Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes

Abstract

Without a doubt, rodent models have been instrumental in describing pathways that lead to pancreatic β-cell destruction, evaluating potential causes of type 1 diabetes and providing proof-of-principle for the potential of immune-based interventions. However, despite more than two decades of productive research, we are still yet to define an initiating autoantigen for the human disease, to determine the precise mechanisms of β-cell destruction in humans and to design interventions that prevent or cure type 1 diabetes. In this Perspective article, we propose that a major philosophical change would benefit this field, a proposition that is based on evaluation of situations in which rodent models have provided useful guidance and in which they have led to disappointments.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Atkinson, M. A. & Maclaren, N. K. The pathogenesis of insulin-dependent diabetes mellitus. N. Engl. J. Med. 331, 1428–1436 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Atkinson, M. A. & Leiter, E. H. The NOD mouse model of type 1 diabetes: as good as it gets? Nature Med. 5, 601–604 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Haskins, K. & McDuffie, M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249, 1433–1436 (1990).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Boitard, C., Yasunami, R., Dardenne, M. & Bach, J. F. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J. Exp. Med. 169, 1669–1680 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Wicker, L. S. et al. Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice — the NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes. J. Exp. Med. 176, 67–77 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Roep, B. O. T-cell responses to autoantigens in IDDM — the search for the holy grail. Diabetes 45, 1147–1156 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Homo-Delarche, F. & Drexhage, H. A. Immune cells, pancreas development, regeneration and type 1 diabetes. Trends Immunol. 25, 222–227 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Roep, B. O. The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia 46, 305–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Bonifacio, E. et al. International Workshop on Lessons From Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid decarboxylase or IA-2 as specific autoantigens of humoral autoimmunity in nonobese diabetic mice. Diabetes 50, 2451–2458 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Bingley, P. J. et al. Proposed guidelines on screening for risk of type 1 diabetes. Diabetes Care 24, 398 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Greeley, S. A. W. et al. Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nature Med. 8, 399–402 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. von Herrath, M. & Bach, J. F. Juvenile autoimmune diabetes: a pathogenic role for maternal antibodies? Nature Med. 8, 331–333 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Koczwara, K., Bonifacio, E. & Ziegler, A. G. Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes 53, 1–4 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Roep, B. O. & Atkinson, M. A. Animal models have little to teach us about type 1 diabetes: 1. In support of this proposal. Diabetologia 47, 1650–1656 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Pozzilli, P., Signore, A., Williams, A. J. K. & Beales, P. E. NOD mouse colonies around the world — recent facts and figures. Immunol. Today 14, 193–196 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Stene, L. C. & Nafstad, P. Relation between occurrence of type 1 diabetes and asthma. Lancet 357, 607–608 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Douek, I. F., Leech, N. J., Gillmor, H. A., Bingley, P. J. & Gale, E. A. M. Children with type-1 diabetes and their unaffected siblings have fewer symptoms of asthma. Lancet 353, 1850 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Yazdanbakhsh, M., Kremsner, P. G. & Van Ree, R. Allergy, parasites, and the hygiene hypothesis. Science 296, 490–494 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Jaeckel, E., Manns, M. & von Herrath, M. Viruses and diabetes. Ann. NY Acad. Sci. 958, 7–25 (2002).

    Article  PubMed  Google Scholar 

  22. Ohashi, P. S. et al. Ablation of tolerance and induction of diabetes by virus-infection in viral-antigen transgenic mice. Cell 65, 305–317 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Oldstone, M. B. Molecular mimicry and autoimmune disease. Cell 50, 819–820 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. von Herrath, M. & Holz, A. Pathological changes in the islet milieu precede infiltration of islets and destruction of β-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. J. Autoimmun. 10, 231–238 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Chong, M. M. W. et al. Suppressor of cytokine signaling-1 overexpression protects pancreatic β-cells from CD8+ T cell-mediated autoimmune destruction. J. Immunol. 172, 5714–5721 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Yang, Y. & Santamaria, P. T-cell receptor-transgenic NOD mice: a reductionist approach to understand autoimmune diabetes. J. Autoimmun. 22, 121–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Verdaguer, J., Amrani, A., Anderson, B., Schmidt, D. & Santamaria, P. Two mechanisms for the non-MHC-linked resistance to spontaneous autoimmunity. J. Immunol. 162, 4614–4626 (1999).

    CAS  PubMed  Google Scholar 

  29. Ji, H. et al. Different modes of pathogenesis in T-cell-dependent autoimmunity: clues from two TCR transgenic systems. Immunol. Rev. 169, 139–146 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Adorini, L., Gregori, S. & Harrison, L. C. Understanding autoimmune diabetes: insights from mouse models. Trends Mol. Med. 8, 31–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Skak, K. et al. TNF-α impairs peripheral tolerance towards β-cells, and local costimulation by B7.1 enhances the effector function of diabetogenic T cells. Eur. J. Immunol. 33, 1341–1350 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Savinov, A. Y., Tcherepanov, A., Green, E. A., Flavell, R. A. & Chervonsky, A. V. Contribution of Fas to diabetes development. Proc. Natl Acad. Sci. USA 100, 628–632 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Christen, U. et al. A dual role for TNF-α in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis. J. Immunol. 166, 7023–7032 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Grewal, I. S., Guerder, S. & Flavell, R. A. Lessons from genetically manipulated animal models — approaches to study activation of self-reactive T cells in autoimmune diseases. Immunologist 6, 106–111 (1998).

    CAS  Google Scholar 

  35. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395–1401 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Katz, J. D., Benoist, C. & Mathis, D. T helper cell subsets in insulin-dependent diabetes. Science 268, 1185–1188 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Delovitch, T. L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Serreze, D. V. & Leiter, E. H. in Molecular Pathology of Insulin-Dependent Diabetes Mellitus 31–67 (Karger, New York, 2001).

    Book  Google Scholar 

  41. Apostolou, I. & von Boehmer, H. The TCR–HA, INS–HA transgenic model of autoimmune diabetes: limitations and expectations. J. Autoimmun. 22, 111–114 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Serreze, D. V. et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new 'speed congenic' stock of NOD.Igμnull mice. J. Exp. Med. 184, 2049–2053 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Apostolou, I., Hao, Z. Y., Rajewsky, K. & von Boehmer, H. Effective destruction of Fas-deficient insulin-producing β cells in type 1 diabetes. J. Exp. Med. 198, 1103–1106 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chatenoud, L., Thervet, E., Primo, J. & Bach, J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 91, 123–127 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elias, D. et al. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat-shock protein. Proc. Natl Acad. Sci. USA 88, 3088–3091 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Makhlouf, L. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Ryu, S., Kodama, S., Ryu, K., Schoenfeld, D. A. & Faustman, D. L. Reversal of established autoimmune diabetes by restoration of endogenous β cell function. J. Clin. Invest. 108, 63–72 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ogawa, N., List, J. F., Habener, J. F. & Maki, T. Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4. Diabetes 53, 1700–1705 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Raz, I. et al. β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358, 1749–1753 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes. N. Engl. J. Med. 346, 1692–1698 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Jolicoeur, C., Hanahan, D. & Smith, K. M. T-cell tolerance toward a transgenic β-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc. Natl Acad. Sci. USA 91, 6707–6711 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cope, A. P. et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J. Exp. Med. 185, 1573–1584 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kurts, C. et al. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity. J. Exp. Med. 186, 2057–2062 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jaeckel, E., Klein, L., Martin-Orozco, N. & von Boehmer, H. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J. Exp. Med. 197, 1635–1644 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoon, J. W. et al. Control of autoimmune diabetes in NOD mice by GAD expression or suppression in β cells. Science 284, 1183–1187 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. von Herrath, M. & Homann, D. Introducing baselines for therapeutic use of regulatory T cells and cytokines in autoirnmunity. Trends Immunol. 24, 540–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Katz, J. D., Benoist, C. & Mathis, D. T helper cell subsets in insulin-dependent diabetes. Science 268, 1185–1188 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Lee, M. S., Mueller, R., Wicker, L. S., Peterson, L. B. & Sarvetnick, N. IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. J. Exp. Med. 183, 2663–2668 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Lee, M. S. & Sarvetnick, N. Induction of vascular addressins and adhesion molecules in the pancreas of IFN-γ transgenic mice. J. Immunol. 152, 4597–4603 (1994).

    CAS  PubMed  Google Scholar 

  60. Anderson, B., Park, B. J., Verdaguer, J., Amrani, A. & Santamaria, P. Prevalent CD8+ T cell response against one peptide/MHC complex in autoimmune diabetes. Proc. Natl Acad. Sci. USA 96, 9311–9316 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gallichan, W. S., Balasa, B., Davies, J. D. & Sarvetnick, N. Pancreatic IL-4 expression results in islet-reactive TH2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J. Immunol. 163, 1696–1703 (1999).

    CAS  PubMed  Google Scholar 

  62. Green, E. A. & Flavell, R. A. The temporal importance of TNF-α expression in the development of diabetes. Immunity 12, 459–469 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Lo, D. et al. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic β cells. Cell 53, 159–168 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Heath, W. R. et al. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature 359, 547–549 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Homann, D. et al. Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/STAT6 pathway. Immunity 11, 463–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Moriyama, H. et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl Acad. Sci. USA 100, 10376–10381 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Thebault-Baumont, K. et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Invest. 111, 851–857 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Thomas, H. E., Parker, J. L., Schreiber, R. D. & Kay, T. W. H. IFN-γ action on pancreatic β cells causes class I MHC upregulation but not diabetes. J. Clin. Invest. 102, 1249–1257 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Seewaldt, S. et al. Virus-induced autoimmune diabetes — most β-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 49, 1801–1809 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Lenschow, D. J. et al. CD28/B7 regulation of TH1 and TH2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Homann, D. et al. CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells. Immunity 16, 403–415 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. von Herrath, M. G., Dockter, J. & Oldstone, M. B. A. How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1, 231–242 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. von Herrath, M. G. et al. In vivo treatment with a MHC class I-restricted blocking peptide can prevent virus-induced autoimmune diabetes. J. Immunol. 161, 5087–5096 (1998).

    CAS  PubMed  Google Scholar 

  74. Santamaria, P. et al. β-cell-cytotoxic CD8+ T cells from nonobese diabetic mice use highly homologous T cell receptor α-chain CDR3 sequences. J. Immunol. 154, 2494–2503 (1995).

    CAS  PubMed  Google Scholar 

  75. Wong, F. S., Dittel, B. N. & Janeway, C. A. Transgenes and knockout mutations in animal models of type 1 diabetes and multiple sclerosis. Immunol. Rev. 169, 93–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Yang, X. D. et al. Effect of tumor necrosis factor α on insulin-dependent diabetes mellitus in NOD mice. 1. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 180, 995–1004 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Jacob, C. O., Aiso, S., Michie, S. A., McDevitt, H. O. & Acha-Orbea, H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-α and interleukin 1. Proc. Natl Acad. Sci. USA 87, 968–972 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hultgren, B., Huang, X. J., Dybdal, N. & Stewart, T. A. Genetic absence of γ-interferon delays but does not prevent diabetes in NOD mice. Diabetes 45, 812–817 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Dalton, D. K. et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Sarvetnick, N. et al. Loss of pancreatic-islet tolerance induced by β-cell expression of interferon-γ. Nature 346, 844–847 (1990).

    Article  CAS  PubMed  Google Scholar 

  81. Holz, A., Brett, K. & Oldstone, M. B. A. Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. J. Clin. Invest. 108, 1749–1758 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Fujihira, K. et al. Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice. Diabetes 49, 1998–2006 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Mueller, R., Bradley, L. M., Krahl, T. & Sarvetnick, N. Mechanism underlying counterregulation of autoimmune diabetes by IL-4. Immunity 7, 411–418 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Yamamoto, A. M. et al. The activity of immunoregulatory T cells mediating active tolerance is potentiated in nonobese diabetic mice by an IL-4-based retroviral gene therapy. J. Immunol. 166, 4973–4980 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nature Rev. Immunol. 4, 665–674 (2004).

    Article  CAS  Google Scholar 

  86. Anderson, J. T., Cornelius, J. G., Jarpe, A. J., Winter, W. E. & Peck, A. B. Insulin-dependent diabetes in the NOD mouse model. 2. β-cell destruction in autoimmune diabetes is a TH2 and not a TH1 mediated event. Autoimmunity 15, 113–122 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. Hussain, M. J. et al. Cytokine overproduction in healthy first degree relatives of patients with IDDM. Diabetologia 41, 343–349 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. von Herrath, M. G., Allison, J., Miller, J. F. A. P. & Oldstone, M. B. A. Focal expression of interleukin-2 does not break unresponsiveness to self (viral) antigen expressed in β-cells but enhances development of autoimmune-disease (diabetes) after initiation of an anti-self immune-response. J. Clin. Invest. 95, 477–485 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shapiro, A. M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. von Herrath, M. G., Wolfe, T., Mohrle, U., Coon, B. & Hughes, A. Protection from type 1 diabetes in the face of high levels of activated autoaggressive lymphocytes in a viral transgenic mouse model crossed to the SV129 strain. Diabetes 50, 2700–2708 (2001).

    Article  CAS  PubMed  Google Scholar 

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

  92. Gale, E. A. M. et al. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 363, 925–931 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Like, A. A., Rossini, A. A., Guberski, D. L., Appel, M. C. & Williams, R. M. Spontaneous diabetes mellitus: reversal and prevention in the BB/W rat with antiserum to rat lymphocytes. Science 206, 1421–1423 (1979).

    Article  CAS  PubMed  Google Scholar 

  94. Roep, B. O. et al. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes 48, 484–490 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Petersen, J. S. et al. Differential expression of glutamic acid decarboxylase in rat and human islets. Diabetes 42, 484–495 (1993).

    Article  CAS  PubMed  Google Scholar 

  97. Elias, D. & Cohen, I. R. Treatment of autoimmune diabetes and insulitis in NOD mice with heat shock protein 60 peptide p277. Diabetes 44, 1132–1138 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Gotfredsen, C. F., Buschard, K. & Frandsen, E. K. Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin-treatment of diabetes-prone animals. Diabetologia 28, 933–935 (1985).

    Article  CAS  PubMed  Google Scholar 

  99. Atkinson, M. A., Maclaren, N. K. & Luchetta, R. Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 39, 933–937 (1990).

    Article  CAS  PubMed  Google Scholar 

  100. Martin, S. et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N. Engl. J. Med. 345, 1036–1040 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Zerhouni, E. The NIH roadmap. Science 302, 63–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Coghlan, A. Have we got it horribly wrong? New Sci. 176, 12–13 (2002).

    Google Scholar 

  103. Peterson, J. D., Karpus, W. J., Clatch, R. J. & Miller, S. D. Split tolerance of TH1 and TH2 cells in tolerance to Theiler's murine encephalomyelitis virus. Eur. J. Immunol. 23, 46–55 (1993).

    Article  CAS  PubMed  Google Scholar 

  104. Kuchroo, V. K. et al. T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu. Rev. Immunol. 20, 101–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Borchers, A., Ansari, A. A., Hsu, T., Kono, D. H. & Gershwin, M. E. The pathogenesis of autoimmunity in New Zealand mice. Semin. Arthritis Rheum. 29, 385–399 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Makino, S. et al. Breeding of a non-obese diabetic strain of mice. Exp. Anim. 29, 1–13 (1980).

    Article  CAS  Google Scholar 

  107. Colle, E., Guttmann, R. D., Seemayer, T. A. & Michel, F. Spontaneous diabetes mellitus syndrome in the rat. IV. Immunogenetic interactions of MHC and non-MHC components of the syndrome. Metabolism 32, 54–61 (1983).

    Article  CAS  PubMed  Google Scholar 

  108. Scott, B. et al. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity 1, 73–82 (1994).

    Article  CAS  PubMed  Google Scholar 

  109. Tisch, R. et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366, 72–75 (1993).

    Article  CAS  PubMed  Google Scholar 

  110. Jaeckel, E., Lipes, M. A. & von Boehmer, H. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nature Immunol. 5, 1028–1035 (2004).

    Article  CAS  Google Scholar 

  111. von Herrath, M. G., Holz, A., Homann, D. & Oldstone, M. B. A. Role of viruses in type 1 diabetes. Semin. Immunol. 10, 87–100 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Ludewig, B., Odermatt, B., Landmann, S., Hengartner, H. & Zinkernagel, R. M. Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J. Exp. Med. 188, 1493–1501 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Morgan, D. J. et al. Ontogeny of T cell tolerance to peripherally expressed antigens. Proc. Natl Acad. Sci. USA 96, 3854–3858 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gaskins, H. R., Prochazka, M., Hamaguchi, K., Serreze, D. V. & Leiter, E. H. β cell expression of endogenous xenotropic retrovirus distinguishes diabetes-susceptible NOD/Lt from resistant NON/Lt mice. J. Clin. Invest. 90, 2220–2227 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Eizirik, D. L. et al. Major species differences between humans and rodents in the susceptibility to pancreatic β-cell injury. Proc. Natl Acad. Sci. USA 91, 9253–9256 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Johnson, E. A., Silveira, P., Chapman, H. D., Leiter, E. H. & Serreze, D. V. 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, 2404–2410 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Quartey-Papafio, R. et al. Aspartate at position 57 of nonobese diabetic I–Ag7 β-Chain diminishes the spontaneous incidence of insulin-dependent diabetes-mellitus. J. Immunol. 154, 5567–5575 (1995).

    CAS  PubMed  Google Scholar 

  118. von Herrath, M. G., Guerder, S., Lewicki, H., Flavell, R. A. & Oldstone, M. B. A. Coexpression of B7-1 and viral ('self') transgenes in pancreatic β cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes. Immunity 3, 727–738 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. Harlan, D. M. et al. Mice expressing both B7-1 and viral glycoprotein on pancreatic β-cells along with glycoprotein-specific transgenic T-cells develop diabetes due to a breakdown of T-lymphocyte unresponsiveness. Proc. Natl Acad. Sci. USA 91, 3137–3141 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Thomas, H. E., Darwiche, R., Corbett, J. A. & Kay, T. W. H. Evidence that β cell death in the nonobese diabetic mouse is Fas independent. J. Immunol. 163, 1562–1569 (1999).

    CAS  PubMed  Google Scholar 

  121. Christen, U. et al. Virally induced inflammation triggers fratricide of Fas-ligand-expressing β-cells. Diabetes 53, 591–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Wang, B. et al. Interleukin-4 deficiency does not exacerbate disease in NOD mice. Diabetes 47, 1207–1211 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Mi, Q. S., Ly, D., Zucker, P., McGarry, M. & Delovitch, T. L. Interleukin-4 but not interleukin-10 protects against spontaneous and recurrent type 1 diabetes by activated CD1d-restricted invariant natural killer T-cells. Diabetes 53, 1303–1310 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are indebted to E. Leiter (Jackson Lab, Bar Harbor, United States) for critical reading of the manuscript, for many helpful suggestions and for providing Box 1.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Bart O. Roep, Mark Atkinson or Matthias von Herrath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

GAD

HSP60

IA2

IL-2

IL-4

insulin

Jackson lab

NOD

OMIM

T1D

FURTHER INFORMATION

Immune Tolerance Network

Type 1 Diabetes TrialNet

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roep, B., Atkinson, M. & von Herrath, M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol 4, 989–997 (2004). https://doi.org/10.1038/nri1502

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1502

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing