar
  104. 104.
    Miller, S.D., C.L. Vanderlugt, W.S. Begolka, W. Pao, R.L. Yauch, K.L. Neville, Y. Katz-Levy, A. Carrizosa, and B.S. Kim. 1997. Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat. Med. 3: 1133–1136.PubMedGoogle Scholar
  105. 105.
    Tisch, R., X.D. Yang, S.M. Singer, R.S. Liblau, L. Fugger, and H.O. Mcdevitt. 1993. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366: 72–75.PubMedGoogle Scholar
  106. 106.
    Kaufman, D.L., M. Clare-salzler, J. Tian, T. Forsthuber, G.S.P. Ting, P. Robinson, M.A. Atkinson, E.E. Sercarz, A.J. Tobin, and P.V. Lehmann. 1993. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366: 69–72.PubMedGoogle Scholar
  107. 107.
    Neighbors, M., S.B. Hartley, X. Xu, A.G. Castro, D.M. Bouley, and A. O’Garra. 2006. Breakpoints in immunoregulation required for Th1 cells to induce diabetes. Eur. J. Immunol. 36: 2315–2323.PubMedGoogle Scholar
  108. 108.
    Vonherrath, M.G., and M.B.A. Oldstone. 1997. Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. J. Exp. Med. 185: 531–539.Google Scholar
  109. 109.
    Bottazzo, G.F., R. Pujol-borrell, T. Hanafusa, and M. Feldmann. 1983. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 2: 1115–1119.PubMedGoogle Scholar
  110. 110.
    Hanafusa, T., R. Pujol-borrell, L. Chiovato, R.C. Russell, D. Doniach, and G.F. Bottazzo. 1983. Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: relevance for autoimmunity. Lancet 2: 1111–1115.PubMedGoogle Scholar
  111. 111.
    Allison, J., I.L. Campbell, G. Morahan, T.E. Mandel, L.C. Harrison, and J.F. Miller. 1988. Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells. Nature 333: 529–533.PubMedGoogle Scholar
  112. 112.
    Gotz, J., H. Eibel, and G. Kohler. 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.PubMedGoogle Scholar
  113. 113.
    Bohme, J., K. Haskins, P. Stecha, W. Van Ewijk, M. Lemeur, P. Gerlinger, C. Benoistt, and D. Mathis. 1989. Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. Science 244: 1179–1183.PubMedGoogle Scholar
  114. 114.
    Markmann, J., D. Lo, A. Naji, R.D. Palmiter, R.L. Brinster, and E. Heber-katz. 1988. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature 336: 476–479.PubMedGoogle Scholar
  115. 115.
    Green, E.A., and R.A. Flavell. 1999. Tumor necrosis factor-alpha and the progression of diabetes in non-obese diabetic mice. Immunol. Rev. 169: 11–22.PubMedGoogle Scholar
  116. 116.
    Guerder, S., D.E. Picarella, P.S. Linsley, and R.A. Flavell. 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.PubMedGoogle Scholar
  117. 117.
    Allison, J., L.A. Stephens, T.W. Kay, C. Kurts, W.R. Heath, J.F. Miller, and M.F. Krummel. 1998. The threshold for autoimmune T cell killing is influenced by B7-1. Eur. J. Immunol. 28: 949–960.PubMedGoogle Scholar
  118. 118.
    Sarvetnick, N., D. Liggitt, S.L. Pitts, S.E. Hansen, and T.A. Stewart. 1988. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52: 773–782.PubMedGoogle Scholar
  119. 119.
    Stewart, T.A., B. Hultgren, X. Huang, S. Pitts-meek, J. Hully, and N.J. Maclachlan. 1993. Induction of type I diabetes by interferon-alpha in transgenic mice. Science 260: 1942–1946.PubMedGoogle Scholar
  120. 120.
    Allison, J., L. Malcolm, N. Chosich, and J.F. Miller. 1992. Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of interleukin-2 in islet beta cells. Eur. J. Immunol. 22: 1115–1121.PubMedGoogle Scholar
  121. 121.
    Elliott, E.A., and R.A. Flavell. 1994. Transgenic mice expressing constitutive levels of IL-2 in islet beta cells develop diabetes. Int. Immunol. 6: 1629–1637.PubMedGoogle Scholar
  122. 122.
    Lee, M.S., R. Mueller, L.S. Wicker, L.B. Peterson, and N. Sarvetnick. 1996. IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. J. Exp. Med. 183: 2663–2668.PubMedGoogle Scholar
  123. 123.
    Higuchi, Y., P. Herrera, P. Muniesa, J. Huarte, D. Belin, P. Ohashi, P. Aichele, L. Orci, J.D. Vassalli, and P. Vassalli. 1992. Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J. Exp. Med. 176: 1719–1731.PubMedGoogle Scholar
  124. 124.
    Picarella, D.E., A. Kratz, C.B. Li, N.H. Ruddle, and R.A. Flavell. 1993. Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J. Immunol. 150: 4136–4150.PubMedGoogle Scholar
  125. 125.
    Jaeckel, E., M.A. Lipes, and H. von Boehmer. 2004. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat. Immunol. 5: 1028–1035.PubMedGoogle Scholar
  126. 126.
    Geng, L.P., M. Solimena, R.A. Flavell, R.S. Sherwin, and A.C. Hayday. 1998. Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proc. Natl. Acad. Sci. U. S. A. 95: 10055–10060.PubMedGoogle Scholar
  127. 127.
    Jaeckel, E., L. Klein, N. Martin-Orozco, and H. von Boehmer. 2003. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J. Exp. Med. 197: 1635–1644.PubMedGoogle Scholar
  128. 128.
    Birk, O.S., D.C. Douek, D. Elias, K. Takacs, H. Dewchand, S.L. Gur, M.D. Walker, R. Van Der Zee, I.R. Cohen, and D.M. Altmann. 1996. A role of hsp60 in autoimmune diabetes: analysis in a transgenic model. Proc. Natl. Acad. Sci. U. S. A. 93: 1032–1037.PubMedGoogle Scholar
  129. 129.
    Nakayama, M., N. Abiru, H. Moriyama, N. Babaya, E. Liu, D. Miao, L. Yu, D.R. Wegmann, J.C. Hutton, J.F. Elliott, and G.S. Eisenbarth. 2005. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435: 220–223.PubMedGoogle Scholar
  130. 130.
    Mueller, R., T. Krahl, and N. Sarvetnick. 1996. Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J. Exp. Med. 184: 1093–1099.PubMedGoogle Scholar
  131. 131.
    Moritani, M., K. Yoshimoto, S.F. Wong, C. Tanaka, T. Yamaoka, T. Sano, Y. Komagata, J. Miyazaki, H. Kikutani, and M. Itakura. 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.PubMedGoogle Scholar
  132. 132.
    King, C., J. Davies, R. Mueller, M.S. Lee, T. Krahl, B. Yeung, E. O’connor, and N. Sarvetnick. 1998. TGF-beta1 alters APC preference, polarizing islet antigen responses toward a Th2 phenotype. Immunity 8: 601–613.PubMedGoogle Scholar
  133. 133.
    Grewal, I.S., K.D. Grewal, F.S. Wong, D.E. Picarella, C.A. Janeway, and R.A. Flavell. 1996. Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. J. Exp. Med. 184: 1963–1974.PubMedGoogle Scholar
  134. 134.
    Wogensen, L., M.S. Lee, and N. Sarvetnick. 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.PubMedGoogle Scholar
  135. 135.
    Moritani, M., K. Yoshimoto, F. Tashiro, C. Hashimoto, J. Miyazaki, S. Ii, E. Kudo, H. Iwahana, Y. Hayashi, T. Sano, and M. Itakura. 1994. Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int. Immunol. 6: 1927–1936.PubMedGoogle Scholar
  136. 136.
    Pennline, K.J., E. Roque-gaffney, and M. Monahan. 1994. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin. Immunol. Immunopathol. 71: 169–175.PubMedGoogle Scholar
  137. 137.
    Moritani, M., K. Yoshimoto, S. Ii, M. Kondo, H. Iwahana, T. Yamaoka, T. Sano, N. Nakano, H. Kikutani, and M. Itakura. 1996. Prevention of adoptively transferred diabetes in nonobese diabetic mice with IL-10-transduced islet-specific Th1 lymphocytes. A gene therapy model for autoimmune diabetes. J. Clin. Invest. 98: 1851–1859.PubMedGoogle Scholar
  138. 138.
    Wong, S., S. Guerder, I. Visintin, E.P. Reich, K.E. Swenson, R.A. Flavell, and C.A. Janeway. 1995. Expression of the co-stimulator molecule B7-1 in pancreatic beta-cells accelerates diabetes in the NOD mouse. Diabetes 44: 326–329.PubMedGoogle Scholar
  139. 139.
    Chervonsky, A.V., Y. Wang, F.S. Wong, I. Visintin, R.A. Flavell, C.A. Janeway Jr, and L.A. Matis. 1997. The role of Fas in autoimmune diabetes. Cell 89: 17–24.PubMedGoogle Scholar
  140. 140.
    Lund, T., L. O’reilly, P. Hutchings, O. Kanagawa, E. Simpson, R. Gravely, P. Chandler, J. Dyson, J.K. Picard, A. Edwards, D. Kioussis, and A. Cooke. 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.PubMedGoogle Scholar
  141. 141.
    Singer, S.M., R. Tisch, X.D. Yang, and H.O. Mcdevitt. 1993. An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells. Proc. Natl. Acad. Sci. U. S. A. 90: 9566–9570.PubMedGoogle Scholar
  142. 142.
    Hutchings, P., P. Tonks, and A. Cooke. 1997. Effect of MHC transgene expression on spontaneous insulin autoantibody class switch in nonobese diabetic mice. Diabetes 46: 779–784.PubMedGoogle Scholar
  143. 143.
    Nishimoto, H., H. Kikutani, K. Yamamura, and T. Kishimoto. 1987. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 328: 432–434.PubMedGoogle Scholar
  144. 144.
    Bohme, J., B. Schuhbaur, O. Kanagawa, C. Benoist, and D. Mathis. 1990. MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science 249: 293–295.PubMedGoogle Scholar
  145. 145.
    Wherrett, D.K., S.M. Singer, and H.O. McDevitt. 1997. Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse line. Diabetes 46: 1970–1974.PubMedGoogle Scholar
  146. 146.
    Jasinski, J.M., L. Yu, M. Nakayama, M.M. Li, M.A. Lipes, G.S. Eisenbarth, and E. Liu. 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.PubMedGoogle Scholar
  147. 147.
    Verdaguer, J., D. Schmidt, A. Amrani, B. Anderson, N. Averill, and P. Santamaria. 1997. Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J. Exp. Med. 186: 1663–1676.PubMedGoogle Scholar
  148. 148.
    Verdaguer, J., J.W. Yoon, B. Anderson, N. Averill, T. Utsugi, B.J. Park, and P. Santamaria. 1996. Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8(+) T cells expressing identical endogenous TCR-alpha chains. J. Immunol. 157: 4726–4735.PubMedGoogle Scholar
  149. 149.
    Luhder, F., P. Hoglund, J.P. Allison, C. Benoist, and D. Mathis. 1998. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J. Exp. Med. 187: 427–432.PubMedGoogle Scholar
  150. 150.
    Andre-Schmutz, I., C. Hindelang, C. Benoist, and D. Mathis. 1999. Cellular and molecular changes accompanying the progression from insulitis to diabetes. Eur. J. Immunol. 29: 245–255.PubMedGoogle Scholar
  151. 151.
    Congia, M., S. Patel, A.P. Cope, S. De Virgiliis, and G. Sonderstrup. 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.PubMedGoogle Scholar
  152. 152.
    Sonderstrup, G., A.P. Cope, S. Patel, M. Congia, N. Hain, F.C. Hall, S.L. Parry, L.H. Fugger, S. Michie, and H.O. McDevitt. 1999. HLA class II transgenic mice: models of the human CD4+ T-cell immune response. Immunol. Rev. 172: 335–343.PubMedGoogle Scholar
  153. 153.
    Takaki, T., M.P. Marron, C.E. Mathews, S.T. Guttmann, R. Bottino, M. Trucco, T.P. DiLorenzo, and D.V. Serreze. 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.PubMedGoogle Scholar
  154. 154.
    Debray-sachs, M., C. Carnaud, C. Boitard, H. Cohen, I. Gresser, P. Bedossa, and J.F. Bach. 1991. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J. Autoimmun. 4: 237–248.PubMedGoogle Scholar
  155. 155.
    Wang, B., I. Andre, A. Gonzalez, J.D. Katz, M. Aguet, C. Benoist, and D. Mathis. 1997. Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes. Proc. Natl. Acad. Sci. U. S. A. 94: 13844–13849.PubMedGoogle Scholar
  156. 156.
    Rapoport, M.J., A. Jaramillo, D. Zipris, A.H. Lazarus, D.V. Serreze, E.H. Leiter, P. Cyopick, J.S. Danska, and T.L. Delovitch. 1993. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J. Exp. Med. 178: 87–99.PubMedGoogle Scholar
  157. 157.
    Tian, J., M.A. Atkinson, M. Clare Salzler, A. Herschenfeld, T. Forsthuber, P.V. Lehmann, and D.L. Kaufman. 1996. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183: 1561–1567.PubMedGoogle Scholar
  158. 158.
    Trembleau, S., G. Penna, E. Bosi, A. Mortara, M.K. Gately, and L. Adorini. 1995. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J. Exp. Med. 181: 817–821.PubMedGoogle Scholar
  159. 159.
    Hultgren, B., X.J. Huang, N. Dybdal, and T.A. Stewart. 1996. Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes 45: 812–817.PubMedGoogle Scholar
  160. 160.
    Trembleau, S., G. Penna, S. Gregori, H.D. Chapman, D.V. Serreze, J. Magram, and L. Adorini. 1999. Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice. J. Immunol. 163: 2960–2968.PubMedGoogle Scholar
  161. 161.
    Wang, B., A. Gonzalez, P. Hoglund, J.D. Katz, C. Benoist, and D. Mathis. 1998. Interleukin-4 deficiency does not exacerbate disease in NOD mice. Diabetes 47: 1207–1211.PubMedGoogle Scholar
  162. 162.
    Lenschow, D.J., K.C. Herold, L. Rhee, B. Patel, A. Koons, H.Y. Qin, E. Fuchs, B. Singh, C.B. Thompson, and J.A. Bluestone. 1996. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5: 285–293.PubMedGoogle Scholar
  163. 163.
    Salomon, B., D.J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, and J.A. Bluestone. 2000. B7/CD28 Costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431–440.PubMedGoogle Scholar
  164. 164.
    Chatenoud, L., B. Salomon, and J.A. Bluestone. 2001. Suppressor T cells—they’re back and critical for regulation of autoimmunity! Immunol. Rev. 182: 149–163.PubMedGoogle Scholar
  165. 165.
    Wicker, L.S., E.H. Leiter, J.A. Todd, R.J. Renjilian, E. Peterson, P.A. Fischer, P.L. Podolin, M. Zijlstra, R. Jaenisch, and L.B. Peterson. 1994. Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43: 500–504.PubMedGoogle Scholar
  166. 166.
    Katz, J., C. Benoist, and D. Mathis. 1993. Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur. J. Immunol. 23: 3358–3360.PubMedGoogle Scholar
  167. 167.
    Sumida, T., M. Furukawa, A. Sakamoto, T. Namekawa, T. Maeda, M. Zijlstra, I. Iwamoto, T. Koike, S. Yoshida, H. Tomioka, et al. 1994. Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice. Int. Immunol. 6: 1445–1449.PubMedGoogle Scholar
  168. 168.
    Kay, T.W.H., J.L. Parker, L.A. Stephens, H.E. Thomas, and J. Allison. 1996. RIP-beta(2)-microglobulin transgene expression restores insulitis, but not diabetes, in beta(2)-microglobulin(null) nonobese diabetic mice. J. Immunol. 157: 3688–3693.PubMedGoogle Scholar
  169. 169.
    Serreze, D.V., S.A. Fleming, H.D. Chapman, S.D. Richard, E.H. Leiter, and R.M. Tisch. 1998. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Immunol. 161: 3912–3918.PubMedGoogle Scholar
  170. 170.
    Falcone, M., J. Lee, G. Patstone, B. Yeung, and N. Sarvetnick. 1998. B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice. J. Immunol. 161: 1163–1168.PubMedGoogle Scholar
  171. 171.
    Maier, L.M., and L.S. Wicker. 2005. Genetic susceptibility to type 1 diabetes. Curr. Opin. Immuno.. 17: 601–608.Google Scholar
  172. 172.
    Reijonen, H., R. Mallone, A.K. Heninger, E.M. Laughlin, S.A. Kochik, B. Falk, W.W. Kwok, C. Greenbaum, and G.T. Nepom. 2004. GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes. Diabetes 53: 1987–1994.PubMedGoogle Scholar
  173. 173.
    Reijonen, H., W.W. Kwok, and G.T. Nepom. 2003. Detection of CD4+ autoreactive T cells in T1D using HLA class II tetramers. Ann. N. Y. Acad. Sci. 1005: 82–87.PubMedGoogle Scholar
  174. 174.
    Ouyang, Q., N.E. Standifer, H. Qin, P. Gottlieb, C.B. Verchere, G.T. Nepom, R. Tan, and C. Panagiotopoulos. 2006. Recognition of HLA class I-restricted β-cell epitopes in type 1 diabetes. Diabetes 55: 3068–3074.PubMedGoogle Scholar
  175. 175.
    Standifer, N.E., Q. Ouyang, C. Panagiotopoulos, C.B. Verchere, R. Tan, C.J. Greenbaum, C. Pihoker, and G.T. Nepom. 2006. Identification of novel HLA-A*0201-restricted epitopes in recent-onset type 1 diabetic subjects and antibody-positive relatives. Diabetes 55: 3061–3067.PubMedGoogle Scholar
  176. 176.
    Atkinson, M.A., and E.H. Leiter. 1999. The NOD mouse model of type 1 diabetes: as good as it gets? Nat. Med. 5: 601–604.PubMedGoogle Scholar
  177. 177.
    Roep, B.O., M. Atkinson, and M. von Herrath. 2004. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat. Rev. Immunol. 4: 989–997.PubMedGoogle Scholar
  178. 178.
    Makhlouf, L., S.T. Grey, V. Dong, E. Csizmadia, M.B. Arvelo, H. Auchincloss Jr, C. Ferran, and M.H. Sayegh. 2004. Depleting anti-CD4 monoclonal antibody cures new-onset diabetes, prevents recurrent autoimmune diabetes, and delays allograft rejection in nonobese diabetic mice. Transplantation 77: 990–997.PubMedGoogle Scholar
  179. 179.
    Shoda, L.K., D.L. Young, S. Ramanujan, C.C. Whiting, M.A. Atkinson, J.A. Bluestone, G.S. Eisenbarth, D. Mathis, A.A. Rossini, S.E. Campbell, R. Kahn, and H.T. Kreuwel. 2005. A Comprehensive Review of Interventions in the NOD Mouse and Implications for Translation. Immunity 23: 115–126.PubMedGoogle Scholar
  180. 180.
    Herold, K.C., W. Hagopian, J.A. Auger, E. Poumian Ruiz, L. Taylor, D. Donaldson, S.E. Gitelman, D.M. Harlan, D. Xu, R.A. Zivin, and J.A. Bluestone. 2002. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346: 1692–1698.PubMedGoogle Scholar
  181. 181.
    Herold, K.C., S.E. Gitelman, U. Masharani, W. Hagopian, B. Bisikirska, D. Donaldson, K. Rother, B. Diamond, D.M. Harlan, and J.A. Bluestone. 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: 1763–1769.PubMedGoogle Scholar
  182. 182.
    Keymeulen, B., E. Vandemeulebroucke, A.G. Ziegler, C. Mathieu, L. Kaufman, G. Hale, F. Gorus, M. Goldman, M. Walter, S. Candon, L. Schandene, L. Crenier, C. De Block, J.M. Seigneurin, P. De Pauw, D. Pierard, I. Weets, P. Rebello, P. Bird, E. Berrie, M. Frewin, H. Waldmann, J.F. Bach, D. Pipeleers, and L. Chatenoud. 2005. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352: 2598–2608.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Lucienne Chatenoud

There are no affiliations available

Personalised recommendations