The Pathogenesis of Immunologically Mediated Diabetes

  • Yi Wang
  • Liming Hao
  • Kevin J. Lafferty
Part of the Endocrinology and Metabolism book series (EAM, volume 4)


Diabetes as a pathologic entity has been with us as long as recorded medical history. Effective treatment for this disease, however, has developed only over the last 60 years, and it is probably fair to say that we still do not understand the physiologic trigger for the process that leads to insulin-dependent (type I) diabetes nor the detailed mechanisms of beta-cell destruction. This lack of detailed knowledge is no reason to shy away from the subject. We are at a time when discussion and speculation is needed to focus our research approach. This is a stage of scientific development when new ideas and theories are hotly debated in the light of experimental data. In this chapter, we approach our subject as immunologists rather than endocrinologists; it is now clear that type I diabetes, both in man and in animal models, is a pathologic process with an immunologic etiology.1–3


Islet Graft Kidney Capsule Islet Tissue Fetal Pancreas Islet Allograft 
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  1. 1.
    Bottazzo GF. Beta cell damage in diabetic insulitis: Are we approaching a solution ? Diabetologia1984; 26: 241.PubMedCrossRefGoogle Scholar
  2. 2.
    Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med1986; 314: 1360.PubMedCrossRefGoogle Scholar
  3. 3.
    Rossini AA, Mordes JP, Like AA. Immunology of insulin-dependent diabetes mellitus. Ann Rev Immunol1985; 3: 289 – 320.CrossRefGoogle Scholar
  4. 4.
    Burnet FM. Cellular Immunology. Melbourne: Melbourne University Press; New York: Cambridge University Press, 1969.Google Scholar
  5. 5.
    Burnet FM. The Clonal Selection Theory of Acquired Immunity. London: Cambridge University Press, 1959.Google Scholar
  6. 6.
    Todd JA, Bell JI, McDevitt HO. A molecular basis for genetic susceptibility to insulin dependent diabetes mellitus (Review). Trends Genet1988; 4: 129.PubMedCrossRefGoogle Scholar
  7. 7.
    Miyazaki A, Hanafusa T, Yamada K, et al. Predominance of T lymphocytes in pancreatic islet and spleen of pre-diabetic non-obese diabetic (NOD) mice. A longitudinal study. Clin Exp Immunol1985; 60: 622.PubMedGoogle Scholar
  8. 8.
    Mordes JP, Desemone J, Rossini AA. The BB rat. Diabetes Metab Rev1987; 3: 725 – 750.PubMedCrossRefGoogle Scholar
  9. 9.
    Logothetopoulos J, Valiquette N, Madura E, Cvet D. The Onset and progression of pancreatic insulitis in the overt, spontaneously diabetic young adult BB rat studied by pancreatic biopsy. Diabetes1984; 33: 33.PubMedCrossRefGoogle Scholar
  10. 10.
    Harada M. Immunological manipulation of diabetes production in NOD mice, in Tarui S, Tochino Y, Nonaka K (eds): Insulitis and Type I Diabetes: Lessons from the NOD Mouse. Academic Press pp 143–153. Tokyo 1986.Google Scholar
  11. 11.
    Mori Y, Suko M, Okudaira H, et al. Preventive effects of cyclosporine on diabetes in NOD mice. Diabetologia1986; 29: 244.PubMedCrossRefGoogle Scholar
  12. 12.
    Like AA, Anthony M, Guberski DL, Rossini AA: Spontaneous diabetes mellitus in the BB/W rat: Effects of glucocorticoids, cyclosporin-A and antiserum to rat lymphocytes. Diabetes1983; 32: 326.PubMedCrossRefGoogle Scholar
  13. 13.
    Like AA, Kislauskis E, Williams RM, Rossini AA: Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB/W rat. Science1982; 216: 644.PubMedCrossRefGoogle Scholar
  14. 14.
    Koevary S; Rossini A, Stoller W, Chick W, Williams RM. Passive transfer of diabetes in the BB/W rat. Science1983; 220: 727 – 728.PubMedCrossRefGoogle Scholar
  15. 15.
    Wicker LS, Miller BJ, Mullen Y. Transfer of autoimmune diabetes mellitus with splenocyte from nonobese diabetes (NOD) mice. Diabetes1986; 35: 855.PubMedCrossRefGoogle Scholar
  16. 16.
    Panitch HS, McFarlin DE: Experimental allegic encephalomyelitis: Enhancement of cell-mediated transfer by concanavalin A. J Immunol1977; 119: 1134 – 1137.PubMedGoogle Scholar
  17. 17.
    Handler ES, Mordes JP, Seals J, Koevary S, Like AA, Nakano K, Rossini AA. Diabetes in the Bio-Breeding/Worcester Rat. Induction and acceleration by spleen cells- conditioned media. J Clin Invest1985; 76: 1692 – 1694.PubMedCrossRefGoogle Scholar
  18. 18.
    Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia1986; 29: 63 – 67.PubMedCrossRefGoogle Scholar
  19. 19.
    Mandrup-Poulsen T, Bendtzen K, Dinarello CA, Nerup J. Human tumour necrosis factor potentiated human interleukin-1 mediated rat pancreatic β cell cytotoxicity. J Immunol1987; 139: 4077.PubMedGoogle Scholar
  20. 20.
    Miller BJ, Appel MC, O’Neil JJ, Wicker LS. Both the lyt-2+ and L3T4 T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol1988; 140: 52 – 58.PubMedGoogle Scholar
  21. 21.
    Koike T, Itoch Y, Ishii T, Ito I, Takabayashi K, Maruyama N, Tomioka H, Yoshida S. Preventive effect of monoclonal anti-L3T4 antibody on development of diabetes in NOD mice. Diabetes1987; 36: 539 – 541.PubMedCrossRefGoogle Scholar
  22. 22.
    Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL. Prevention of diabetes in Bio-Breeding/Worcester rats with monocolonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med1986; 164: 1145 – 1159.PubMedCrossRefGoogle Scholar
  23. 23.
    Lafferty KJ, Prowse SJ, Simeonovic CJ, Warren HS. Immunobiology of tissue transplantation: A return to the passenger leucocyte concept. Ann Rev Immunol1983; 1: 143 – 173.CrossRefGoogle Scholar
  24. 24.
    Prowse SJ, Simeonovic CJ, Lafferty KJ, Bond BC, Magi CE, Mackie D. Allogenic islet transplantation without recipient immunosuppression. Methods Diabetes Res1984; 1: 253 – 269.Google Scholar
  25. 25.
    Prowse SJ, Bellgrau D, Lafferty KJ. Islet allografts are destroyed by disease occurrence in the spontaneously diabetic BB rat. Diabetes1986; 35: 110 – 114.PubMedCrossRefGoogle Scholar
  26. 26.
    Prowse S, Nomikos IN, Pratt PF, Lafferty KJ. Islet transplantation in spontaneous dia¬betic animals, in Jaworski MA et al (eds): The Immunology of Diabetes Mellitus. Amsterdam: Elsevier Science Publishers, 1986, pp 175 – 180.Google Scholar
  27. 27.
    Weringer EJ, Like AA. Immune attack on pancreatic islet transplants in the spontaneously diabetic Bio-Breeding/Worcester (BB/W) rat is not MHC restricted. J Immunol1985; 134: 2383 – 2386.PubMedGoogle Scholar
  28. 28.
    Woehrle M, Markmann JF, Silvers WK, Barker CF, Naji A. Transplantation of cultured pancreatic islets to BB rats. Surgery1986; 100: 334 – 341.PubMedGoogle Scholar
  29. 29.
    Bendelac A, Carnaud C, Boitard C, Bach JF. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4 and Lyt2 T cells. J Exp Med1987; 166: 823 – 832.PubMedCrossRefGoogle Scholar
  30. 30.
    Wang Y, McDuffie M, Nomikos IN, Hao L, Lafferty KJ. Effect of cyclosporine on immunologically mediated diabetes in NOD mice. Transplantation 1988 vol 46: 101S–106S, suppl.Google Scholar
  31. 31.
    Wang Y, Hao L, Gill RD, Lafferty KJ. Autoimmune Diabetes in NOD mouse is L3T4 T-lymphocyte dependent. Diabetes1987; 36: 535.PubMedCrossRefGoogle Scholar
  32. 32.
    Gill RG, Lafferty KJ. A novel form of T-T collaboration requiring the active participation of the antigen presenting cell. Proc. NY Acad Sci1988; 542: 421 – 423.CrossRefGoogle Scholar
  33. 33.
    Okamoto H. Regulation of proinsulin synthesis in pancreatic islets and a new aspect to insulin-dependent diabetes. Mol Cell Biochem1981; 37: 43 – 61.PubMedCrossRefGoogle Scholar
  34. 34.
    Okamoto H. The role of poly (ADP-ribose) synthetase in the development of insulin dependent diabetes and islet β cell regeneration. Biomed Biochem Acta1985; 44: 15 – 20.Google Scholar
  35. 35.
    Fantone JC, Ward PA. Role of oxygen-derived free radicals and metabolites in leucocyte dependent inflammatory reactions. Am J Pathol1982; 107: 397 – 418.Google Scholar
  36. 36.
    Nathan CF. Neutrophil activation on biological surfaces. Massive secretion of hydro-gen peroxide in response to products of macrophages and lymphocytes. J Clin Invest1987; 80: 1550.PubMedCrossRefGoogle Scholar
  37. 37.
    Wang Y, Goodman M, Lumerman J, Sussman KE, Dahl R, Lafferty KJ, Draznin B. In vivo administration of interleukin-1 inhibits glucose-stimulated insulin release. Diabetes Research and Clinical Practice1989; 7: 205.PubMedCrossRefGoogle Scholar
  38. 38.
    Yamada K, Nonaka K, Hanafusa T, Miyazaki A, Toyoshima H, Tarui S. Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulities. An observation in nonobese diabetic (NOD) mice. Diabetes1982; 31: 749 – 753.PubMedCrossRefGoogle Scholar
  39. 39.
    Nomikos IN, Prowse SJ, Carotenuto P, Lafferty KJ. Combined treatment with nicotinamide and desferoxamine prevents islet allograft destruction in NOD mice. Diabetes1986; 36: 1302.CrossRefGoogle Scholar
  40. 40.
    Nomikos IN, Wang Y, Lafferty KJ. Involvement of 02 radicals in “autoimmune” diabetes. Immunol. Cell Biol1989; 67: 85 – 87.Google Scholar
  41. 41.
    Nakajima H, Yamada K, Hanafusa T, Fujino-Kurihara H, Miyagara J. Elevated antibody-mediated cytotoxicity and its inhibition by nicotinamide in the diabetic NOD mouse. Immunol Lett1986; 12: 91.PubMedCrossRefGoogle Scholar
  42. 42.
    Clark IA, Chaudhri G, Cowden WB. Interplay of reactive oxygen and tumor necrosis factor in tissue injury. Oxy-radicals in molecular biology and pathology. UCLA Symposia on Molecular and Cellular Biology, New Series, vol. 82. New York: Alan R. Liss, 1988.Google Scholar
  43. 43.
    Oschilewski U, Kiesel U, Kolb L. Administration of silica prevents diabetes in BB rats. Diabetes 1985; 34: 197 – 199.PubMedCrossRefGoogle Scholar
  44. 44.
    Lafferty KJ, Paris LL. Cyclosporin A and the regulation of autoimmune disease. J of Autoimmunity1988; 1: 519.CrossRefGoogle Scholar
  45. 45.
    Granelli-Piperno A, Inaba K, Steinman RM. Stimulation of lymphokine release from T lymphoblasts, requirement for mRNA synthesis and inhibition by cyclosporine. A. J Exp Med1984; 160: 1792.PubMedCrossRefGoogle Scholar
  46. 46.
    Hodgkin PD, Hapel AJ, Johnson RM, Young IG, Lafferty KJ. Blocking of delivery of the antigen-mediated signal to the nucleus of T cells by cyclosporine. Transplantation1987; 43: 685.PubMedCrossRefGoogle Scholar
  47. 47.
    Andrus L, Lafferty KJ. Inhibition of T-cell activity by cyclosporine A. Scand J Immunol1982; 15: 449.CrossRefGoogle Scholar
  48. 48.
    Laupacis A, Stiller CR, Gardell C, et al. Cyclosporine prevents diabetes in BB/Wistar rats. Lancet 1983;i:10.CrossRefGoogle Scholar
  49. 49.
    Brayman KL, Armstrong J, Shaw LM, et al. Prevention of diabetes in BB rats by intermittent administration of cyclosporine. Surgery1987; 102: 235.PubMedGoogle Scholar
  50. 50.
    Bougneries PF, Carel JC, Castano L, Bottard C, Gardin JP, Landais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL, Bach JF. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med1988; 318: 663 – 670.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1990

Authors and Affiliations

  • Yi Wang
  • Liming Hao
  • Kevin J. Lafferty

There are no affiliations available

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