Targeting IL-12, the key cytokine driving Th1-mediated autoimmune diseases

Chemical Immunology

Volumn 68, Issue , 1997, Pages 175-197

  Adorini, Luciano ^a   Aloisi, Francesca ^b   Galbiati, Francesca ^a   Gately, Maurice K ^c   Gregori, Silvia ^a   Penna, Giuseppe ^a   Ria, Francesco ^d   Smiroldo, Simona ^a   Trembleau, Sylvie ^a  

^a ROCHE MILANO RICERCHE   (Italy)

^b ISTITUTO SUPERIORE DI SANITÀ   (Italy)

^c HOFFMANN LA ROCHE INC   (United States)

^d CATHOLIC UNIVERSITY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 12;

ANTIGEN PRESENTING CELL; AUTOIMMUNITY; ETIOLOGY; HELPER CELL; INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; REVIEW;

EID: 0030884061     PISSN: 10150145     EISSN: None     Source Type: Journal    
DOI: 10.1159/000058691     Document Type: Review

References (128)

1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffmann RL: Two types of murine helper T cell clone. I. Definition according to profile of lymphokine activities and secreted proteins. J Immunol 1986;136:2348-2357.
2. Del Prete G, De Carli M, Mastromauro C, Biagiotti R, Macchia D, Falagiani P, Ricci M, Romagnani S: Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest 1991;88:346-350.
3. H2 cytokines and help B cells. Science 1993;260:1802-1805.
4. Romagnani S: Lymphokine production by human T cells in disease states. Annu Rev Immunol 1994;12:227-257.
5. Trinchieri G: Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 1995;13:251-276.
6. Paul WE, Seder RA: Lymphocytes responses and cytokines. Cell 1994;76:241-251.
7. Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K: Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med 1995;182:1591-1596.
8. + helper cell phenotype development in a T cell receptor-αβ-transgenic model. J Exp Med 1995;182: 1579-1584.
9. Chen Y, Inobe J-I, Marks R, Gonnella P, Kuchroo VK, Weiner HL: Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995;376:177-180.
10. Guéry J-C, Galbiati F, Smiroldo S, Adorini L: Selective development of Th2 cells induced by continuous administration of low dose soluble proteins to normal and β2-microglobulin-deficient BALB/c mice. J Exp Med 1996;183:485-497.
11. Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK: An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995;3:397-405.
12. + T cells through IL-12 produced by Listeria-induced macrophages. Science 1993;260:547-549.
13. Reiner SL, Locksley RM: The regulation of immunity to Leishmania major. Annu Rev Immunol 1995;13:151-177.
14. Openshaw P, Murphy EE, Hosken NA, Maino V, Davis K, Murphy K, O'Garra A: Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J Exp Med 1995;182:1357-1367.
15. Mosmann TR, Sad S: The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996;17:138-146.
16. Pernis A, Gupta S, Gollob KJ, Garfein E, Coffman RL, Schindler C, Rothman P: Lack of interferon γ receptor β chain and the prevention of interferon γ signaling in Th1 cells. Science 1995;269: 245-247.
17. Bach EA, Szabo S, Dighe AS, Ashkenazi A, Aguet M, Murphy KM, Schreiber RD: Ligand-induced autoregulation of IFN-γ receptor β chain expression in T helper cell subsets. Science 1995;270: 1215-1218.
18. Szabo SJ, Jacobson AG, Gubler U, Murphy KM: Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity 1995;2:665-675.
19. Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F: Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 1997; 185:825-831.
20. Szabo SJ, Dighe AS, Gubler U, Murphy KM: Th cell developmental commitment by regulation of the IL-12R β2 subunit. J Exp Med 1997;185:817-824.
21. Manetti R, Parronchi P, Giudizi MG, Piccinni M-P, Maggi E, Trinchieri G, Romagnani S: Natural killer cell stimulatory factor (interleukin 12, IL-12) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 1993;177:1199-1204.
22. Afonso LCC, Scharton TM, Vieira LQ, Wysocka M, Trinchieri G, Scott P: The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 1994;263:235-237.
23. Kiniwa M, Gately M, Gubler U, Chizzonite R, Fargeas C, Delespesse G: Recombinant interleukin-12 suppresses the synthesis of IgE by interleukin-4 stimulated human lymphocytes. J Clin Invest 1992;90:262-266.
24. Schmitt E, Hoehn P, Huels C, Goedert S, Palm N, Ruede E, Germann T: T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-γ and is inhibited by transforming growth factor-β. Eur J Immunol 1994;24:793-798.
25. Gajewski TF, Fitch FW: Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 1988;140:4245-4253.
26. Moore K, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR: Interleukin-10. Annu Rev Immunol 1993;11:165-190.
27. D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G: Interleukin-10 (IL-10) inhibits human lymphocyte interferon-γ production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 1993;178:1041-1048.
28. de Waal Malefyt R, Figdor CG, Huijbens R, Mohan-Peterson S, Bennett B, Culpepper J, Dang W, Zurawski G, de Vries JE: Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-γ or IL-10. J Immunol 1993;151:6370-6381.
29. Wang ZE, Zheng S, Corry DB, Dalton DK, Seder RA, Reiner SL, Locksley RM: Interferon gamma-independent effects of interleukin-12 administered during acute or established infection due to Leishmania major. Proc Natl Acad Sci USA 1994;91:12932-12936.
30. Lamont AG, Adorini L: IL-12: A key cytokine in immune regulation. Immunol Today 1996;17: 214-217.
31. + T cells to protein antigens in vivo. J Immunol 1995;155:3734-3741.
32. Epstein MM, Di Rosa F, Jankovic D, Sher A, Matzinger P: Successful T cell priming in B cell-deficient mice. J Exp Med 1995;182:915-922.
33. + T cells. J Immunol 1995;154:4915-4923.
34. Crowley MT, Inaba K, Steinman RM: Dendritic cells are the principal cells in mouse spleen bearing immunogenic fragments of foreign proteins. J Exp Med 1990;172:383-386.
35. Guéry J-C, Sette A, Leighton J, Dragomir A, Adorini L: Selective immunosuppression by administration of MHC class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation. J Exp Med 1992;175:1345-1352.
36. Guéry J-C, Neagu M, Rodriguez-Tarduchy G, Adorini L: Selective immunosuppression by administration of major histocompatibility complex class II-binding peptides. II. Preventive inhibition of primary and secondary antibody responses. J Exp Med 1993;177:1461-1468.
37. Guéry JC, Ria F, Adorini L: Dendritic cells but not B cells present antigenic complexes to class II-restricted T cells following administration of protein in adjuvant. J Exp Med 1996;183:751-757.
38. Guéry J-C, Ria F, Galbiati F, Smiroldo S, Adorini L: The mode of protein antigen administration determines preferential presentation of peptide-class II complexes by lymph node dendritic or B cells. Int Immunol 1997;9:9-15.
39. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G: Identification and purification of natural killer cell stimulatory factor, a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 1989;170:827-845.
40. Stern AS, Podlaski FJ, Hulmes JD, Pan Y-CE, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, Gately MK: Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci USA 1990;87:6808-6812.
41. O'Garra A, Hosken N, Macatonia S, Wenner CA, Murphy K: The role of macrophage- and dendritic cell-derived IL-12 in Th1 phenotype development. Res Immunol 1995;146:466-472.
42. Maruo S, Oh-hora M, Ahn H-J, Wysocka M, Kaneko Y, Yagita H, Okumura K, Kikutani H, Kishimoto T, Kobayashi M, Hamaoka T, Trinchieri G, Fujiwara H: B cells regulate CD40 ligand-induced IL-12 production in antigen-presenting cells (APC) during T cell/APC interactions. J Immunol 1997;158:120-126.
43. D'Andrea A, Rengaraju M, Valiante NM, Chehimi J, Kubin M, Aste M, Chan SH, Kobayashi M, Young D, Nickbarg E, Chizzonite R, Wolf SF, Trinchieri G: Production of natural killer cell stimulatory factor (interleukin-12) by peripheral blood mononuclear cells. J Exp Med 1992;176: 1387-1398.
44. + T cells. J Immunol 1995;154:5071-5079.
45. Heufler C, Koch F, Stanzl U, Topar G, Wysoka M, Trinchieri G, Enk A, Steinman RM, Romani N, Schuler G: Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-γ production by T helper 1 cells. Eur J Immunol 1996;26:659-668.
46. Koch F, Stanzl U, Jennewein P, Janke K, Heufler C, Kaempgen E, Romani N, Schuler G: High level IL-12 production by murine dendritic cells: Upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med 1996;184:741-746.
47. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184:747-752.
48. Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L: IL-12 administration induces Th1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 1995;181:817-821.
49. Trembleau S, Germann T, Gately MK, Adorini L: The role of IL-12 in the induction of organ-specific autoimmune diseases. Immunol Today 1995;16:383-386.
50. Ronchese F, Hausmann B: B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes. J Exp Med 1993;177:679-690.
51. Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, Shevach EM, Roecken M: Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994;180:1961-1966.
52. Croft M, Swain SL: Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines. J Immunol 1995;154:4269-4282.
53. Stockinger B, Zal T, Zal A, Gray D: B cells solicit their own help from T cells. J Exp Med 1996; 183:891-899.
54. Day MJ, Tse AGD, Puklavec M, Simmonds SJ, Mason DW: Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats. J Exp Med 1992;175:655-659.
55. Saoudi A, Simmonds S, Huitinga I, Mason DW: Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: Evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of autoantigen-specific T cells. J Exp Med 1995;182:335-344.
56. Eynon EE, Parker DC: Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 1992;175:131-138.
57. Wolf SD, Dittel BN, Hardardottir F, Janeway CA: Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 1996;184:2271-2278.
58. Degermann S, Pria E, Adorini L: Soluble protein but not peptide administration diverts the immune response of a clonal CD4+ T cell population to the T helper 2 pathway. J Immunol 1996;157: 3260-3269.
59. Goodman RE, Nestle F, Naidu YM, Green JM, Thompson CB, Nickoloff BJ, Turka LA: Keratinocyte-derived T cell costimulation induces preferential production of IL-2 and IL-4 but not IFN-gamma. J Immunol 1994;152:5189-5198.
60. Becher B, Dodelet V, Fedorowicz V, Antel JP: Soluble tumor necrosis factor receptor inhibits interleukin-12 production by stimulated human adult microglial cells in vitro. J Clin Invest 1996; 98:1539-1543.
61. Aloisi F, Penna G, Cerase J, Menendez Iglesias B, Adorini L: Astrocytes inhibit IL-12 production by central nervous system microglia. J Immunol 1997;159, in press.
62. Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospisil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G: Induction of interferon γ production by natural killer cell stimulatory factor: Characterization of the responder cells and synergy with other inducers. J Exp Med 1991;173: 869-879.
63. Frei K, Siepl P, Groscurth P, Bodmer S, Schwerdel C, Fontana A: Antigen presentation and tumor cytotoxicity by interferon-γ-treated microglial cells. Eur J Immunol 1987;17:1271-1278.
64. Murphy EE, Terres G, Macatonia SE, Hsieh C-S, Mattson J, Lanier L, Wysocka M, Trinchieri G, Murphy K, O'Garra A: B7 and interleukin-12 cooperate for proliferation and interferon γ production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med 1994;180:223-231.
65. Kubin M, Kamoun M, Trinchieri G: Interleukin-12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med 1994;180:211-222.
66. Rott O, Fleisher B, Cash E: Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994;24:1434-1440.
67. Issazadeh S, Ljungdahl A, Hoejeberg B, Mustafa M, Olsson T: Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: Dynamics of mRNA expression for interleukin-10, interleukin-12, tumor necrosis factor α and tumor necrosis factor β. J Neuroimmunol 1995;61:205-212.
68. Hart MN, Fabry Z: CNS antigen presentation. Trends Neurosci 1995;18:475-481.
69. Powrie F, Coffmann RL: Cytokine regulation of T cell function: Potential for therapeutic intervention. Immunol Today 1993;14:270-274.
70. O'Garra A, Murphy K: T-cell subsets in autoimmunity. Curr Opin Immunol 1993;5:880-886.
71. + T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995;16:34-38.
72. Ando DG, Clayton J, Kong D, Urban JL, Sercarz EE: Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis are of the Th1 lymphokine subtype. Cell Immunol 1989;124:132-143.
73. + islet-specific T cell clone. Science 1990;249:1433-1436.
74. Bergman B, Haskins K: Islet-specific T-cell clones from the NOD mouse respond to beta-granule antigen. Diabetes 1994;43:197-203.
75. Katz JD, Benoist C, Mathis D: T helper cell subsets in insulin-dependent diabetes. Science 1995; 268:1185-1188.
76. Yang X-D, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, McDevitt HO: Effect of tumor 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.
77. Wogesen L, Lee M-S, Sarvetnick N: Production of interleukin-10 by islet cells accelerates immune-mediated destruction of β cells in nonobese diabetic mice. J Exp Med 1994;179:1379-1384.
78. Anderson JT, Cornelius JG, Jarpe AJ, Winter WE, Peck AB: Insulin-dependent diabetes in the NOD mouse model. II. Beta cell destruction in autoimmune diabetes is a Th2 and not a Th1 mediated event. Autoimmunity 1993;15:113-122.
79. + β islet cell-reactive T cell clones that suppress autoimmune diabetes in nonobese diabetic mice. J Exp Med 1995;182: 87-97.
80. Van der Veen RC, Stohlman SA: Encephalitogenic Th1 cells are inhibited by Th2 cells with related peptide specificity: Relative roles of interleukin (IL)-4 and IL-10. J Neuroimmunol 1993;48:213-220.
81. Khoury SJ, Hancock WW, Weiner HL: Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β, interleukin-4, and prostaglandin E expression in the brain. J Exp Med 1992;176:1355-1364.
82. Rapoport MJ, Jaramillo A, Zipris D, Lazarus AH, Serreze DV, Leiter EH, Cyopick P, Danska JS, Delovitch TL: Interleukin-4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med 1993;178:87-99.
83. Pennline KJ, Roquegaffney E, Monahan M: Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 1994;71:169-175.
84. + T cell subset that inhibits this autoimmune potential. J Exp Med 1993;177:627-636.
85. Scott B, Liblau R, Degermann S, Marconi LA, Ogata L, Caton AJ, McDevitt HO, Lo D: A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity 1994;1:1-20.
86. Mueller R, Krahl T, Sarvetnick N: Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabeuc mice. J Exp Med 1996;184:1093-1099.
87. Healey D, Ozegbe P, Arden S, Chandler P, Hutton J, Cooke A: In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. J Clin Invest 1995; 95:2979-2985.
88. Moritani M, Yoshimoto K, Tashiro F, Hashimoto C, Miyazaki J, Ii S, Kudo E, Izahana H, Hayashi Y, Sano T, Itakura M: Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int Immunol 1994;6:1927-1936.
89. De Carli M, D'Elios M, Mariotti S, Marcocci C, Pinchera A, Ricci M, Romagnani S, Del Prete GF: Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy. J Clin Endocrinol Metab 1993;77:1120-1124.
90. Brod SA, Benjamin D, Hafler DA: Restricted T cell expression of IL-2, IFN-γ mRNA in human inflammatory disease. J Immunol 1991;147:810-815.
91. Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, Hafler DA: Expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86), and interleukin-12 cytokine in multiple sclerosis lesions. J Exp Med 1995;182:1985-1996.
92. + T cells via CD40 ligand. Proc Natl Acad Sci USA 1997;94:599-603.
93. Foulis AK, McGill M, Farquahrson MA: Insulitis in type I (insulin-dependent) diabetes mellitus in man. Macrophages, lymphocytes and interferon-γ-containing cells. J Pathol 1991;165:97-103.
94. Miltenburg AM, van Laar JM, de Kuiper R, Daha MR, Breedveld FC: T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol 1992;35: 603-610.
95. De Carli M, D'Elios MM, Zancuoghi G, Romagnani S, Del Prete G: Human TH1 and TH2 cells: Functional properties, regulation of development and role in autoimmunity. Autoimmunity 1994; 18:301-308.
96. Simon AK, Seipelt E, Sieper J: Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 1994;91:8562-8566.
97. Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz D, Hewick RM, Kelleher H, Herrmann SH, Clark SC, Azzoni L, Chan SH, Trinchieri G, Perussia B: Cloning of cDNA for natural killer stimulatory factor, a heterodimeric cytokine with multiple biological effects on T and natural killer cells. J Immunol 1991;146:3074-3081.
98. Gubler U, Chua AO, Schoenhaut DS, Dwyer CM, McComas W, Motyka R, Nabavi N, Wolitzky AG, Quinn PM, Familletti PC, Gately MK: Coexpression of two distinct genes is required to generate secreted, bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci USA 1991;88:4143-4147.
99. Cassatella MA, Meda L, Gasperini S, D'Andrea A, Ma X, Trinchieri G: Interleukin-12 production by human polymorphonuclear leukocytes. Eur J Immunol 1995;25:1-5.
100. Trinchieri G: Interleukin-12: A cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 1994; 84:4008-4027.
101. h2 cells. Eur J Immunol 1993;23:1762-1770.
102. O'Hara RM, Henderson SL: Interleukin-12 prevents the onset of diabetes in NOD mice. FASEB J 1995;9:5938.
103. Magram J, Connaughton S, Warrier R, Carvajal D, Wu C, Ferrante J, Stewart C, Sarmiento U, Faherty D, Gately MK: IL-12 deficient mice are defective in IFN-γ production and type 1 cytokine responses. Immunity 1996;4:471-482.
104. Santambrogio L, Crisi GM, Leu J, Hochwald GM, Ryan T, Thorbecke GJ: Tolerogenic forms of auto-antigens and cytokines in the induction of resistance to experimental allergic encephalomyelitis. J Neuroimmunol 1995;58:211-222.
105. Leonard JP, Waldburger KE, Goldman SJ: Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin-12. J Exp Med 1995;181:381-386.
106. Germann T, Szeliga J, Hess H, Stoerkel S, Podlaski FJ, Gately MK, Schmitt E, Ruede E: Administration of IL-12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA 1995;92:4823-4827.
107. McIntyre KW, Shuster DJ, Gillooly KM, Warrier RR, Connaughton SE, Hall RB, Arp LH, Gately MK, Magram J: Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol 1996;26:2933-2938.
108. Hess H, Gately MK, Ruede E, Schmitt E, Szeliga J, Germann T: High doses of interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund's adjuvant. Eur J Immunol 1996;26:187-191.
109. Neurath MF, Fuss I, Kelsall BL, Stueber E, Strober W: Antibodies to interleukin-12 abrogate established experimental colitis in mice. J Exp Med 1995;182:1281-1290.
110. Stuber E, Strober W, Neurath M : Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin-12 secretion. J Exp Med 1996; 183:693-698.
111. Neurath MF, Fuss I, Kelsall BL, Presky DH, Waegell W, Strober W: Experimental granulomatous colitis in mice is abrogated by induction of TGF-β-mediated oral tolerance. J Exp Med 1996;183: 2605-2616.
112. Mattner F, Fischer S, Guckes S, Jin S, Kaulen H, Schmitt E, Rüde E, Germann T: The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer. Eur J Immunol 1993; 23:2202-2208.
113. Gillessen S, Carvajal D, Ling P, Podlaski FJ, Stremlo DL, Familletti PC, Gubler U, Presky DH, Stern AS, Gately MK: Mouse interleukin-12 p40 homodimer: A potent IL-12 antagonist. Eur J Immunol 1995;25:200-206.
114. Ling P, Gately MK, Gubler U, Stern A, Lin P, Hollfelder K, Su C, Pan Y-CE, Hakimi J: Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol 1995;1995:116-127.
115. Podlaski FJ, Nanduri VB, Hulmes JD, Pan Y-CE, Levin W, Danho W, Chizzonite R, Gately MK, Stern AS: Molecular characterization of interleukin-12. Arch Biochem Biophys 1992;294:230-236.
116. Heinzel FP, Rerko RM, Ling P, Hakimi J, Schoenhaut DS: Interleukin-12 is produced in vivo during endotoxemia and stimulates synthesis of interferon-γ. Infect Immun 1994;62:4244-4249.
117. Wysoka M, Kubin M, Vieira LQ, Ozmen L, Garotta G, Scott P, Trinchieri G: Interleukin-12 is required for IFN-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol 1995;25:672-676.
118. 118a Gately MK, Carvajal DM, Connaughton SE, Gillessen S, Warrier RR, Kolinsky KD, Wilkinson VL, Dwyer CM, Higgins GF, Podlaski FJ, Faherty DA, Familletti PC, Stern AS, Presky DH: IL-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo. Ann NY Acad Sci 1996;795:1-12.
119. 118b Trembleau S, Penna G, Gregori S, Gately MK, Adorini L: Deviation of pancreas-infiltrating cells to Th2 by IL-12 antagonist administration inhibits autoimmune diabetes. Eur J Immunol 1997;27, in press.
120. Rocken M, Shevach EM: Immune deviation - The third dimension of nondeletional T cell tolerance. Immunol Rev 1996;149:175-194.
121. Harrison LC: Islet cell autoantigens in insulin-dependent diabetes: Pandora's box re-visited. Immunol Today 1992;13:348-352.
122. g7, the class II MHC molecule of NOD and Biozzi AB/H mice. J Exp Med 1997;185:1013-1021.
123. Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GSP, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV: Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993;366:69-72.
124. Tisch R, Yang X-D, Singer SM, Liblau RS, Fugger L, McDevitt HO: Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993;366: 72-75.
125. Tian J, Atkinson MA, Clare-Salzer M, Herschenfeld A, Forsthuber T, Lehmann PV, Kaufman DL: Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med 1996;183:1561-1567.
126. Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevitt HO, Steinman L: Limited heterogeneity of T cell receptors in experimental allergic encephalomyelitis. Cell 1988;54:263-273.
127. Waisman A, Ruiz PJ, Hirschenberg DL, Gelman A, Oskenberg JR, Brocke S, Mor F, Cohen IR, Steinman L: Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. Nat Med 1996;2: 899-905.
128. Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK: Recombinant interleukin-12 cures mice infected with Leishmania major. J Exp Med 1993;177:1505-1509.