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Reviews in Endocrine and Metabolic Disorders

, Volume 4, Issue 3, pp 291–299 | Cite as

Role of Cytokines in the Pathogenesis of Autoimmune Diabetes Mellitus

  • Alex Rabinovitch
  • Wilma L. Suarez-Pinzon
Article
cytokines type 1 diabetes immunoregulation Th1/Th2 cells islet β-cells 

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References

  1. 1.
    Foulis AK, Farquharson MA, Meager A. Immunoreactive alphainterferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 1987;2:1423–1427.Google Scholar
  2. 2.
    Huang X, Yuan J, Goddard A, Foulis A, James RF, Lernmark Å, Pujol-Borrell R, Rabinovitch A, Somoza N, Stewart TA. Interferon expression in the pancreases of patients with type 1 diabetes. Diabetes 1995;44:658–664.Google Scholar
  3. 3.
    Somoza N, Vargas F, Roura-Mir C, Vives-Pi M, Fernandez-Figueras MT, Ariza A, Gomis R, Bragado R, Marti M, Jaraquemada D. Pancreas in recent onset insulin-dependent diabetes mellitus: Changes in HLA, adhesion molecules and autoantigens, restricted TCR Vb usage, and cytokine profile. J Immunol 1994;153:1360–1377.Google Scholar
  4. 4.
    Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulindependent) diabetes mellitus in man: Macrophages, lymphocytes, and interferon-γ containing cells. J Pathol 1991;165:97–103.Google Scholar
  5. 5.
    Yamagata K, Nakajima H, Tomita K, Itoh N, Miyagawa J-I, Hamaguchi T, Namba M, Tamura S, Kawata S, Kono N, Kuwajima M, Noguchi T, Hanafusa T, Matsuzawa Y. Dominant TCR α-chain clonotypes and interferon-γ are expressed in the pancreas of patients with recent-onset insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1996;34:37–46.Google Scholar
  6. 6.
    Suarez-Pinzon W, Rajotte RV, Mosmann TR, Rabinovitch A. Both CD4+ and CD8+ T cells in syngeneic islet grafts in NOD mice produce interferon-gamma during beta-cell destruction. Diabetes 1996;45:1350–1357.Google Scholar
  7. 7.
    Mandrup-Poulsen T, Helqvist S, Wogensen LD, Molvig J, Pociot F, Johannesen J, Nerup J. Cytokines and free radicals as effector molecules in the destruction of pancreatic β-cells. Curr Top Microbiol Immunol 1990;164:169–193.Google Scholar
  8. 8.
    Rabinovitch A. Roles of cytokines in IDDM pathogenesis and islet β-cell destruction. Diabetes Rev 1993;1:215–240.Google Scholar
  9. 9.
    Bolaffi JL, Nowlain RE, Cruz L, Grodsky GM. Progressive damage of cultured pancreatic islets after single early exposure to streptozotocin. Diabetes 1986;35:1027–1033.Google Scholar
  10. 10.
    Pipeleers D, Van de Winkel M. Pancreatic β-cells possess defense mechanisms against cell-specific toxicity. Proc Natl Acad Sci USA 1986;83:5267–5271.Google Scholar
  11. 11.
    Ling Z, In't Veld PA, Pipeleers DG. Interaction of interleukin-1 with islet β-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression. Diabetes 1993;42:56–65.Google Scholar
  12. 12.
    Poo W-J, Conrad L, Janeway CA. Receptor-directed focusing of lymphokine release by helper T cells. Nature 1988;332:378– 380.Google Scholar
  13. 13.
    Kurt-Jones EA, Beller DI, Mizel SB, Unanue ER. Identification of a membrane associated interleukin-1 in macrophages. Proc Natl Acad Sci USA 1985;82:1204–1208.Google Scholar
  14. 14.
    Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/cachetin is a cell surface cytotoxic transmembrane protein: Ramifications for the complex physiology of TNF. Cell 1988;53:45– 53.Google Scholar
  15. 15.
    Sutton R, Gray DWR, McShane P, Dallman MJ, Morris PJ. The specificity of rejection and the absence of susceptibility of pancreatic islet β-cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat. J Exp Med 1989;170:751–762.Google Scholar
  16. 16.
    Korsgren O, Jansson L. Characterization of mixed syngeneicallogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections. J Clin Invest 1994;93:1113–1119.Google Scholar
  17. 17.
    Thomas HE, Parker JL, Schreiber RD, Kay TWH. IFN-γ action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest 1998;102:1249–1257.Google Scholar
  18. 18.
    Wang B, André I, Gonzalez A, Katz JD, Aguet M, Benoist C, Mathis D. Interferon-γ impacts at multiple points during the progression of autoimmune diabetes. Proc Natl Acad Sci USA 1997;94:13844–13849.Google Scholar
  19. 19.
    Corbett JA, McDaniel ML. Intraislet release of IL-1 inhibits ß-cell function by inducing β-cell expression of iNOS. J Exp Med 1995;181:559–568.Google Scholar
  20. 20.
    Arnush M, Heitmeier MR, Scarim AL, Marino MH, Manning PT, Corbett JA. IL-1 produced and released endogenously within human islets inhibits β-cell function. J Clin Invest 1998;102:516–526.Google Scholar
  21. 21.
    Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 1996;39:1005–1029.Google Scholar
  22. 22.
    Eizirik DL, Pavlovic D. Is there a role for nitric oxide in β-cell dysfunction and damage in IDDM? Diabetes Metab Rev 1997;13:293–307.Google Scholar
  23. 23.
    Rabinovitch A, Suarez-Pinzon WL. Cytokines and their roles in pancreatic islet β-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 1998;55:1139–1149.Google Scholar
  24. 24.
    Serreze DV, Leiter EH. Defective activation of T suppressor cell function in nonobese diabetic mice: Potential relation to cytokine deficiencies. J Immunol 1988;140:3801–3807.Google Scholar
  25. 25.
    Rapoport MJ, Jaramillo A, Zipris D, Lazarus AH, Serreze DV, Leiter EH, Cyopick P, Danska JS, Delovitch TL. IL-4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in NOD mice. J Exp Med 1993;178:87–99.Google Scholar
  26. 26.
    Jacob CO, Asiso S, Michie SA, McDevitt HO, 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 1990;87:968–972.Google Scholar
  27. 27.
    Satoh J, Seino H, Abo T, Tanaka S, Shintani S, Ohta S, Tamura K, Sawai T, Nobunaga T, Oteki T. Recombinant human tumor necrosis factor-α suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest 1989;84:1345–1348.Google Scholar
  28. 28.
    Lapchak PH, Guilbert LJ, Rabinovitch A. Tumor necrosis factor production is deficient in diabetes-prone BB rats and can be corrected by complete Freund's adjuvant: A possible immunoregulatory role of tumor necrosis factor in the prevention of diabetes. Clin Immunol Immunopathol 1992;65:129–134.Google Scholar
  29. 29.
    Takahashi K, Satoh J, Seino H, Zhu XP, Sagara M, Masuda T, Toyota T. Prevention of type 1 diabetes with lymphotoxin in BB rats. Clin Immunol Immunopathol 1993;69:318–323.Google Scholar
  30. 30.
    Cameron MJ, Arreaza GA, Zuker P, Chensue SW, Strieter RM, Chakrabarti S, Delrvitan TL. IL-4 prevents insulitis and insulindependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 1997;159:4686–4692.Google Scholar
  31. 31.
    Stewart TA, Hultgren B, Huang X, Pitts-Meek S, Hully J, MacLachlan NJ. Induction of type 1 diabetes by interferon-α in transgenic mice. Science 1993;260:1942–1946.Google Scholar
  32. 32.
    Chakrabarti D, Hultgren B, Stewart TA. IFN-α induces autoimmune T cells through the induction of intracellular adhesion molecule-1 and B7.2. J Immunol 1996;157:522–528.Google Scholar
  33. 33.
    Sobel DO, Ahvazi B. α-Interferon inhibits the development of diabetes in NOD mice. Diabetes 1998;47:1867–1872.Google Scholar
  34. 34.
    Sobel DO, Creswell K, Yoon J-W, Holterman D. Alpha interferon administration paradoxically inhibits the development of diabetes in BB rats. Life Sci 1998;62:1293–1302.Google Scholar
  35. 35.
    Campbell IL, Oxbrow L, Harrison LC. Reduction in insulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. J Autoimmun 1991;4:249–262.Google Scholar
  36. 36.
    Nicoletti F, Zaccone P, Di Marco R, Magro G, Grasso S, Stivala F, Calori G, Mughini L, Meroni PL, Garotta G. Paradoxical antidiabetogenic effect of γ-interferon in DP-BB rats. Diabetes 1998;47:32–38.Google Scholar
  37. 37.
    Balashov KE, Khoury SJ, Hafler DA, Weiner HL. Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis. J Clin Invest 1995;95:2711–2719.Google Scholar
  38. 38.
    Willenborg DO, Fordham S, Bernard CCA, Cowden WB, Ramshaw IA. IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 1996;157:3223–3227.Google Scholar
  39. 39.
    Rothe H, Jenkins NA, Copeland NG, Kolb H. Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. J Clin Invest 1997;99:469– 474.Google Scholar
  40. 40.
    Rothe H, Hausmann A, Casteels K, Okamura H, Kurimoto M, Burkart V, Mathieu C, Kolb H. IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. J Immunol 1999;163:1230–1236.Google Scholar
  41. 41.
    Mandrup-Poulsen T, Nerup J, Reimers JI, Pociot F, Andersen HU, Karlsen A, Bjerre U, Bergholdt R. Cytokines and the endocrine system. I. The immunoendocrine network. Eur J Endocrinol 1995;133:660–671.Google Scholar
  42. 42.
    Ramirez F, Fowell DJ, Puklavec M, Simmonds S, Mason D. Glucocorticoids promote a Th2 cytokine response by CD4+ T cells in vitro. J Immunol 1996;156:2406–2412.Google Scholar
  43. 43.
    Blotta MH, DeKruyff RH, Umetsu DT. Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes. J Immunol 1997;158:5589–5595.Google Scholar
  44. 44.
    Wilson CA, Jacobs C, Baker P, Baskin DG, Dower S, Lernmark Å, Toivola B, Vertrees S, Wilson D. IL-1β modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat. J Immunol 1990;144:3784–3788.Google Scholar
  45. 45.
    Scott P. IL-12: Initiation cytokine for cell-mediated immunity. Science 1993;260:496–497.Google Scholar
  46. 46.
    Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L. Interleukin-12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 1995;181:817–821.Google Scholar
  47. 47.
    O'Hara RM, Henderson SL, Nagelin AM. Prevention of a Th1 disease by a Th1 cytokine: IL-12 and diabetes in NOD mice. Ann NY Acad Sci 1996;795:241–249.Google Scholar
  48. 48.
    Balasa B, Davies DJ, Lee J, Good A, Yeung BT, Sarvetnick N. Interleukin-10 impacts on autoimmune diabetes via a CD8+ T cell pathway circumventing the requirement for CD4+ T-and Blymphocytes. J Immunol 1998;161:4420–4427.Google Scholar
  49. 49.
    Zheng XX, Steele AW, Hancock WW, Stevens AC, Nickerson PW, Roy-Chaudhury P, Tian Y, Strom TB. A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice. J Immunol 1997;158:4507–4513.Google Scholar
  50. 50.
    Yang X-D, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, McDevitt HO. Effect of tumor necrosis factor α on insulindependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med 1994;180:995–1004.Google Scholar
  51. 51.
    Cope AP, Liblau RS, Yang X-D, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997;185:1573–1584.Google Scholar
  52. 52.
    Rabinovitch A, Suarez-Pinzon WL, Sorenson O, Rajotte RV, Power RF. TNF-α down-regulates type 1 cytokines and prolongs survival of syngeneic islet grafts in nonobese diabetic mice. J Immunol 1997;159:6298–6303.Google Scholar
  53. 53.
    Piccirillo CA, Chang Y, Prud'homme GJ. TGF-β1 somatic gene therapy prevents autoimmune disease in nonobese diabetic mice. J Immunol 1998;161:3950–3956.Google Scholar
  54. 54.
    Gallichan WS, Katri T, Krahl T, Verma IM, Sarvetnick N. Lentivirusmediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis. Hum Gene Ther 1998;9:2717–2726.Google Scholar
  55. 55.
    Suarez-Pinzon WL, Marcoux Y, Ghahary A, Rabinovitch A. Gene transfection and expression of transforming growth factor-β1 in nonobese diabetic mouse islets protects β-cells in syngeneic islet grafts from autoimmune destruction. Cell Transplantation 2002;11:519–528.Google Scholar
  56. 56.
    Trembleau S, Penna G, Gregori S, Chapman HD, Serreze DV, Magram J, Adorini L. Pancreas-infiltrating Th1 cells and diabetes develop in IL-12–deficient nonobese diabetic mice. J Immunol 1999;163:2960–2968.Google Scholar
  57. 57.
    Hultgren B, Huang X, Dybdal N, Stewart TA. Genetic absence of γ-interferon delays but does not prevent diabetes in NOD mice. Diabetes 1996;45:812–817.Google Scholar
  58. 58.
    Rothe H, O'Hara RM Jr, Martin S, Kolb H. Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2. Diabetologia 1997;40:641–646.Google Scholar
  59. 59.
    Yasuda H, Nagata M, Arisawa K, Yoshida R, Fujihira K, Okamoto N, Moriyama H, Masatoshi M, Saito I, Hamada H, Yokono K, Kasuga M. Local expression of immunoregulatory IL-12p40 gene prolonged syngeneic islet graft survival in diabetic NOD mice. J Clin Invest 1998;102:1807–1814.Google Scholar
  60. 60.
    Campbell IL, Kay TWH, Oxbrow L, Harrison LC. Essential role for interferon-gamma and interleukin-6 in autoimmune insulindependent diabetes in NOD/Wehi mice. J Clin Invest 1991;87:739–742.Google Scholar
  61. 61.
    Debray-Sachs M, Carnaud C, Boitard C, Cohen H, Gresser I, Bedossa P, Bach JF. Prevention of diabetes in NOD mice treated with antibody to murine IFN-γ. J Autoimmun 1991;4:237–248.Google Scholar
  62. 62.
    Nicoletti F, Zaccone P, Di Marco R, Lunetta M, Magro G, Crasso S, Meroni PL, Garotta G. Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-γ antibody. Endocrinology 1997;138:281–288.Google Scholar
  63. 63.
    Nicoletti F, Zaccone P, Di Marco R, Di Mauro M, Magro G, Grasso S, Mughini L, Meroni P, Garotta G. The effects of a nonimmunogenic form of murine soluble interferon-γ receptor on the development of autoimmune diabetes in the NOD mouse. Endocrinology 1996;137:5567–5575.Google Scholar
  64. 64.
    Varela-Calvino R, Ellis R, Sgardi G, Dayan CM, Peakman M. Characterization of the T-cell response to coxsackievirus B4, evidence that effector memory cells predominate in patients with type 1 diabetes. Diabetes 2002;51:1745–1753.Google Scholar
  65. 65.
    Hänninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simell O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 1992;90:1901–1910.Google Scholar
  66. 66.
    Itoh N, Hanafusa T, Miyazaki A, Miyagawa J, Yamagata K, Yamamoto K, Waguri M, Imagawa A, Tamura S, Inada M. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 1993;92:2313–2322.Google Scholar
  67. 67.
    Stassi G, De Maria R, Trucco G, Rudert W, Testi R, Galluzzo A, Giordano C, Trucco M. Nitric oxide primes pancreatic ß-cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med 1997;186:1193–1200.Google Scholar
  68. 68.
    Cavallo MG, Pozzilli P, Bird C, Wadhwa M, Meager A, Visalli N, Gearing AJ, Adreani D, Thorpe R. Cytokines in sera from insulin-dependent diabetic patients at diagnosis. Clin Exp Immunol 1991;86:256–259.Google Scholar
  69. 69.
    Ciampolillo A, Guastamacchia E, Caragiulo L, Lollino G, De Robertis O, Lattanzi V, Giorgino R. In vitro secretion of interleukin-1 beta and interferon-gamma by peripheral blood lymphomononuclear cells in diabetic patients. Diabetes Res Clin Pract 1993;21:87–93.Google Scholar
  70. 70.
    Kallmann BA, Hüther M, Tubes M, Feldkamp J, Bertrams J, Gries FA, Lampeter EF, Kolb H. Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. Diabetes 1997;46:237–243.Google Scholar
  71. 71.
    Rapoport MJ, Mor A, Vardi P, Ramot Y, Winker R, Hindi A, Bistritzer T. Decreased secretion of Th2 cytokines precedes upregulated and delayed secrtion of Th1 cytokines in activated peripheral blood mononuclear cells from patients with insulin-dependent diabetes mellitus. J Autoimmun 1998;11:635–642.Google Scholar
  72. 72.
    Berman MA, Sandborg CI, Wang Z, Imfeld KL, Zaldivar F Jr, Dadufalza V, Buckingham BA. Decreased IL-4 production in new onset type 1 insulin-dependent diabetes mellitus. J Immunol 1996;157:4690–4696.Google Scholar
  73. 73.
    Hussain MJ, Peakman M, Gallati H, Lo SS, Hawa M, Viberti GC, Watkins PJ, Leslie RD, Vergani D. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia 1996;39:60–69.Google Scholar
  74. 74.
    Hussain MJ, Maher J, Warnock T, Vats A, Peakman M, Vergani D. Cytokine overproduction in healthy first degree relatives of patients with IDDM. Diabetologia 1998;41:343–349.Google Scholar
  75. 75.
    Karlsson MGE, Sederholm Lawesson S, Ludvigsson J. Th1-like dominance in high-risk first-degree relatives of type 1 diabetic patients. Diabetologia 2000;43:742–749.Google Scholar
  76. 76.
    Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA. Extreme Th1 bias of regulatory V-α24J-αQ T cells in type 1 diabetes. Nature 1998;391:177–181.Google Scholar
  77. 77.
    Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, Pocelli S, Maclaren N. Multiple immunoregulatory defects in type 1 diabetes. J Clin Invest 2002;109:131–140.Google Scholar
  78. 78.
    Halminen M, Simell O, Knip M, Ilonen J. Cytokine expression in unstimulated PBMC of children with type 1 diabetes and subjects positive for diabetes-associated antibodies. Scand J Immunol 2001;53:510–513.Google Scholar
  79. 79.
    Lee PT, Putnan A, Benlagha K, Teyton L, Gottlieb PA, Bendelac A. Testing the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest 2002;110:793–800.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Alex Rabinovitch
    • 1
  • Wilma L. Suarez-Pinzon
    • 1
  1. 1.University of AlbertaEdmontonCanada

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