Immune Pathogenesis of Diabetes in the Nonobese Diabetic Mouse: An Overview

Conference paper
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 156)


A considerable amount of evidence suggests that human type 1 or insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a long preclinical period. It is extremely difficult to study the process of pancreatic beta cell damage during the preclinical stage of the disease, and only detailed analysis of animal models appears to give us some answers in this important area. In 1974 a female mouse in the normoglycemic subline of Jcl-ICR mice was found to show overt diabetes, and the nonobese diabetic (NOD) mouse strain was subsequently established in the Shionogi Laboratories (TOCHINO 1986). These mice have many characteristics similar to human type 1 diabetic patients and have been increasingly used as an animal model for type 1 diabetes (TARUI and HANAFUSA 1988). This review summarizes the current knowledge on the immune pathogenesis of diabetes in NOD mice.


Beta Cell Islet Cell Antibody Overt Diabetes Immune Pathogenesis Diabetogenic Gene 
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  1. Acha-Orbea H, McDevitt HO (1987) The first external domain of the nonobese diabetic mouse class II I-A chain-is unique. Proc Natl Acad Sci USA 84: 2435–2439PubMedCrossRefGoogle Scholar
  2. Atkinson MA, Maclaren NK (1988) Autoantibodies in nonobese diabetic mice immunoprecipitate 64,000-M(r) islet antigen. Diabetes 37: 1587–1590PubMedCrossRefGoogle Scholar
  3. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt2+ cells. J Exp Med 166: 823–832PubMedCrossRefGoogle Scholar
  4. Bottazzo GF, Pujol-Borrell R, Hanafusa T, Feldmann M (1983) Role of aberrant HLA-DR expression and antigen presentation in the induction of endocrine autoimmunity. Lancet 2:1115–1119PubMedCrossRefGoogle Scholar
  5. Bottazzo GF, Dean BM, McNally JM, Mackay EH, Swift PGF, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 313: 353–360PubMedCrossRefGoogle Scholar
  6. Charlton B, Mandel TE (1988) Progression from insulitis to beta-cell destruction in NOD mouse requires L3T4+ T-lymphocytes. Diabetes 37: 1108–1112PubMedCrossRefGoogle Scholar
  7. Charlton B, Bacelj A, Mandel TE (1988) Administration of silica particles or anti-Lyt2 antibody prevents beta-cell destruction in NOD mice given cyclophosphamide. Diabetes 37: 930–935PubMedCrossRefGoogle Scholar
  8. Dyrberg T, Schwimmbeck PL, Oldstone MBA (1988) Inhibition of diabetes in BB rats by virus infection. J Clin Invest 81: 928–931PubMedCrossRefGoogle Scholar
  9. Elliott RB, Reddy SN, Bibby NJ, Kida K (1988) Dietary prevention of diabetes in the non-obese diabetic mouse. Diabetologia 31: 62–64PubMedGoogle Scholar
  10. Formby B, Miller N, Peterson CM (1988) Adoptive immunotherapy of diabetes in autologous nonobese diabetic mice with lymphoid cells ex vivo exposed to cyclosporin plus interleukin 2. Diabetes 37: 1305–1309PubMedCrossRefGoogle Scholar
  11. Foulis AK, Farquharson MA (1986) Aberrant expression of HLA-DR antigens by insulin containing beta-cells in recent-onset Type I diabetes mellitus. Diabetes 35: 1215–1224PubMedCrossRefGoogle Scholar
  12. Fujino-Kurihara H, Fujita H, Hakura A, Nonaka K, Tarui S (1985) Morphological aspects on pancreatic islets of nonobese diabetic (NOD) mice. Virchows Arch B [Cell Pathol] 49: 107–120CrossRefGoogle Scholar
  13. Fujita H, Fujino H, Nonaka K, Tarui S, Tochino Y (1984) Retrovirus-like particles in pancreatic B-cells of NOD (nonobese diabetic) mice. Biomed Res 5: 67–70Google Scholar
  14. Hanafusa T, Tarui S (1989) Immunotherapy of the NOD mouse. In: Eisenbarth GS (ed) Immunotherapy of diabetes and selected autoimmune diseases. CRC Press, Boca Raton, Florida, pp 53–60Google Scholar
  15. Hanafusa T, Pujol-Borrell R, Chiovato L, Russell RCG, Doniach D, Bottazzo GF (1983) Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: relevance for autoimmunity. Lancet 2: 1111–1115PubMedCrossRefGoogle Scholar
  16. Hanafusa T, Fujino-Kurihara H, Miyazaki A, Yamada K, Nakajima H, Miyagawa J, Kono N, Tarui S (1987) Expression of class II major histocompatibility complex antigens on pancreatic B cells in the NOD mouse. Diabetologia 30: 104–108PubMedGoogle Scholar
  17. Hanafusa T, Sugihara S, Fujino-Kurihara H, Miyagawa J, Miyazaki A, Yoshioka T, Yamada K, Nakajima H, Asakawa H, Kono N, Fujiwara H, Hamaoka T, Tarui S (1988) The induction of insulitis by adoptive transfer with L3T4+Lyt-2 T-lymphocytes in T-lymphocyte-depleted NOD mice. Diabetes 37: 204–208PubMedCrossRefGoogle Scholar
  18. Hanafusa T, Miyazaki A, Yamada K, Miyagawa J, Fujino-Kurihara H, Nakajima H, Kono N, Nonaka K, Tarui S (1988) Autoantibodies to islet cells and multiple organs in the NOD mouse. Diabetes Nutr Metab 1: 273–276Google Scholar
  19. Harada M (1987) Immune disturbance and pathogenesis of non-obese diabetes-prone (NOD) mice. Exp Clin Endocrinol 89: 251–258PubMedCrossRefGoogle Scholar
  20. Hari J, Yokono K, Yonezawa K, Amano K, Yaso S, Shii K, Imamura Y, Baba S (1986) Immunochemical characterization of anti-islet cell surface monoclonal antibody from nonobese diabetic mice. Diabetes 35: 517–522PubMedCrossRefGoogle Scholar
  21. Haskins K, Portas M, Bradley B, Wegmann D, Lafferty K (1988) T-lymphocyte clone specific for pancreatic islet antigen. Diabetes 37: 1444–1448PubMedCrossRefGoogle Scholar
  22. Hattori M, Buse JB, Jackson RA, Glimcher L, Dorf ME, Minami M, Makino, Moriwaki K, Kuzuya H, Imura H, Strauss WM, Scidman JG, Eisenbarth GS (1986) The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231: 733–735PubMedCrossRefGoogle Scholar
  23. Ikegami H, Hattori M, Makino S, Eisenbarth GS (1986) Analysis of the immunogenetics of the NOD mouse utilizing multiple strain combinations: two recessive diabetogenic genes linked with H-2 (chromosome 17) and Thy-1 (chromosome 9). Paper presented at the symposium on the immunology of diabetes, Edmonton, Canada, June 1986 Abstract no S7Google Scholar
  24. Ikehara S, Ohtsuki H, Good RA, Asamoto H, Nakamura T, Sekita K, Muso E, Tochino Y, Ida T, Kuzuya H, Imura H, Hamashima Y (1985) Prevention of type I diabetes in nonobese diabetic mice by allogeneic bone marrow transplantation. Proc Natl Acad Sci USA 82: 7743–7747PubMedCrossRefGoogle Scholar
  25. Kida K, Kaino Y, Miyagawa T, Gotoh Y, Matsuda H (1986) Effect of cyclosporin on insulitis and ICSA in NOD mice. In: Tarui S, Nonaka K, Tochino Y (eds) Insulitis and Type I diabetes: lessons from animal diabetes. Academic, Tokyo, pp 137–142Google Scholar
  26. Koike T, Itoh Y, Ishii T, Ito I, Takabayashi K, Maruyama N, Tomioka H, Yoshida S (1987) Preventive effect of monoclonal anti-L3T4 antibody on development of diabetes in NOD mice. Diabetes 36: 539–541PubMedCrossRefGoogle Scholar
  27. Lee K, Amano K, Yoon J (1988) Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes 37: 989–991PubMedCrossRefGoogle Scholar
  28. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y (1980) Breeding of a nonobese diabetic strain of mice. Exp Animals (Tokyo) 29: 1–13Google Scholar
  29. Makino S, Kunimoto K, Muraoka Y, Katagiri K (1981) Effect of castration on the appearance of diabetes in NOD mouse. Exp Anim 30: 137–140Google Scholar
  30. Maruyama T, Takei I, Yanagawa T, Takahashi T, Asaba Y, Kataoka K, Ishii T (1988) Insulin autoantibodies in nonobese diabetic (NOD) mice and streptozotocin-induced diabetic mice. Diabetes Res 7: 93–96PubMedGoogle Scholar
  31. Miller BJ, Appel MC, O’Neil JJ, Wicker LS (1988) Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol 140: 52–58PubMedGoogle Scholar
  32. Miyazaki A, Hanafusa T, Yamada K, Miyagawa J, Fujino-Kurihara H, Nakajima H, Nonaka K, Tarui S (1985) Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic nonobese diabetic (NOD) mice: a longitudinal study. Clin Exp Immunol 60: 622–630PubMedGoogle Scholar
  33. Mori Y, Suko M, Okudaira H, Matsuba I, Tsuruoka A, Sasaki A, Yokoyama H, Tanase T, Shiba T, Nishimura M, Terada E, Ikeda Y (1986) Preventive effects of cyclosporin on diabetes in NOD mice. Diabetologia 29: 244–247PubMedCrossRefGoogle Scholar
  34. Nakajima H, Fujino-Kurihara H, Hanafusa T, Yamada K, Miyazaki A, Miyagawa J, Nonaka K, Tarui S, Tochino Y (1985) Nicotinamide prevents the development of cyclophosphamide-induced diabetes mellitus in male non-obese diabetic (NOD) mice. Biomed Res 6: 185–189Google Scholar
  35. Nakajima H, Yamada K, Hanafusa T, Fujino-Kurihara H, Miyagawa J, Miyazaki A, Saitoh R, Minami Y, Kono N, Nonaka K, Tochino Y, Tarui S (1986) Elevated antibody-dependent cell-mediated cytotoxicity and its inhibition by nicotinamide in the diabetic NOD mouse. Immunol Lett 12: 91–94PubMedCrossRefGoogle Scholar
  36. Nishimoto H, Kikutani H, Yamamura K, Kishimoto T (1987) Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 328: 432–434PubMedCrossRefGoogle Scholar
  37. Nomikos IN, Prowse SJ, Carotenuto P, Lafferty KJ (1986) Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice. Diabetes 35: 1302–1304PubMedCrossRefGoogle Scholar
  38. Ogawa M, Maruyama T, Hasegawa T, Kanaya T, Kobayashi F, Tochino Y, Uda H (1985) The inhibitory effect of neonatal thymectomy on the incidence of insulitis in non-obese diabetes (NOD) mice. Biomed Res 6: 103–105Google Scholar
  39. Oldstone MBA (1988) Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 239: 500–502PubMedCrossRefGoogle Scholar
  40. Pontesilli O, Carotenuto P, Gazda LS, Pratt PF, Prowse SJ (1987) Circulating lymphocyte populations and autoantibodies in non-obese diabetic (NOD) mice: a longitudinal study. Clin Exp Immunol 70: 84–93PubMedGoogle Scholar
  41. Prochazka M, Leiter EH, Serreze DV, Coleman DL (1987) Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science 237: 286–289PubMedCrossRefGoogle Scholar
  42. Reddy S, Bibby NJ, Elliott RB (1988) Ontogeny of islet cell antibodies, insulin autoantibodies and insulitis in the non-obese diabetic mouse. Diabetologia 31: 322–328PubMedGoogle Scholar
  43. 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
  44. Serreze DV, Leiter EH, Worthen SM, Shultz LD (1988a) NOD marrow stem cells adoptively transfer diabetes to resistant (NOD x NON)Fl mice. Diabetes 37: 252–255PubMedCrossRefGoogle Scholar
  45. Serreze DV, Leiter EH, Kuff TEL, Jardieu P, Ishizaka K (1988b) Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice. Diabetes 37: 351–358PubMedCrossRefGoogle Scholar
  46. Signore A, Cooke A, Pozzilli P, Butcher F, Simpson E, Beverley PCL (1987) Class-II and IL2 receptor positive cells in the pancreas of NOD mice. Diabetologia 30: 902–905PubMedGoogle Scholar
  47. Suenaga K, Yoon JW (1988) Association of beta-cell-specific expression of endogenous retrovirus with development of insulitis and diabetes in NOD mouse. Diabetes 37: 1722–1726PubMedCrossRefGoogle Scholar
  48. Tarui S, Hanafusa T (1988) The NOD mouse. In: Alberti KGMM, Krall LP (eds) The diabetes annual/4. Elsevier, Amsterdam, pp 609–620Google Scholar
  49. Terada M, Salzler M, Lennartz K, Mullen Y (1988) The effect of H-2 compatibility on pancreatic beta cell survival in the nonobese diabetic mouse. Transplantation 45: 622–627PubMedCrossRefGoogle Scholar
  50. Timsit J, Debray-Sachs M, Boitard C, Bach JF (1988) Cell-mediated immunity to pancreatic islet cells in the non-obese diabetic (NOD) mouse: in vitro characterization and time course study. Clin Exp Immunol 73: 260–264PubMedGoogle Scholar
  51. Tochino Y (1986) Discovery and breeding of the NOD mouse. In: Tarui S, Nonaka K, Tochino Y (eds) Insulitis and Type 1 diabetes: lessons from animal diabetes. Academic, Tokyo, pp3–10Google Scholar
  52. Todd JA, Bell JI, McDevitt HO (1987) HLA-DQ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604PubMedCrossRefGoogle Scholar
  53. Uchigata Y, Yamamoto H, Kawamura A, Okamoto H (1982) Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin- induced islet DNA strand breaks and against the inhibition of proinsulin synthesis. J Biol Chem 257: 6084–6088PubMedGoogle Scholar
  54. Wang Y, Hao L, Gill RG, Lafferty KJ (1987) Autoimmune diabetes in NOD mouse is L3T4 T-lymphocyte dependent. Diabetes 36: 535–538PubMedCrossRefGoogle Scholar
  55. Wang Y, McDuffie M, Nomikos IN, Hao L, Lafferty KJ (1988) Effect of cyclosporine on immunologically mediated diabetes in nonobese diabetic mice. Transplantation 46[Suppl]: 101S–106SGoogle Scholar
  56. Wicker LS, Miller BJ, Mullen Y (1986) Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes 35: 855–860PubMedCrossRefGoogle Scholar
  57. Wicker LS, Miller BJ, Coker LZ, McNally SE, Scott S, Mullen Y, Appel MC (1987) Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med 165: 1639–1654PubMedCrossRefGoogle Scholar
  58. Wicker LS, Miller BJ, Chai A, Terada M, Mullen Y (1988) Expression of genetically determined diabetes and insulitis in the nonobese diabetic (NOD) mouse at the level of bone marrow-derived cells. Transfer of diabetes and insulitis to nondiabetic (NOD x B10)F1 mice with bone marrow cells from NOD mice. J Exp Med 167: 1801–1810PubMedCrossRefGoogle Scholar
  59. Yamada K, Nonaka K, Hanafusa T, Miyazaki A, Toyoshima H, Tarui S (1982) Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice. Diabetes 31: 749–753PubMedCrossRefGoogle Scholar
  60. Yasunami R, Bach JF (1988) Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol 18: 481–484PubMedCrossRefGoogle Scholar
  61. Yokono K, Shii K, Hari J, Yaso S, Imamura Y, Ejiri K, Ishihara K, Fujii S, Kazumi T, Taniguchi H, Baba S (1984) Production of monoclonal antibodies to islet cell surface antigens using hybridization of spleen lymphocytes from non-obese diabetic mice. Diabetologia 26: 379–385PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin · Heidelberg 1990

Authors and Affiliations

  1. 1.The Second Department of Internal MedicineOsaka University Medical SchoolOsakaJapan

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