Immunomodulation and regeneration of islet beta cells by cytokines in autoimmune type 1 diabetes

Journal of Interferon and Cytokine Research

Volumn 31, Issue 10, 2011, Pages 711-719

  Singh, Bhagirath ^a   Nikoopour, Enayat ^a   Huszarik, Katrina ^a   Elliott, John F ^b   Jevnikar, Anthony M ^a,c  

^a UNIVERSITY OF WESTERN ONTARIO   (Canada)

^b UNIVERSITY OF ALBERTA   (Canada)

^c LONDON HEALTH SCIENCES CENTRE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; BETA INTERFERON; CD4 ANTIGEN; CD8 ANTIGEN; CYTOKINE; GAMMA INTERFERON; GRANULOCYTE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 17; INTERLEUKIN 18; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 27; INTERLEUKIN 4; PEPTIDES AND PROTEINS; REGENERATING PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL POPULATION; CELL REGENERATION; HUMAN; IMMUNOMODULATION; IMMUNOTHERAPY; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; MYCOBACTERIUM; NATURAL KILLER T CELL; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; TH17 CELL;

ADAPTIVE IMMUNITY; ANIMALS; APOPTOSIS; AUTOIMMUNITY; DIABETES MELLITUS, TYPE 1; HUMANS; IMMUNITY, INNATE; IMMUNOMODULATION; INSULIN-SECRETING CELLS; INTERLEUKINS; MICE; MICE, INBRED NOD; REGENERATION; TH17 CELLS;

MUS;

EID: 80054698474     PISSN: 10799907     EISSN: 15577465     Source Type: Journal    
DOI: 10.1089/jir.2011.0025     Document Type: Article

References (98)

1. Ablamunits V, Sherry NA, Kushner JA, Herold KC. 2007. Au-toimmunity and beta cell regeneration in mouse and human type 1 diabetes: the peace is not enough. Ann N Y Acad Sci 1103:19-32. (Pubitemid 46791108)
2. Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL. 2001. Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res 21:1047-1053. (Pubitemid 34114283)
3. Anderson MS, Bluestone JA. 2005. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447-485. (Pubitemid 40563177)
4. Bach JF. 1994. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516-542.
5. Baeza N, Sanchez D, Vialettes B, Figarella C. 1997. Specific reg II gene overexpression in the non-obese diabetic mouse pancreas during active diabetogenesis. FEBS Lett 416:364-368. (Pubitemid 27475398)
6. Bending D, De La Pena H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, Cooke A. 2009. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 119:565-572.
7. Boehm BO, Bluestone JA. 2004. Differential roles of costimula-tory signaling pathways in type 1 diabetes mellitus. Rev Diabet Stud 1:156-164.
8. Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, Sharma A. 2010. Beta-cell growth and regeneration: replication is only part of the story. Diabetes 59:2340-2348.
9. Boraschi D, Dinarello CA. 2006. IL-18 in autoimmunity: review. Eur Cytokine Netw 17:224-252.
10. Bray-Sachs M, Carnaud C, Boitard C, Cohen H, Gresser I, Bed-ossa P, Bach JF. 1991. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun 4:237-248.
11. Campbell IL, Oxbrow L, Harrison LC. 1991. Reduction in in-sulitis following administration of IFN-gamma and TNF-alpha in the NOD mouse. J Autoimmun 4:249-262.
12. Chatenoud L, Thervet E, Primo J, Bach JF. 1994. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91:123-127. (Pubitemid 24018655)
13. Chong AS, Shen J, Tao J, Yin D, Kuznetsov A, Hara M, Philipson LH. 2006. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 311:1774-1775.
14. Clough LE, Wang CJ, Schmidt EM, Booth G, Hou TZ, Ryan GA, Walker LS. 2008. Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J Immunol 180:5393-5401.
15. Datta S, Sarvetnick NE. 2008. IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS One 3:e3118.
16. Delovitch TL, Singh B. 1997. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:727-738. (Pubitemid 28064887)
17. Dinarello CA. 2011. Blocking interleukin-1beta in acute and chronic autoinflammatory diseases. J Intern Med 269:16-28.
18. Dugas V, Beauchamp C, Chabot-Roy G, Hillhouse EE, Lesage S. 2010. Implication of the CD47 pathway in autoimmune diabetes. J Autoimmun 35:23-32.
19. Dungan KM, Buse JB, Ratner RE. 2009. Effects of therapy in type 1 and type 2 diabetes mellitus with a peptide derived from islet neogenesis associated protein (INGAP). Diabetes Metab Res Rev 25:558-565.
20. Eldor R, Kassem S, Raz I. 2009. Immune modulation in type 1 diabetes mellitus using DiaPep277: a short review and update of recent clinical trial results. Diabetes Metab Res Rev 25:316-320.
21. Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A, Shapiro AM. 2009. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 58:1302-1311.
22. Esensten JH, Lee MR, Glimcher LH, Bluestone JA. 2009. T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function. J Immunol 183:75-82.
23. Faustman DL, Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Toth ZE, Mezey E. 2006. Comment on papers by Chong and others, Nishio and others, and Suri and others, on diabetes reversal in NOD mice. Science 314:1243.
24. Feuerer M, Shen Y, Littman DR, Benoist C, Mathis D. 2009. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity 31:654-664.
25. Gaudreau S, Guindi C, Menard M, Besin G, Dupuis G, Amrani A. 2007. Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells. J Immunol 179:3638-3647.
26. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O'Shea JJ. 2010. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967-971.
27. Goudy K, Song S, Wasserfall C, Zhang YC, Kapturczak M, Muir A, Powers M, Scott-Jorgensen M, Campbell-Thompson M, Crawford JM, Ellis TM, Flotte TR, Atkinson MA. 2001. Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice. Proc Natl Acad Sci USA 98:13913-13918. (Pubitemid 33115998)
28. Goudy KS, Burkhardt BR, Wasserfall C, Song S, Campbell-Thompson ML, Brusko T, Powers MA, Clare-Salzler MJ, Sobel ES, Ellis TM, Flotte TR, Atkinson MA. 2003. Systemic over-expression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J Immunol 171:2270-2278. (Pubitemid 37025531)
29. Goudy KS, Johnson MC, Garland A, Li C, Samulski RJ, Wang B, Tisch R. 2011. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J Immunol 186:3779-3786.
30. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, Cagnard N, Carpentier W, Tang Q, Bluestone J, Chatenoud L, Klatzmann D, Salomon BL, Piaggio E. 2010a. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med 207:1871-1878.
31. Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Gregoire S, Martin GH, Elhage R, Derian N, Carpentier W, Marodon G, Klatzmann D, Piaggio E, Salomon BL. 2010b. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest 120: 4558-4568.
32. Gross DJ, Weiss L, Reibstein I, van den BJ, Okamoto H, Clark A, Slavin S. 1998. Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immuno-regulation combined with Reg protein treatment. Endocrinology 139:2369-2374. (Pubitemid 28513761)
33. Gurney AL. 2004. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int Immunopharmacol 4:669-677. (Pubitemid 38553887)
34. Gurr W, Shaw M, Li Y, Sherwin R. 2007. RegII is a beta-cell protein and autoantigen in diabetes of NOD mice. Diabetes 56:34-40.
35. Gysemans C, Callewaert H, Overbergh L, Mathieu C. 2008. Cytokine signalling in the beta-cell: a dual role for IFNgamma. Biochem Soc Trans 36:328-333. (Pubitemid 351839325)
36. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA
37. Bluestone JA. 2002. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692-1698. (Pubitemid 34547482)
38. Hillhouse EE, Beauchamp C, Chabot-Roy G, Dugas V, Lesage S. 2010. Interleukin-10 limits the expansion of immunoregula-tory CD4-CD8-T cells in autoimmune-prone non-obese diabetic mice. Immunol Cell Biol 88:771-780.
39. Hultgren B, Huang X, Dybdal N, Stewart TA. 1996. Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes 45:812-817. (Pubitemid 26166778)
40. Huszarik K, Wright B, Keller C, Nikoopour E, Krougly O, Lee-Chan E, Qin HY, Cameron MJ, Gurr WK, Hill DJ, Sherwin RS, Kelvin DJ, Singh B. 2010. Adjuvant immunotherapy increases beta cell regenerative factor Reg2 in the pancreas of diabetic mice. J Immunol 185:5120-5129.
41. Jain R, Tartar DM, Gregg RK, Divekar RD, Bell JJ, Lee HH, Yu P, Ellis JS, Hoeman CM, Franklin CL, Zaghouani H. 2008. Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. J Exp Med 205:207-218. (Pubitemid 351185727)
42. Katz JD, Benoist C, Mathis D. 1995. T helper cell subsets in insulin-dependent diabetes. Science 268:1185-1188.
43. Kaye WA, Adri MN, Soeldner JS, Rabinowe SL, Kaldany A, Kahn CR, Bistrian B, Srikanta S, Ganda OP, Eisenbarth GS. 1986. Acquired defect in interleukin-2 production in patients with type I diabetes mellitus. N Engl J Med 315:920-924. (Pubitemid 16023678)
44. Kim SK, Tarbell KV, Sanna M, Vadeboncoeur M, Warganich T, Lee M, Davis M, McDevitt HO. 2004. Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. Proc Natl Acad Sci USA 101:14204-14209. (Pubitemid 39305054)
45. King C, Ilic A, Koelsch K, Sarvetnick N. 2004. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117:265-277. (Pubitemid 38496245)
46. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. 2003. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 302:1223-1227. (Pubitemid 37421029)
47. 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. J Clin Invest 109:131-140. (Pubitemid 34052549)
48. Lee IF, Qin H, Priatel JJ, Tan R. 2008. Critical role for IFN-gamma in natural killer cell-mediated protection from diabetes. Eur J Immunol 38:82-89.
49. Lee MS, Mueller R, Wicker LS, Peterson LB, Sarvetnick N. 1996. IL-10 is necessary and sufficient for autoimmune diabetes in conjunction with NOD MHC homozygosity. J Exp Med 183:2663-2668. (Pubitemid 26192375)
50. Li B, Wang X, Liu JL. 2010. Pancreatic acinar-specific over-expression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 299:G413-G421.
51. Liu JL, Cui W, Li B, Lu Y. 2008. Possible roles of reg family proteins in pancreatic islet cell growth. Endocr Metab Immune Disord Drug Targets 8:1-10.
52. Liu L, Liu JL, Srikant CB. 2010. Reg2 protects mouse insulinoma cells from streptozotocin-induced mitochondrial disruption and apoptosis. Growth Factors 28:370-378.
53. Luo X, Herold KC, Miller SD. 2010. Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 32:488-499.
54. Mandrup-Poulsen T, Pickersgill L, Donath MY. 2010. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev En-docrinol 6:158-166.
55. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. 2009. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39:216-224.
56. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. 2007. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8:1390-1397. (Pubitemid 350138974)
57. McGuire HM, Vogelzang A, Hill N, Flodstrom-Tullberg M, Sprent J, King C. 2009. Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus. Proc Natl Acad Sci USA 106:19438-19443.
58. McGuire HM, Walters S, Vogelzang A, Lee CM, Webster KE, Sprent J, Christ D, Grey S, King C. 2011. Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models. Diabetes 60:867-875.
59. Nikoopour E, Schwartz JA, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, Singh B. 2010. Th17 polarized cells from non-obese diabetic mice following mycobacterial adjuvant immu-notherapy delay type 1 diabetes. J Immunol 184:4779-4788.
60. Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. 2006. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 311:1775-1778.
61. Nurieva R, Yang XO, Chung Y, Dong C. 2009. Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol 182:2565-2568.
62. Okamoto H, Takasawa S. 2002. Recent advances in the Okamoto model: the CD38-cyclic ADP-ribose signal system and the regenerating gene protein (Reg)-Reg receptor system in beta-cells. Diabetes 51 (Suppl. 3):S462-S473. (Pubitemid 35403431)
63. Phillips JM, O'Reilly L, Bland C,Foulis AK, Cooke A. 2007. Patients with chronic pancreatitis have islet progenitor cells in their ducts, but reversal of overt diabetes in NOD mice by anti-CD3 shows no evidence for islet regeneration. Diabetes 56:634-640. (Pubitemid 46348455)
64. Planas R, Alba A, Carrillo J, Puertas MC, Ampudia R, Pastor X, Okamoto H, Takasawa S, Gurr W, Pujol-Borrell R, Verdaguer J, Vives-Pi M. 2006. Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNbeta. Diabetologia 49:2379-2387. (Pubitemid 44359099)
65. Podolin PL, Wilusz MB, Cubbon RM, Pajvani U, Lord CJ, Todd JA, Peterson LB, Wicker LS, Lyons PA. 2000. Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene? Cytokine 12:477-482. (Pubitemid 30449846)
66. Qin HY, Chaturvedi P, Singh B. 2004. In vivo apoptosis of dia-betogenic T cells in NOD mice by IFN-gamma/TNF-alpha. Int Immunol 16:1723-1732. (Pubitemid 40003860)
67. Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B. 1993. Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. J Immunol 150:2072-2080. (Pubitemid 23129686)
68. Rabinovitch, A. 1993. Roles of cytokines in IDDM pathogenesis and islet beta cell destruction. Diabetes Rev 1:215-240.
69. Rabinovitch A. 1998. An update on cytokines in the pathogen-esis of insulin-dependent diabetes mellitus. Diabetes Metab Rev 14:129-151. (Pubitemid 28346261)
70. Rabinovitch A, Suarez-Pinzon WL. 2007. Roles of cytokines in the pathogenesis and therapy of type 1 diabetes. Cell Biochem Biophys 48:159-163. (Pubitemid 47340882)
71. Rajagopalan G, Kudva YC, Sen MM, Marietta EV, Murali N, Nath K, Moore J, David CS. 2006. IL-10-deficiency unmasks unique immune system defects and reveals differential regulation of organ-specific autoimmunity in non-obese diabetic mice. Cytokine 34:85-95. (Pubitemid 43817556)
72. Rapoport MJ, Jaramillo A, Zipris D, Lazarus AH, Serreze DV, Leiter EH, Cyopick P, Danska JS, Delovitch TL. 1993. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset ofdiabetes innonobese diabetic mice. J Exp Med 178:87-99. (Pubitemid 23173245)
73. Sabatos-Peyton CA, Verhagen J, Wraith DC. 2010. Antigen-specific immunotherapy of autoimmune and allergic diseases. Curr Opin Immunol 22:609-615.
74. Sadelain MW, Qin HY, Lauzon J, Singh B. 1990. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39:583-589. (Pubitemid 20223784)
75. Sekikawa A, Fukui H, Suzuki K, Karibe T, Fujii S, Ichikawa K, Tomita S, Imura J, Shiratori K, Chiba T, Fujimori T. 2010. Involvement of the IL-22/REG Ialpha axis in ulcerative colitis. Lab Invest 90:496-505.
76. Serreze DV, Chapman HD, Post CM, Johnson EA, Suarez-Pinzon WL, Rabinovitch A. 2001. Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimula-tion. J Immunol 166: 1352-1359. (Pubitemid 32060298)
77. Serreze DV, Leiter EH. 1988. Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol 140:3801-3807.
78. Sgouroudis E, Albanese A, Piccirillo CA. 2008. Impact of protective IL-2 allelic variants on CD4 + Foxp3 + regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice. J Immunol 181:6283-6292.
79. Shioya M, Andoh A, Kakinoki S, Nishida A, Fujiyama Y. 2008. Interleukin 22 receptor expression in pancreas islets. Pancreas 36:197-199.
80. Singh B, Prange S, Jevnikar AM. 1998. Protective and destructive effects of microbial infection in insulin-dependent diabetes mellitus. Semin Immunol 10:79-86. (Pubitemid 28108133)
81. Smith DK, Korbutt GS, Suarez-Pinzon WL, Kao D, Rajotte RV, Elliott JF. 1997. Interleukin-4 or interleukin-10 expressed from adenovirus-transduced syngeneic islet grafts fails to prevent beta cell destruction in diabetic NOD mice. Transplantation 64:1040-1049. (Pubitemid 27446771)
82. Sobel DO, Han J, Williams J, Yoon JW, Jun HS, Ahvazi B. 2002. Gamma interferon paradoxically inhibits the development of diabetes in the NOD mouse. J Autoimmun 19:129-137. (Pubitemid 35341862)
83. Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ. 2008. IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci USA 105:14028-14033.
84. Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. 2006. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 311:1778-1780.
85. Sutherland AP, Van BT, Wurster AL, Suto A, Michaud M, Zhang D, Grusby MJ, von HM. 2009. Interleukin-21 is required for the development of type 1 diabetes in NOD mice. Diabetes 58:1144-1155.
86. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. 2008. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28:687-697.
87. Tian B, Hao J, Zhang Y, Tian L, Yi H, O'Brien TD, Sutherland DE, Hering BJ, Guo Z. 2009. Upregulating CD4+CD25 + FOXP3+ regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy. Transplantation 87:198-206.
88. Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L. 1995. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181:817-821.
89. Trembleau S, Penna G, Gregori S, Chapman HD, Serreze DV, Magram J, Adorini L. 1999. Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice. J Immunol 163:2960-2968. (Pubitemid 29399229)
90. Trembleau S, Penna G, Gregori S, Giarratana N, Adorini L. 2003. IL-12 administration accelerates autoimmune diabetes in both wild-type and IFN-gamma-deficient nonobese diabetic mice, revealing pathogenic and protective effects of IL-12-induced IFN-gamma. J Immunol 170:5491-5501. (Pubitemid 36617837)
91. van Belle TL, Coppieters KT, von Herrath MG. 2011. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79-118.
92. van den Heuvel MJ, Garg N, Van KL, Haeryfar SM. 2011. NKT cell costimulation: experimental progress and therapeutic promise. Trends Mol Med 17:65-77.
93. Wang T, Singh B, Warnock GL, Rajotte RV. 1992. Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy. Diabetes 41:114-117.
94. Wolk K, Witte E, Witte K, Warszawska K, Sabat R. 2010. Biology of interleukin-22. Semin Immunopathol 32:17-31.
95. Wraith DC, Nicolson KS, Whitley NT. 2004. Regulatory CD4+ T cells and the control of autoimmune disease. Curr Opin Immunol 16:695-701. (Pubitemid 39423656)
96. Xiong X, Wang X, Li B, Chowdbury S, Lu Y, Srikant CB, Ning G, Liu JL. 2011. Pancreatic islet-specific overexpression of Reg3{beta} protein induced the expression of pro-islet genes and protected mice against streptozotocin-induced diabetes. Am J Physiol Endocrinol Metab 300:E669-E680.
97. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P. 2007. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 39:329-337. (Pubitemid 46328484)
98. You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach JF, Chatenoud L. 2005. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54:1415-1422. (Pubitemid 40586672)