Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 159–163 | Cite as

Roles of cytokines in the pathogenesis and therapy of type 1 diabetes

  • Alex RabinovitchEmail author
  • Wilma L. Suarez-Pinzon
Original Paper


Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans by autoreactive T helper 1 (Th1) cells characterized by their cytokine secretory products, interleukin-2 (IL-2) and interferon γ (IFNγ). Th1-type cytokines (IL-2 and IFNγ) correlate with T1D, whereas Th2 (IL-4 and IL-10), Th3 (transforming growth factor beta [TGFβ]), and T regulatory cell-type cytokines (IL-10 and TGFβ) correlate with protection from T1D. Paradoxically, however, administrations of Th1-type cytokines (IL-2 and IFNγ) and immunotherapies that induce Th1-type cytokine responses actually prevent T1D, at least in animal models. Therefore, immunotherapies that inhibit IL-2 production/action will block Th1 cell/cytokine-driven effector mechanisms of pancreatic islet β-cell destruction; however, anti-IL-2 therapy will not allow immune tolerance to be established. In contrast, immunotherapies that increase IL-2 production/action may correct an immunodeficiency in IL-2 production that appears to underlie the autoimmunity of T1D, thereby restoring immune tolerance to islet β-cells and prevention of T1D.


Type 1 diabetes Cytokines Autoimmunity Immune tolerance Immunotherapy 


  1. 1.
    Arif, S., Tree, T. I., Astill, T. P., Tremble, J. M., Bishop, A. J., Dayan, C., Roep, B. O., & Peakman, M. (2004). Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. Journal of Clinical Investigation, 113, 451–463.PubMedCrossRefGoogle Scholar
  2. 2.
    Herold, K. C., Hagopian, W., Auger, J. A., Poumian-Ruiz, E., Taylor, L., Donaldson, D., Gitelman, S. E., Harlan, D. M., Xu, D., Zivin, R., & Bluestone, J. A. (2002). Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. The New England Journal of Medicine, 346, 1692–1698.PubMedCrossRefGoogle Scholar
  3. 3.
    Herold, K. C., Burton, J. B., Francois, F., Poumian-Ruiz, E., Glandt, M., & Bluestone, J. A. (2003). Activation of human T cells by FcR nonbinding anti-CD3mAb, hOKT3γ1 (Ala-Ala). Journal of Clinical Investigation, 111, 409–418.PubMedCrossRefGoogle Scholar
  4. 4.
    Serreze, D. V., Chapman, H. D., Post, C. M., Johnson, E. A., Suarez-Pinzon, W. L., & Rabinovitch, A. (2001). Th1 to Th2 cytokine shifts in nonobese diabetic mice: Sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. Journal of Immunology, 166, 1352–1359.Google Scholar
  5. 5.
    Raefaeliy, Y., Parijs, L. V., Alexander, S. I., & Abbas, A. K. (2002). Interferon γ is required for activation-induced death of T lymphocytes. Journal of Experimental Medicine, 196, 999–1005.CrossRefGoogle Scholar
  6. 6.
    Mallek, T. R., & Bayer, A. L. (2004). Tolerance, not immunity, crucially depends on IL-2. Nature Reviews/Immunology, 4, 665–674.CrossRefGoogle Scholar
  7. 7.
    Lakkis, F. G. (1998). Role of cytokines in transplantation tolerance: Lessons learned from gene-knockout mice. Journal of the American Society of Nephrology, 9, 2361–2367.PubMedGoogle Scholar
  8. 8.
    Wells, A. D., Li, X. C., Li, Y., Walsh, M. C., Zheng, X. X., Wu, Z., Nunez, G., Tang, A., Sayegh, M., Hancock, W. W., Strom, T. B., & Turka, L. A. (1999). Requirement for T-cell apoptosis in the induction of peripheral transplant tolerance. Nature Medicine, 5, 1303–1307.PubMedCrossRefGoogle Scholar
  9. 9.
    Varadhachary, A. S., Perdow, S. N., Hu, C., Ramanarayanan, M., & Salgami, P. (1997). Differential ability of T cell subsets to undergo activation-induced cell death. Proceedings of the National Academy of Sciences of the United States of America, 94, 5778–5783.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang, X., Brunner, T., Carter, L., Dutton, R. W., Rogers, P., Bradley, L., Sato, T., Reed, J. C., Green, D., & Swain, S. L. (1997). Unequal death in T helper (Th) 1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-Mediated apoptosis. Journal of Experimental Medicine, 185, 1837–1849.PubMedCrossRefGoogle Scholar
  11. 11.
    Bensinger, S. J., Walsh, P. T., Zhang, J., Carroll, M., Parsons, R., Rathmell, J. C., Thompson, C. B., Burchill, M. A., Farrar, M. A., & Turka, L. A. (2004). Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. Journal of Immunology, 172, 5287–5296.Google Scholar
  12. 12.
    Tian, L., Lu, L., Yuan, Z., Lamb, J. R., & Tam, P. K. (2004). Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery. Transplantation, 77, 183–189.PubMedCrossRefGoogle Scholar
  13. 13.
    Rabinovitch, A., Suarez-Pinzon, W. L., Shapiro, A. M. J., Rajotte, R. V., & Power, R. (2002). Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent diabetes in NOD mice. Diabetes, 51, 638–645.PubMedCrossRefGoogle Scholar
  14. 14.
    Encinas, J. A., Wicker, L. S., Peterson, L. B., Mukasa, A., Teuscher, C., Sobel, R., Weiner, H. L., Seidman, C. E., Seidman, J. G., & Kuchroo, V. K. (1999). QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nature Genetics, 21, 158–160.PubMedCrossRefGoogle Scholar
  15. 15.
    Pololin, P. L., Wilusz, M. B., Cubbon, R. M., Pajvani, U., Lord, C. J., Todd, J. A., Peterson, L. B., Wicker, L. S., & Lyons, P. A. (2000). Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene? Cytokine, 12, 477–482.CrossRefGoogle Scholar
  16. 16.
    Vella, A., Cooper, J. D., Lowe, C. E., Walker, N., Nutland, S., Widmer, B., Jones, R., Ring, S. M., McArdle, W., Pembrey, M. E., Strachan, D. P., Dunger D. B., Twells, R. C. J., Clayton, D. G., & Todd, J. A. (2005). Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. American Journal of Human Genetics, 76, 773–779.PubMedCrossRefGoogle Scholar
  17. 17.
    Zier, K. S., Leo, M. M., Spielman, R. S., & Baker, L. (1984). Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus. Diabetes, 33, 552–555.PubMedCrossRefGoogle Scholar
  18. 18.
    Chandy, K. G., Charles, A. M., Kershnar, A., Buckingham, B., Waldeck, N., & Gupta, S. (1984). Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus. Journal of Clinical Immunology, 4, 424–428.PubMedCrossRefGoogle Scholar
  19. 19.
    Kaye, W. A., Adri, M. N., Soeldner, J. S., Rabinowe, S. L., Kaldany, A., Kahn, C. R., Bistrian, B., Srikanta, S., Ganda, O. P., & Eisenbarth, G. S. (1986). Acquired defect in interleukin-2 production in patients with type 1 diabetes mellitus. The New England Journal of Medicine, 315, 920–924.PubMedCrossRefGoogle Scholar
  20. 20.
    Roncarolo, M. G., Zoppo, M., Bacchetta, R., Gabiono, C., Sachetti, C., Cerutti, F., & Tovo, P. A. (1988). Interleukin-2 production and interleukin-2 receptor expression in children with newly diagnosed diabetes. Clinical Immunology and Immunopathology, 49, 53–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Kukreja, A., Cost G., Marker, J., Zhang, C., Sun, Z., Lin-Su, K., Ten, S., Sanz, M., Exley, M., Wilson, B., Porcelli, S., & Maclaren, N. (2002). Multiple immuno-regulatory defects in type 1 diabetes. Journal of Clinical Investigation, 109, 131–140.PubMedCrossRefGoogle Scholar
  22. 22.
    Brusko, T. M., Wasserfall, C. H., Clare-Salzler, M. J., Schatz, D. A., & Atkinson, M. A. (2005). Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes, 54, 1407–1414.PubMedCrossRefGoogle Scholar
  23. 23.
    Lindley, S., Dayan, C. M., Bishop, A., Roep, B. O., Peakman, M., & Tree, T. I. (2005). Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes, 54, 92–99.PubMedCrossRefGoogle Scholar
  24. 24.
    Setoguchi, R., Hori, S., Takahashi, T., & Sakaguchi, S. (2005). Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. Journal of Experimental Medicine, 201, 723–735.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of MedicineUniversity of AlbertaEdmontonCanada

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