Letter | Published:

Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice

Naturevolume 366pages7275 (1993) | Download Citation



KNOWING the autoantigen target(s) in an organ-specific autoimmune disease is essential to understanding its pathogenesis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the islets of Langerhans (insulitis) and destruction of insulin-secreting pancreatic β-cells1. Several β-cell proteins have been identified as autoantigens, but their importance in the diabetogenic process is not known2. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM3. Here we determine the temporal sequence of T-cell and antibody responses in NOD mice to a panel of five murine β-cell antigens and find that antibody and T-cell responses specific for the two isoforms of glutamic acid decarboxylase (GAD) are first detected in 4-week-old NOD mice. This GAD-specific reactivity coincides with the earliest detectable response to an islet extract, and with the onset of insulitis. Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes. These results indicate that the spontaneous response to β-cell antigens arises very early in life and that the anti-GAD immune response has a critical role in the disease process during this period.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Eisenbarth, G. S. New Engl. J. Med. 314, 1360–1368 (1986).

  2. 2

    Harrison, L. C. Immun. Today 13, 348–352 (1992).

  3. 3

    Makino, S. et al. Expl Anim. 29, 1 (1980).

  4. 4

    Baekkeskov, S. et al. Nature 298, 167–169 (1982).

  5. 5

    Baekkeskov, S. et al. Nature 347, 151–166 (1990).

  6. 6

    Honeyman, M. C., Cram, D. S. & Harrison, L. C. J. exp. Med. 177, 535–540 (1993).

  7. 7

    Boitard, C. et al. Proc. natn. Acad. Sci. U.S.A. 89, 172–176 (1992).

  8. 8

    Castano, L., Russo, E., Zhou, L., Lipes, M. A. & Eisenbarth, G. S. J. clin. Endocrin. Metab. 73, 1197–1201 (1991).

  9. 9

    Elias, D., Markovits, D., Reshef, T., van der Zee, R. & Cohen, I. R. Proc. natn. Acad. Sci. U.S.A. 87, 1576–80 (1990).

  10. 10

    Shizuru, J., Taylor-Edwards, C., Banks, B. A., Gregory, A. K. & Fathman, C. G. Science 240, 659–662 (1988).

  11. 11

    Miller, B. J., Appel, M. C., O'Neil, J. J. & Wicker, L. S. J. Immun. 140, 52–58 (1988).

  12. 12

    Hayward, A. & Schreiber, M. J. Immun. 143, 1555–1559 (1989).

  13. 13

    Reich, E. P., Sherwin, R. S., Kanagawa, O. & Janeway, C. A. Nature 341, 326–328 (1989).

  14. 14

    Leffert, J. D., Newgard, C. B., Okamoto, H., Miburn, J. L. & Luskey, K. L. Proc. natn. Acad. Sci. U.S.A. 86, 3127–3130 (1989).

  15. 15

    Prochazka, M., Serreze, D. V., Frankel, W. N. & Leiter, E. H. Diabetes 41, 98–106 (1992).

  16. 16

    Gerling, I. C. et al. Diabetes 41, 1672–1676 (1992).

  17. 17

    Coffman, R. L. et al. Immun. Rev. 102, 5–28 (1988).

  18. 18

    Atkinson, M. A. et al. Lancet 339, 458–459 (1992).

  19. 19

    O'Reilly, D. R., Miller, L. K. & Luckow, V. A. Baculovirus Expression Vectors: A Laboratory Manual (Freeman, New York, 1992).

Download references

Author information

Author notes

  1. Hugh O. McDevitt: Medicine, Stanford University Medical Center, Stanford, California 94305, USA


  1. Departments of Microbiology and Immunology

    • Roland Tisch
    • , Xiao-Dong Yang
    • , Steven M. Singer
    • , Roland S. Liblau
    • , Lars Fugger
    •  & Hugh O. McDevitt


  1. Search for Roland Tisch in:

  2. Search for Xiao-Dong Yang in:

  3. Search for Steven M. Singer in:

  4. Search for Roland S. Liblau in:

  5. Search for Lars Fugger in:

  6. Search for Hugh O. McDevitt in:

About this article

Publication history



Issue Date



Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.