Immunologic Research

, Volume 30, Issue 3, pp 309–325 | Cite as

Manipulating the type 1 vs type 2 balance in type 1 diabetes

  • Urs Christen
  • Mathias G. von Herrath


Virus infections cause a strong inflammatory reaction that is dominated by the expression of type 1 cytokines and chemokines. Such an aggressive immune response by the host is necessary to eliminate intracellular pathogens. However, because of this shift in the type 1 vs type 2 balance of the immune response, virus infections are potential candidates for triggering autoimmune diseases, such as type 1 diabetes (T1D), herpes stromal keratitis, or multiple sclerosis (MS). In this review we will focus on the pathogenesis of T1D in a virus-induced transgenic mouse model and discuss possibilities of how an aggressive type 1-dominated immune response can be restrained and autoimmunity be abrogated.

Key Words

Chemokines cytokines CXCL10 TNFα LCMV autoimmunity inflammation 


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  1. 1.
    Mosmann TR, Coffman RL: Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145–173.PubMedGoogle Scholar
  2. 2.
    Mosmann TR, Sad S: The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996;17:138–146.PubMedGoogle Scholar
  3. 3.
    Peritt D, Robertson S, Gri G, Showe L, Aste-Amezaga M, Trinchieri G, et al.: Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol 1998;161:5821–5824.PubMedGoogle Scholar
  4. 4.
    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al.: Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194:863–869.PubMedGoogle Scholar
  5. 5.
    Liu YJ, Kanzler H, Soumelis V, Gilliet M: Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2001;2:585–589.PubMedGoogle Scholar
  6. 6.
    Murphy KM, Ouyang W, Farrar JD, Yang J, Ranganath S, Asnagli H, et al.: Signaling and transcription in T helper development. Annu Rev Immunol 2000;18:451–494.PubMedGoogle Scholar
  7. 7.
    Ho IC, Hodge MR, Rooney JW, Glimcher LH: The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 1996;85:973–983.PubMedGoogle Scholar
  8. 8.
    Zheng W, Flavell RA: The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997;89:587–596.PubMedGoogle Scholar
  9. 9.
    Zhang DH, Cohn L, Ray P, Bottomly K, Ray A: Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 1997;272:21597–21603.PubMedGoogle Scholar
  10. 10.
    Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM: Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 1998;9:745–755.PubMedGoogle Scholar
  11. 11.
    Lee HJ, Takemoto N, Kurata H, Kamogawa Y, Miyatake S, O'Garra A, Arai N: GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J Exp Med 2000;192:105–115.PubMedGoogle Scholar
  12. 12.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH: A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100:655–669.PubMedGoogle Scholar
  13. 13.
    Szabo SJ, Sullivan BM, Peng SL, Glimcher LH: Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003;21:713–758.PubMedGoogle Scholar
  14. 14.
    Loza MJ, Perussia B: Final steps of natural killer cell maturation: a model for type 1-type 2 differentiation? Nat Immunol 2001;2:917–924.PubMedGoogle Scholar
  15. 15.
    O'Garra A, McEvoy LM, Zlotnik A: T-cell subsets: chemokine receptors guide the way. Curr Biol 1998; 8:R646–649.PubMedGoogle Scholar
  16. 16.
    Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity 2000; 12:121–127.PubMedGoogle Scholar
  17. 17.
    Sallusto F, Lanzavecchia A, Mackay CR: Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today 1998;19:568–574.PubMedGoogle Scholar
  18. 18.
    Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM: CCR5 is characteristic of Th1 lymphocytes. Nature 1998;391:344–345.PubMedGoogle Scholar
  19. 19.
    Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, et al.: Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998;187:129–134.PubMedGoogle Scholar
  20. 20.
    D'Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A, Sinigaglia F: Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol 1998;161:5111–5115.PubMedGoogle Scholar
  21. 21.
    Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J, et al.: Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol 1999;11:81–88.PubMedGoogle Scholar
  22. 22.
    Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature 1996;383:787–793.PubMedGoogle Scholar
  23. 23.
    Yoon J-W: The role of viruses and environmental factors in the induction of diabetes. Curr Top Microbiol Immunol 1990;164:95–123.PubMedGoogle Scholar
  24. 24.
    Notkins AL, Yoon J-W. Virus-induced diabetes mellitus, in Concepts in Viral Pathogenesis. Notkins AL, Oldstone MBA, eds. Springer-Verlag New York, 1984, pp. 241–247.Google Scholar
  25. 25.
    Menser MA, Forrest JM, Bransby RD: Rubella infection and diabetes mellitus. Lancet 1978;1:57–60.PubMedGoogle Scholar
  26. 26.
    Zhao ZS, Granucci F, Yeh L, Schaffer PA, Cantor H: Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection [see comments]. Science 1998;279:1344–1347.PubMedGoogle Scholar
  27. 27.
    Fujinami RS, Oldstone MB: Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985;230:1043–1045.PubMedGoogle Scholar
  28. 28.
    Ohashi P, Oehen S, Buerki K, Pircher H, Ohashi C, Odermatt B, et al.: Ablation of tolerance and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991;65:305–317.PubMedGoogle Scholar
  29. 29.
    Oldstone MBA, Nerenberg M, Southern P, Price J, Lewicki H: Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: Role of antiself (virus) immune response. Cell 1991;65:319–331.PubMedGoogle Scholar
  30. 30.
    von Herrath MG, Fujinami RS, Whitton JL: Microorganisms and autoimmunity: making the barren field fertile. Nat Rev Microbiol 2003;1:151–157.Google Scholar
  31. 31.
    von Herrath MG, Oldstone MBA: Interferon-γ is essential for destruction of β-cells and development of insulin-dependent diabetes mellitus. J Exp Med 1997; 185:531–539.Google Scholar
  32. 32.
    Liblau RS, Singer SM, McDevitt H: Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol. Today 1995;16:34–38.PubMedGoogle Scholar
  33. 33.
    Christen U, Wolfe T, Mohrle U, Hughes AC, Rodrigo E, Green EA, et al.: A dual role for TNF-alpha in type 1 diabetes: islet-specific expression abrogates the ongoing autoimmune process when induced late but not early during pathogenesis. J Immunol 2001;166:7023–7032.PubMedGoogle Scholar
  34. 34.
    Christen U, McGavern DB, Luster AD, von Herrath MG, Oldstone MB: Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL 10) but not monokine induced by IFN-gamma (CXCL 9) imprints a pattern for the subsequent development of autoimmune disease. J Immunol 2003;171:6838–6845.PubMedGoogle Scholar
  35. 35.
    Charlton B, Lafferty KJ: The Th1/Th2 balance in autoimmunity. Curr Opin Immunol 1995;7:793–798.PubMedGoogle Scholar
  36. 36.
    Han HS, Jun HS, Utsugi T, Yoon J-W: Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T-cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice. J Autoimmun 1997;10:299–307.PubMedGoogle Scholar
  37. 37.
    Haneda K, Sano K, Tamura G, Sato T, Habu S, Shirato K: TGF-β induced by oral tolerance ameliorates experimental tracheal eosinophilia. J Immunol 1997;159:4686–4690.Google Scholar
  38. 38.
    von Herrath MG, Homann D, Gairin JE, Oldstone MBA: Pathogenesis and treatment of virus-induced autoimmune diabetes: novel insights gained from RIP-LCMV transgenic mouse model. Biochemical Society Transactions 1997;25:630–635.Google Scholar
  39. 39.
    Gianani R, Sarvetnick N: Viruses, cytokines, antigens, and autoimmunity. Proc Natl Acad Sci USA 1996;93:2257–2259.PubMedGoogle Scholar
  40. 40.
    Lafaille JJ, Van de Kerre F, Hsu AL, Baron JL, Haas W, Raine CS, Tonegawa S: Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J Exp Med 1997;186:307–312.PubMedGoogle Scholar
  41. 41.
    McSorley SJ, Soldera S, Malherbe L, Carnaud C, Locksley RM, Flavell RA, Glaichenhaus N: Immunological tolerance to a pancreatic antigen as a result of local expression of TNFα by islet β cells. Immunity 1997;7:401–409.PubMedGoogle Scholar
  42. 42.
    Rabinovitch A, Suarez-Pinzon WL, Sorensen 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.PubMedGoogle Scholar
  43. 43.
    Garside P, Steel M, Worthey A, Satoskar A, Alexander J, Bluethmann H, et al.: T helper 2 cells are subject to high dose oral tolerance and are not essential for its induction. J Immunol 1995;154:5649–5655.PubMedGoogle Scholar
  44. 44.
    Christen U, Benke D, Wolfe T, Rhode A, Hughes AC, Oldstone MBA, von Herrath MG: Old players at a new game: cure of pre-diabetic mice by viral infection, through a TNFα and IFNγ dependent mechanism. J Clin Invest 2004;113:74–84.PubMedGoogle Scholar
  45. 45.
    Christen U, Von Herrath MG: Apoptosis of autoreactive CD8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific TNF-alpha expression at a time when the autoimmune process in already ongoing. Ann NY Acad Sci 2002;958:166–169.PubMedGoogle Scholar
  46. 46.
    von Herrath MG, Harrison LC: Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 2003;3:223–232.Google Scholar
  47. 47.
    Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y: Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 1980;29:1–13.PubMedGoogle Scholar
  48. 48.
    Delovitch TL, Singh B: The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 1997;7:727–738.PubMedGoogle Scholar
  49. 49.
    Wong FS, Janeway CA, Jr: Insulin-dependent diabetes mellitus and its animal models. Curr Opin Immunol 1999;11:643–647.PubMedGoogle Scholar
  50. 50.
    Rabinovitch A: An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1998;14:129–151.PubMedGoogle Scholar
  51. 51.
    Sarvetnick N, Shizuru J, Liggitt D, Martin L, McIntyre B, Gregory A, et al.: Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature 1990;346:844–847.PubMedGoogle Scholar
  52. 52.
    Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA: Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 1988;52:773–782.PubMedGoogle Scholar
  53. 53.
    Allison J, Oxbrown L, Miller JF: Consequences of situ production of IL-2 for islet cell death. Int Immunol 1994;6:541–549.PubMedGoogle Scholar
  54. 54.
    von Herrath MG, Allison J, Miller JF, Oldstone MBA: Focal expression of interleukin-2 does not break unreponsiveness to “self” (viral) antigen expressed in beta-cells but enhances development of atoimmune disease (diabetes) after initiation of an anti-self immune response. J Clin Invest 1995;95:477–485.Google Scholar
  55. 55.
    Guerder S, Picarella DE, Linsley PS, Flavell RA: Cos-timulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc Natl Acad Sci USA 1994;91:5138–5142.PubMedGoogle Scholar
  56. 56.
    Green EA, Wong FS, Eshima K, Mora C, Flavell RA: Neonatal tumor necrosis factor alpha promotes diabetes gen presentation to CD8(+) T cells. J Exp Med 2000;191:225–238.PubMedGoogle Scholar
  57. 57.
    Green EA, Eynon EE, Flavell RA: Local expression of TNFα in neonatal NOD mice promotes diabetes by enhancing presentation of islet antigens. Immunity 1998;9:733–743.PubMedGoogle Scholar
  58. 58.
    Allison J, McClive P, Oxbrow L, Baxter A, Morahan G, Miller JF: Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta-cells. Eur J Immunol 1994;24:2535–2541.PubMedGoogle Scholar
  59. 59.
    Sanvito F, Nichols A, Herrera PL, Huarte J, Wohlwend A, Vassalli JD, Orci L: TGF-beta I overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Commun 1995;217:1279–1286.PubMedGoogle Scholar
  60. 60.
    Mueller RT, Sarvetnick N: Pancreatic expression of IL-4 abrogates insulitis and diabetes in NOD mice. J Exp Med 1996;184:1093–1099.PubMedGoogle Scholar
  61. 61.
    Mueller R, Bradley LM, Krahl T, Sarvetnick N: Mechanism underlying counterregulation of autoimmune diabetes by IL-4. Immunity 1997;7:411–418.PubMedGoogle Scholar
  62. 62.
    Gallichan WS, Balasa B, Davies JD, Sarvetnick N: Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J Immunol 1999;163:1696–1703.PubMedGoogle Scholar
  63. 63.
    Moritani M, Yoshimoto K, Wong SF, Tanaka C, Yamaoka T, Sano T, et al.: Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-betal. J Clin Invest 1998;102:499–506.PubMedGoogle Scholar
  64. 64.
    Grewal IS, Grewal KD, Wong S, Picarella DE, Janeway CA, Flavell RA: Local expression of transgene encoded TNF alpha in islets prevets autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. J Exp Med 1996;184:1963–1974.PubMedGoogle Scholar
  65. 65.
    Wogensen L, Lee MS, Sarvetnick N: Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice. J Exp Med 1994;179:1379–1384.PubMedGoogle Scholar
  66. 66.
    Balasa B, D. DJ, Lee J, Good A, Yeung BT, Sarvetnick N: IL-10 impacts autoimmune diabetes via a CD8+T cell pathway circumventing the requirement for CD4+ T and B lymphocytes. J Immunol 1998;161:4420–4427.PubMedGoogle Scholar
  67. 67.
    Balasa B, Van Gunst K, Jung N, Balakrishna D, Santamaria P, Hanafusa T, et al.: Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-I, and TNF receptor-2 molecules. J Immunol 2000;165:2841–2849.PubMedGoogle Scholar
  68. 68.
    Lo D, Freedman J, Hesse S, Palmiter RD, Brinster RL, Sherman LA: Peripheral tolerance to an islet cell-specific hemagglutinin transgene affects both CD4+ and CD8+T cells. Eur Immunol 1992;22:1013–1022.Google Scholar
  69. 69.
    Lo D, Reilly CR, Scott B, Liblau R, McDevitt HO, Burkly LC: Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes. Eur J Immunol 1993;23:1693–1698.PubMedGoogle Scholar
  70. 70.
    Seewaldt S, Thomas H, Ejrnaes M, Christen U, Wolfe T, Rodrigo E, et al.: Virus-induced autoimmune diabetes: most b-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) CTL. Diabetes 2000;49:1801–1809.PubMedGoogle Scholar
  71. 71.
    Degermann S, Reilly C, Scott B, Ogata L, von Boehmer H, Lo D: On the various manifestations of spontaneous autoimmune diabetes in rodent models. Eur J Immunol 1994;24:3155–3160.PubMedGoogle Scholar
  72. 72.
    Scott B, Liblau R, Degermann S, Marconi LA, Ogata L, Caton AJ, et al.: A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity 1994;1:73–83.PubMedGoogle Scholar
  73. 73.
    Sarukhan A, Lanoue A, Franzke A, Brousse N, Buer J, von Boehmer H: Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model. Embo J 1998;17:71–80.PubMedGoogle Scholar
  74. 74.
    Yoon JW: A new look at viruses in type 1 diabetes. Diabetes Metab Rev 1995;11:83–107.PubMedCrossRefGoogle Scholar
  75. 75.
    Patterson K, Chandra RS, Jenson AB: Congenital rubella, insulitis, and diabetes mellitus in an infant [lett]. Lancet 1981;1:1048–1049.PubMedGoogle Scholar
  76. 76.
    Oldstone MBA: Molecular mimicry as a mechanism for the cause and as a probe uncovering etiologic agent(s) of autoimmune disease. Curr Top Microbiol Immunol 1989;145:127–136.PubMedGoogle Scholar
  77. 77.
    Oldstone MBA: Molecular mimicry and autoimmune disease. Cell 1987;50:819–820.PubMedGoogle Scholar
  78. 78.
    Tian J, Lehmann PV, Kaufman DL: T cell cross-reactivity between coxsackievirus and glutamate decarboxylase is associated with a murine diabetes susceptibility allele. J Exp Med 1994;180:1979–1984.PubMedGoogle Scholar
  79. 79.
    Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK: Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes [see comments]. J Clin Invest 1994;94:2125–2129PubMedGoogle Scholar
  80. 80.
    Oldstone MB: Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 1988;239:500–502.PubMedGoogle Scholar
  81. 81.
    Oldstone MB: Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence. J Exp Med 1990;171:2077–2089.PubMedGoogle Scholar
  82. 82.
    Kappler JW, Roehn N, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 1987;49:273–280.PubMedGoogle Scholar
  83. 83.
    Kisielow P, Bluthmann H, Staerz UD, Steinmetz M, von Bohemer H: Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+thymocytes. Nature 1988;333:742–746.PubMedGoogle Scholar
  84. 84.
    Schwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349–1356.PubMedGoogle Scholar
  85. 85.
    Sprent J, Gao EK, Webb SR: T cell reactivity to MHC molecules: immunity versus tolerance. Science 1990;248:1357–1363.PubMedGoogle Scholar
  86. 86.
    von Herrath MG, Dockter J, Oldstone MBA: How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1994;1:231–242.Google Scholar
  87. 87.
    Loestcher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, et al.: Chemokine receptor specific for IP10 and Mig: Structure, function, and expression in activated lymphocytes. J Exp Med 1996;184:963–969.Google Scholar
  88. 88.
    Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Hollander GA, Piali L: beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 2002;8:1414–1420.PubMedGoogle Scholar
  89. 89.
    Baggiolini M, Dewald B, Moser B: Human chemokines: an update. Annu Rev Immunol 1997;15:675–705.PubMedGoogle Scholar
  90. 90.
    Luster AD: Chemokines: chemtactic cytokines that mediate inflammation. N Engl J Med 1998;338:436–445.PubMedGoogle Scholar
  91. 91.
    Rossi D, Zlotnik A: The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:217–242.PubMedGoogle Scholar
  92. 92.
    Sallusto F, Mackay CR, Lanzavecchia A: The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 2000;18:593–620.PubMedGoogle Scholar
  93. 93.
    Fife BT, Kennedy KJ, Paniagua MC, Lukacs NW, Kunkel SL, Luster AD, Karpus WJ: CXCL10 (IFN-gamma-inducible protein-10) control of encephalitogenic CD4+T cell accumulation in the central nervous system during experimental autoimmune encepha lomyelitis. J Immunol 2001;166:7617–7624.PubMedGoogle Scholar
  94. 94.
    Wildbaum G, Netzer N, Karin N: Plasmid DNA encoding IFN-gamma-inducible protein 10 redirects antigen-specific T cell polarization and suppresses experimental autoimmune encephalomyelitis. J Immunol 2002;168:5885–5892.PubMedGoogle Scholar
  95. 95.
    Narumi S, Kaburaki T, Yoneyama H, Iwamura H, Kobayashi Y, Matsushima K: Neutralization of IFN-inducible protein 10/CXCL10 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol 2002;32:1784–1791.PubMedGoogle Scholar
  96. 96.
    Liu MT, Keirstead HS, Lane TE: Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. J Immunol 2001;167:4091–4097.PubMedGoogle Scholar
  97. 97.
    Salomon I, Netzer N, Wildbaum G, Schif-Zuck S, Maor G, Karin N: Targeting the function of IFN-gamma-inducible protein 10 suppresses ongoing adjuvant arthritis. J Immunol 2002;169:2685–2693.PubMedGoogle Scholar
  98. 98.
    Hancock WW, Gao W, Faia KL, Csizmadia V: Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000;12:511–516.PubMedGoogle Scholar
  99. 99.
    Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, et al.: Requirement of the chemokine receptor CXCR 3 for acute allograft rejection. J Exp Med 2000;192:1515–1520.PubMedGoogle Scholar
  100. 100.
    Kapoor A, Morita K, Engeman TM, Koga S, Vapnek EM, Hobart MG, Fairchild RL: Early expression of interferon-gamma inducible protein 10 and monokine induced by interferon-gamma in cardiac allografts is mediated by CD8+ T cells. Transplantation 2000; 69:1147–1155.PubMedGoogle Scholar
  101. 101.
    Meyer M, Hensbergen PJ, van der Raaij-Helmer FM, Brandacher G, Margreiter R, Heufler C, et al.: Cross reactivity of three T cell attracting murine chemokines stimulating the CXC chemokine receptor CXCR3 and their induction in cultured cells and during allograft rejection. Eur J Immunol 2001;31:2521–2527.PubMedGoogle Scholar
  102. 102.
    Morita K, Miura M, Paolone DR, Engeman TM, Kapoor A, Remick DG, Fairchild RL: Early chemokine cascades in murine cardiac grafts regulate T cell recruitment and progression of acute allograft rejection. J Immunol 2001;167:2979–2984.PubMedGoogle Scholar
  103. 103.
    Goddard S, Williams A, Morland C, Qin S, Gladue R, Hubscher SG, Adams DH: Differential expression of chemokines and chemokine receptors shapes the inflammatory response in rejecting human liver transplants. Transplantation 2001;72:1957–1967.PubMedGoogle Scholar
  104. 104.
    Yamagami S, Miyazaki D, Ono SJ, Dana MR: Differential chemokine gene expression in corneal transplant rejection. Invest Ophthalmol Vis Sci 1999;40:2892–2897.PubMedGoogle Scholar
  105. 105.
    Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins KL, Mack M, et al.: Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis 2001;37:518–531.PubMedCrossRefGoogle Scholar
  106. 106.
    Agostini C, Calabrese F, Rea F, Facco M, Tosoni A, Loy M, et al.: Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. Am J Pathol 2001;158:1703–1711.PubMedGoogle Scholar
  107. 107.
    Koga S, Auerbach MB, Engeman TM, Novick AC, Toma H, Fairchild RL: T cell infiltration into class II MHC-disparate allografts and acute rejection is dependent on the IFN-gamma-induced chemokine Mig. J Immunol 1999;163:4878–4885.PubMedGoogle Scholar
  108. 108.
    Watarai Y, Koga S, Paolone DR, Engeman TM, Tannenbaum C, Hamilton TA, Fairchild RL: Intraallograft chemokine RNA and protein during rejection of MHC-matched/multiple minor histocompatibility-disparate skin grafts. J Immunol 2000;164:6027–6033.PubMedGoogle Scholar
  109. 109.
    Melter M, Exeni A, Reinders ME, Fang JC, McMahon G, Ganz P, Hancock WW, Briscoe DM: Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection. Circulation 2001;104:2558–2564.PubMedGoogle Scholar
  110. 110.
    Luster AD, Ravetch JV: Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med 1987;166:1084–1097.PubMedGoogle Scholar
  111. 111.
    Vanguri P, Farber JM: Identification of CRG-2: an interferone-inducible mRNA predicted to encode a murine monokine. J Biol Chem 1990;265:15049–15057.PubMedGoogle Scholar
  112. 112.
    Green EA, Flavell RA: The temporal importance of TNFalpha expression in the development of diabetes. Immunity 2000;12:459–469.PubMedGoogle Scholar
  113. 113.
    Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, et al.: Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997;185:1573–1584.PubMedGoogle Scholar
  114. 114.
    Yang X-D, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, McDevitt HO: Effect of tumour necrosis factor α on insulin-dependent diabetes mellitus in NOD mice: I. the early development of autoimmunity and the diabetogenic process. J Exp Med 1994;180:995–1004.PubMedGoogle Scholar
  115. 115.
    Jacob CO, Aiso S, Michie SA, McDevitt HO, Acha-Orbea H: Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. Proc Natl Acad Sci USA 1990;87:968–972.PubMedGoogle Scholar
  116. 116.
    Jacob CO, Aiso S, Schreiber RD, McDevitt HO: Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development. Int Immunol 1992;4:611–614.PubMedGoogle Scholar
  117. 117.
    Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Luebbert H, Bujard H: Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 1996;93:10933–10938.PubMedGoogle Scholar
  118. 118.
    Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL: Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001;108:63–72.PubMedGoogle Scholar
  119. 119.
    Palombella VJ, Rando OJ, Goldberg AL, Maniatis T: The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994;78:773–785.PubMedGoogle Scholar
  120. 120.
    Homann D, Holz A, Bot A, Coon B, Wolfe T, Petersen J, et al.: Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. Immunity 1999;11:463–472.PubMedGoogle Scholar
  121. 121.
    Bergerot I, Fabien N, Mayer A, Thivolet C: Active suppression of diabetes after oral administration of insulin is determined by antigen dosage. Ann NY Acad Sci 1996;778:362–367.PubMedGoogle Scholar
  122. 122.
    Komagata Y, Weiner HL: Oral tolerance. Rev Immunogenet 2000;2:61–73.PubMedGoogle Scholar
  123. 123.
    Zang JA, Davidson L, Eisenbarth G, Weiner H: Suppression of diabetes in NOD mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 1991;88:10252.Google Scholar
  124. 124.
    von Herrath MG, Dyrberg T, Oldstone MBA: Oral insulin treatment suppresses virus-induced antigen-specific destruction of β-cells and prevents autoimmune diabetes in transgenic mice. J Clin Invest 1996;98:1324–1331.CrossRefGoogle Scholar
  125. 125.
    Seifarth C, Pop S, Liu B, Wong CP, Tisch R: More stringent conditions of plasmid DNA vaccination are required to protect grafted versus endogenous islets in nonobese diabetic mice. J Immunol 2003;171:469–476.PubMedGoogle Scholar
  126. 126.
    Coon B, An L-L, Whitton JL, von Herrath MG: DNA immunization to prevent autoimmune diabetes. J Clin Invest 1999;104:189–194.PubMedGoogle Scholar
  127. 127.
    Wolfe T, Bot A, Hughes A, Mohrle U, Rodrigo E, Jaume JC, et al.: Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety. Eur J Immunol 2002;32:113–121.PubMedGoogle Scholar
  128. 128.
    Weaver DJ, Jr., Liu B, Tisch R: Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice. J Immunol 2001;167:586–592.PubMedGoogle Scholar
  129. 129.
    Tisch R, Wang B, Weaver DJ, Liu B, Bui T, Arthos J, Serreze DV: Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination. J Immunol 2001;166:2122–2132.PubMedGoogle Scholar
  130. 130.
    King C, Mueller Hoenger R, Malo Cleary M, Murali-Krishna K, Ahmed R, King E, Sarvetnick N: Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nat Med 2001;7:206–214.PubMedGoogle Scholar
  131. 131.
    Kawamoto S, Nitta Y, Tashiro F, Nakano A, Yamato E, Tahara H, et al.: Suppression of T(h)1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10. Int Immunol 2001;13:685–694.PubMedGoogle Scholar
  132. 132.
    Lee M, Ko KS, Oh S, Kim SW: Prevention of autoimmune insulitis by delivery of a chimeric plasmid encoding interleukin-4 and interleukin-10. J Control Release 2003;88:333–342.PubMedGoogle Scholar
  133. 133.
    Zhang YC, Pileggi A, Agarwal A, Molano RD, Powers M, Brusko T, et al.: Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice. Diabetes 2003;52:708–716.PubMedGoogle Scholar
  134. 134.
    Lee MS, Wogensen L, Shizuru J, Oldstone MB, Sarvetnick N: Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction. J Clin Invest 1994;93:1332–1338.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Urs Christen
    • 1
  • Mathias G. von Herrath
    • 1
  1. 1.Dept of Developmental ImmunologyLa Jolla Institute for Allergy and ImmunologySan Diego

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