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Interleukin-4

Potential Immunoregulatory Agent in Therapy of Insulin-Dependent Diabetes Mellitus

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Summary

The nonobese diabetic (NOD) mouse spontaneously develops a diabetic syndrome that closely resembles human insulin-dependent diabetes mellitus (IDDM). T cell-mediated destruction of pancreatic cells may result from an unresponsiveness in regulatory T helper 2 (TH2) cells, favouring a T helper 1 (TH1) cell-mediated environment, in the pancreas. In the NOD mouse, this T cell unresponsiveness can be reversed completely in vitro by exogenous interleukin-4 (IL-4), and in vivo administration of recombinant IL-4 (rIL-4) completely prevents insulitis and the onset of diabetes. These effects may in part be a consequence of an IL-4-directed shift from a TH1 (effector) dominant to a TH2 (protective) dominant immune response. The administration of IL-4 during the course of an inflammatory autoimmune disease could prime developing autoreactive T cells for IL-4 production and may prevent the tissue-damaging effects of autoreactive TH1 cells. In this regard, IL-4 emerges as an excellent potential immunotherapeutic agent in IDDM and other human organ-specific autoimmune diseases.

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References

  1. Bach J. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocrine Rev 1994; 15: 516–42

    CAS  Google Scholar 

  2. Bosi E, Botazzo GF. Autoimmunity in insulin-dependent diabetes mellitus. Clin Immunother 1995; 3: 125–35

    Article  Google Scholar 

  3. Atkinson MA, Maclaren NK. Mechanisms of disease: the pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331: 1428–36

    Article  PubMed  CAS  Google Scholar 

  4. Ogawa M, Maruyama T, Hasegawa T, et al. The inhibitory effect of neonatal thymectomy on the incidence of insulitis in non-obese diabetic (NOD) mice. Biomed Res 1985; 6: 103–5

    CAS  Google Scholar 

  5. Bendelac A, Carnaud C, Boitard C, et al. Syngeneic transfer of autoimmune diabetes from NOD mice to healthy neonates. J Exp Med 1987; 166: 823–32

    Article  PubMed  CAS  Google Scholar 

  6. Rohane PW, Shimada A, Kim DT, et al. Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice. Diabetes 1995; 44: 550–4

    Article  PubMed  CAS  Google Scholar 

  7. Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice: relative contributions of CD4+ and CD8+ T cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 1993; 42: 44–55

    Article  PubMed  CAS  Google Scholar 

  8. Wang Y, Pontesilli O, Gill RG, et al. The role of CD4+ and CD8+ T cells in the destruction of islets grafts by spontaneously diabetic mice. Proc Natl Acad Sci USA 1991; 88: 527–31

    Article  PubMed  CAS  Google Scholar 

  9. Seder R, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 1994; 12: 635–73

    Article  PubMed  CAS  Google Scholar 

  10. Paul WE, Seder RA. Lymphocyte responses and cytokines. Cell 1994; 76: 241–51

    Article  PubMed  CAS  Google Scholar 

  11. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol 1994; 12: 227–57

    Article  PubMed  CAS  Google Scholar 

  12. De Carli M, D’elios MM, Zancuoghi G, et al. Human TH1 and TH2 cells: functional properties, regulation of development and role in autoimmunity. Autoimmunity 1994; 18: 301–8

    Article  PubMed  Google Scholar 

  13. Ridgway WM, Weiner HL, Fathman CG. Regulation of autoimmune response. Curr Opin Immunol 1994; 6: 946–55

    Article  PubMed  CAS  Google Scholar 

  14. Liblau RS, Singer SM, McDevitt HO. TH1 and TH2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995; 16: 34–8

    Article  PubMed  CAS  Google Scholar 

  15. Katz JD, Benoist C, Mathis D. T helper cell subsets in insulin-dependent diabetes. Science 1995; 268: 1185–8

    Article  PubMed  CAS  Google Scholar 

  16. Jaramillo A, Gill BM, Delovitch TL. Insulin-dependent diabetes mellitus in the non-obese diabetic mouse: a disease mediated by T cell anergy? Life Sci 1994; 55: 1163–77

    Article  PubMed  CAS  Google Scholar 

  17. Berman MA, Wang Z, Sandborg CI, et al. Deficiency in interleukin 4 (IL-4) production by T cells from new onset type I diabetes patients [abstract]. Diabetes 1995 May; 44 (Suppl. 1A-333): 137A

    Google Scholar 

  18. Rapoport MJ, Jaramillo A, Zipris D, et al. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med 1993; 178: 87–99

    Article  PubMed  CAS  Google Scholar 

  19. Arreaza G, Cameron M, Chakrabarti S, et al. Effects of interleukin-4 administration and CD28 costimulation in the pathogenesis of insulin dependent diabetes mellitus in the NOD mouse [abstract]. In: Keystone Symposia on Molecular and Cellular Biology; 1996 Mar 20–26: Hilton Head, South Carolina, USA: E4–4006

  20. Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Diabetes 1994; 43: 613–21

    Article  PubMed  CAS  Google Scholar 

  21. Racke MK, Bonomo A, Scott DE, et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994; 180: 1961–6

    Article  PubMed  CAS  Google Scholar 

  22. Rocken M, Shevach E. Immune deviation: the third dimension of nondeletional T cell tolerance. Immunol Rev 1996; 149: 175–94

    Article  PubMed  CAS  Google Scholar 

  23. Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 1991; 77: 1859–70

    PubMed  CAS  Google Scholar 

  24. Ricci M. IL-4: a key cytokine in atopy. Clin Exp Allergy 1994; 24: 801–12

    Article  PubMed  CAS  Google Scholar 

  25. Izuhara K, Yang G, Miyajima A, et al. Structure of the IL-4 receptor and signal transduction mechanism of IL-4. Res Immunol 1993; 144: 584–90

    Article  PubMed  CAS  Google Scholar 

  26. Keegan AD, Nelms K, Wang L, et al. Interleukin 4 receptor: signaling mechanisms. Immunol Today 1994; 15: 423–32

    Article  PubMed  CAS  Google Scholar 

  27. Ivashkiv LB. Cytokines and STATs: how can signals achieve specificity? Immunity 1995; 3: 1–4

    Article  PubMed  CAS  Google Scholar 

  28. Quelle F, Shimoda K, Thierfelder W, et al. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-13 but are not required for mitogenesis. Mol Cell Biol 1995; 15: 3336–43

    PubMed  CAS  Google Scholar 

  29. Kaplan MH, Schindler U, Smiley ST, et al. Stat6 is required for mediating responses to IL-4 and for the development of TH2 cells. Immunity 1996; 4: 313–9

    Article  PubMed  CAS  Google Scholar 

  30. Aulitzky WE, Shuler M, Peschel C, et al. Interleukins: clinical pharmacology and therapeutic use. Drugs 1994; 48: 667–77

    Article  PubMed  CAS  Google Scholar 

  31. de Vries JE, Punnonen J, Cocks BG, et al. Regulation of the human IgE response by IL-4 and IL-13. Res Immunol 1993; 144: 597–601

    Article  PubMed  Google Scholar 

  32. de Waal Malefyt R, Figdor CG, de Vries JE. Effects of interleukin 4 on monocyte functions: comparison to interleukin 13. Res Immunol 1993; 144: 629–31

    Article  PubMed  Google Scholar 

  33. Zlotnick A, Godfrey DI, Fisher M, et al. Cytokine production by mature and immature CD4− CD8− T cells: αβ TCR+ CD4− CD8− T cells produce IL-4. J Immunol 1992; 149: 1211–5

    Google Scholar 

  34. MacDonald HR. NK1.1+ T cell receptor-αβ+ cells: new clues to their origin, specificity and function. J Exp Med 1995; 182: 633–8

    Article  PubMed  CAS  Google Scholar 

  35. Arase H, Arase N, Nakagawa K, et al. NK1.1+ CD4+ CD8− thymocytes with specific lymphokine secretion. Eur J Immunol 1993; 23: 307–10

    Article  PubMed  CAS  Google Scholar 

  36. Yoshimoto T, Paul WE. CD4+, NK1.1+ T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med 1994; 179: 1285–95

    Article  PubMed  CAS  Google Scholar 

  37. Holter W. Regulation of IL-4 production and of IL-4 producing cells. Int Arch Allergy Immunol 1992; 98: 273–8

    Article  PubMed  CAS  Google Scholar 

  38. Kopf M, Legros G, Bachmann M, et al. Disruption of the murine IL-4 gene blocks TH2 cytokine responses. Nature 1993; 326: 245–7

    Article  Google Scholar 

  39. Tepper RI. The anti-tumour and proinflammatory actions of IL-4. Res Immunol 1993; 144: 633–7

    Article  PubMed  CAS  Google Scholar 

  40. Obiri NI, Hillman GG, Haas GP, et al. Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. J Clin Invest 1993; 91: 88–93

    Article  PubMed  CAS  Google Scholar 

  41. Krauss JC, Strome SE, Chang AE, et al. Enhancement of immune reactivity in the lymph nodes draining a murine melanoma engineered to elaborate interleukin-4. J Immunother 1994; 16: 77–84

    Article  CAS  Google Scholar 

  42. Miossec P, Chomarat P, Dechanet J, et al. IL-4 inhibits bone resorption through an effect on osteoclasts and pro-inflammatory cytokines in an ex vivo model of bone resorption in rheumatoid arthritis. Arthritis Rheum 1994; 37: 1715–22

    Article  PubMed  CAS  Google Scholar 

  43. Kunkel SL, Strieter RM, Lindley I, et al. Chemokines: new ligands, receptors and activities. Immunol Today 1995; 16: 559–61

    Article  PubMed  CAS  Google Scholar 

  44. Heinzel FP, Sadick MD, Holaday BJ, et al. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis: evidence for expansion of distinct helper T cell subsets. J Exp Med 1989; 168: 59

    Article  Google Scholar 

  45. Sadick MD, Heinzel FP, Holaday BJ, et al. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody: evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med 1990; 171: 115

    Article  PubMed  CAS  Google Scholar 

  46. Heinzel FP, Schoenhaut DS, Rerko RM, et al. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med 1993; 177: 1505–9

    Article  PubMed  CAS  Google Scholar 

  47. Sypek JP, Chung CL, Mayor SEH, et al. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med 1993; 177: 1797–802

    Article  PubMed  CAS  Google Scholar 

  48. Wang Z, Reiner SL, Zheng S, et al. CD4+ effector cells default to the TH2 pathway in interferon γ-deficient mice infected with Leishmania major. J Exp Med 1994; 179: 1367–71

    Article  PubMed  CAS  Google Scholar 

  49. Salgame P, Abrams JS, Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991; 254: 279–82

    Article  PubMed  CAS  Google Scholar 

  50. Sieling PA, Abrams JS, Yamamura M, et al. Immunosuppressive roles for IL-10 and IL-4 in human infection. J Immunol 1993; 150: 5501–10

    PubMed  CAS  Google Scholar 

  51. Harrison LC, Honeyman MC, DeAizpurua HJ, et al. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 1993; 341: 1365–9

    Article  PubMed  CAS  Google Scholar 

  52. Shehadeh NN, LaRosa F, Lafferty KJ. Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun 1993, 291–300

    Google Scholar 

  53. Rabinovitch A, Sorensen O, Suarez-Pinzon WL, et al. Analysis of cytokine mRNA expression in syngeneic islet grafts of NOD mice: interleukin 2 and interferon gamma mRNA expression correlate with graft rejection and interleukin 10 with graft survival. Diabetologia 1994; 37: 833–7

    Article  PubMed  CAS  Google Scholar 

  54. Suarez-Pinzon WL, Sorensen O, Guilbert LJ, et al. Analysis of cytokine-producing cells in syngeneic islet grafts in nonobese diabetic (NOD) mice: TH1-type cytokines are correlative with islet β-cell destruction and TH2-type cytokines with islet graft survival [abstract no. 6.8]. 5th International Congress on Pancreas and Islet Transplantation; 1995 Jun 18–22; Miami

  55. Rabinovitch A, Suarez-Pinzon WL, Sorensen O, et al. Combined therapy with interleukin-4 and interleukin-10 inhibits autoimmune diabetes recurrence in syngeneic islet-transplanted nonobese diabetic mice. Transplantation 1995; 60: 368–74

    Article  PubMed  CAS  Google Scholar 

  56. Kennedy MK, Torrance DS, Picha KS, et al. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol 1992; 149: 2496–505

    PubMed  CAS  Google Scholar 

  57. Burlison EL, Drakes ML, Wood PJ. Differential patterns of production of granulocyte macrophage-colony stimulating factor, IL-2, IL-3 and IL-4 by cultured islets of Langerhans from non-obese diabetic and non-diabetic strains of mice. Int Immunol 1995; 7: 79–87

    Article  Google Scholar 

  58. Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes: characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med 1993; 177: 627–36

    Article  PubMed  CAS  Google Scholar 

  59. Katz J, Wang B, Haskins K, et al. Following a diabetogenic T cell from genesis through pathogenesis. Cell 1993; 74: 1089–100

    Article  PubMed  CAS  Google Scholar 

  60. Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell 1995; 81: 979–82

    Article  PubMed  CAS  Google Scholar 

  61. Bluestone JA. New perspectives of CD28-B7-mediated T cell costimulation. Immunity 1995; 2: 555–9

    Article  PubMed  CAS  Google Scholar 

  62. Kuchroo VK, Das MP, Brown JA, et al. B7-1 and B7-2 co-stimulatory molecules activate differentially the TH1/TH2 developmental pathways: application to autoimmune disease therapy. Cell 1995; 80: 701–18

    Article  Google Scholar 

  63. Freeman GJ, Boussiotis VA, Anumanthan A, et al. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 1995; 2: 523–32

    Article  PubMed  CAS  Google Scholar 

  64. Kawamura T, Furue M. Comparative analysis of B7-1 and B7-2 expression in Langerhans cells: differential regulation by T helper type 1 and T helper type 2 cytokines. Eur J Immunol 1995; 25: 1913–7

    Article  PubMed  CAS  Google Scholar 

  65. Sayegh MH, Akalin E, Hancock WW, et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits TH1 cytokines but spares TH2. J Exp Med 1995; 181: 1869–74

    Article  PubMed  CAS  Google Scholar 

  66. King CL, Stupi RJ, Craighead N, et al. CD28 activation promotes TH2 subset differentiation by human CD4+ cells. Eur J Immunol 1995; 25: 587–95

    Article  PubMed  CAS  Google Scholar 

  67. Kaufman DL, Clare-Salzler M, Tian J, et al. Spontaneous loss of T cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993; 366: 69–72

    Article  PubMed  CAS  Google Scholar 

  68. Tisch R, Yang X-D, Singer SM, et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993; 366: 72–5

    Article  PubMed  CAS  Google Scholar 

  69. Ramiya V, Muir A, Maclaren N. Insulin prophylaxis in insulin-dependent diabetes mellitus: immunological rationale and therapeutic use. Clin Immunother 1995; 3: 177–83

    Article  Google Scholar 

  70. Schloot N, Eisenbarth GS. Isohormonal therapy of endocrine autoimmunity. Immunol Today 1995; 16: 289–94

    Article  PubMed  CAS  Google Scholar 

  71. Weiner HL, Friedman A, Miller A, et al. Oral tolerance: immunologic mechanisms of treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol 1994; 12: 809–37

    Article  PubMed  CAS  Google Scholar 

  72. Guimaraes V, Quintans J, Fisfalen ME, et al. Immunosuppression of thyroiditis [abstract]. Thyroid 1995; 5 Suppl. 1: S20

    Google Scholar 

  73. Wang T, Singh B, Warnock GL, et al. Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy. Diabetes 1992; 41: 114–7

    Article  PubMed  CAS  Google Scholar 

  74. Chatenoud L, Thervet E, Primo J, et al. Anti-CD3 antibody induces long-term remission of overt autoimmunity in non-obese diabetic mice. Proc Natl Acad Sci USA 1994; 91: 123–7

    Article  PubMed  CAS  Google Scholar 

  75. Pennline KJ, Roque-Gaffney E, Monahan M. Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 1994; 71: 169–75

    Article  PubMed  CAS  Google Scholar 

  76. Serreze DV, Hamaguchi K, Leiter EH. Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmun 1989; 2: 759–76

    Article  PubMed  CAS  Google Scholar 

  77. Cash E, Minty A, Ferrara P, et al. Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J Immunol 1994; 153: 4258–67

    PubMed  CAS  Google Scholar 

  78. Trembleau S, Germann T, Gately MK, et al. The role of IL-12 in the induction of organ-specific autoimmune diseases. Immunol Today 1995; 16: 383–6

    Article  PubMed  CAS  Google Scholar 

  79. Campbell IL, Oxbrow L, Koulmanda M, et al. IFN-γ induces islet cell MHC antigens and enhances autoimmune streptozotocin-induced diabetes in the mouse. J Immunol 1988; 140: 1111–6

    PubMed  CAS  Google Scholar 

  80. Debray-Sachs M, Carnaud C, Boitard C, et al. Prevention of diabetes in NOD mice treated with antibody to murine IFN-γ. J Autoimmun 1991; 4: 237–48

    Article  PubMed  CAS  Google Scholar 

  81. Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 1995; 181: 381–6

    Article  PubMed  CAS  Google Scholar 

  82. Wogensen L, Lee MS, Sarvetnick N. Production of interleukin 10 by islet cells accelerates immune-mediated destruction of cells in nonobese diabetic mice. J Exp Med 1994; 179: 1379–84

    Article  PubMed  CAS  Google Scholar 

  83. Sarvetnick N, Shizurus J, Liggit D, et al. Loss of pancreatic islet tolerance induced by beta cell expression of interferon gamma. Nature 1990; 346: 844–7

    Article  PubMed  CAS  Google Scholar 

  84. Mueller R, Krahl T, Sarvetnick N. Amelioration of diabetes by ectopic expression of interleukin-4 in NOD mice [abstract]. In: Keystone Symposia on Molecular and Cellular Biology; 1996 Mar 20–26: Hilton Head, South Carolina, USA: E4–4088

  85. Perez VL, Lederer JA, Lichtman AH, et al. Stability of TH1 and TH2 populations. Int Immunol 1995; 7: 869–75

    Article  PubMed  CAS  Google Scholar 

  86. Szabo SJ, Jacobson NG, Dighe AS, et al. Developmental commitment to the TH2 lineage by extinction of IL-12 signaling. Immunity 1995; 2: 665–75

    Article  PubMed  CAS  Google Scholar 

  87. Murphy E, Shibuya K, Hosken N, et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J Exp Med 1996; 183: 901–13

    Article  PubMed  CAS  Google Scholar 

  88. Plum J, De Smedt M, Leclercq G, et al. Inhibitory effect of murine recombinant IL-4 on thymocyte development in fetal thymus organ cultures. J Immunol 1990; 145: 1066–73

    PubMed  CAS  Google Scholar 

  89. Gill BM, Delovitch TL. Elevated T cell PCD susceptibility may mediate onset of insulin-dependent diabetes mellitus [abstract]. In: 9th International Congress of Immunology; 1995. San Francisco: 4419

  90. Standiford TJ, Kunkel SL, Liebler JM et al. Gene expression of macrophage inflammatory protein-1 alpha from human blood monocytes and alveolar macrophages is inhibited by interleukin 4. Am J Respir Cell Mol Biol 1993; 9: 192–8

    PubMed  CAS  Google Scholar 

  91. Sandler S, Sternesjö J. Interleukin 4 impairs rat pancreatic islet function in vitro by an action different to that of interleukin 1. Cytokine 1995; 7: 296–300

    Article  PubMed  CAS  Google Scholar 

  92. Clerici M, Shearer GM. The TH1-TH2 hypothesis of HIV infection: new insights. Immunol Today 1994; 15: 575–81

    Article  PubMed  CAS  Google Scholar 

  93. Anderson GP, Coyle AJ. TH1- and TH2-like cells in allergy and asthma: pharmacological perspectives. Trends Pharmacol Sci 1994; 15: 324–32

    Article  PubMed  CAS  Google Scholar 

  94. Yoshimoto T, Bendelac A, Watson C, et al. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 1995; 270: 1845–7

    Article  PubMed  CAS  Google Scholar 

  95. Schmidt-Wolf GD, Schmidt-Wolf IGH. Cytokines and gene therapy. Immunol Today 1995; 16: 173–5

    Article  PubMed  CAS  Google Scholar 

  96. Hunt JD, Pippin BA, Landreneau RJ, et al. Transfer and expression of the human interleukin-4 gene in carcinoma and stromal cell lines derived from lung cancer patients. J Immunother 1993; 14: 314–21

    Article  CAS  Google Scholar 

  97. Chernajovsky Y, Feldmann M, Maini RN. Gene therapy of rheumatoid arthritis via cytokine regulation: future perspectives. Br Med Bull 1995; 51: 503–16

    PubMed  CAS  Google Scholar 

  98. Atkins MB, Vachino G, Tilg HJ, et al. Phase I evaluation of thrice-daily intravenous bolus interleukin-4 in patients with refractory malignancy. J Clin Oncol 1992; 10: 1802–9

    PubMed  CAS  Google Scholar 

  99. Gilleece MH, Scarffe JH, Ghosh A, et al. Recombinant human interleukin 4 (IL-4) given as daily subcutaneous injections: a phase I dose toxicity trial. Br J Cancer 1992; 66: 204–10

    Article  PubMed  CAS  Google Scholar 

  100. Sosman J, Fisher S, Kefer C, et al. A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Ann Oncol 1994; 5: 447–52

    PubMed  CAS  Google Scholar 

  101. Margolin K, Aronson FR, Sznol M, et al. Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma. J Immunother 1994; 15: 147–53

    Article  CAS  Google Scholar 

  102. Trehu E, Isner J, Mier J, et al. Possible myocardial toxicity associated with interleukin-4 therapy. J Immunother 1993; 14: 348–51

    Article  CAS  Google Scholar 

  103. Yoshimoto K, Swain SL, Bradley LM. Enhanced development of TH2-like CD4 effectors in response to sustained exposure to limited rIL-4 in vivo. J Immunol 1996; 156: 3267–74

    PubMed  CAS  Google Scholar 

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  1. Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, 1400 Western Road, London, Ontario, N6G 2V4, Canada

    Guillermo A. Arreaza, Mark J. Cameron &  Terry L. Delovitch

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  1. Guillermo A. Arreaza
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  2. Mark J. Cameron
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  3. Terry L. Delovitch
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Correspondence to Terry L. Delovitch.

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Arreaza, G.A., Cameron, M.J. & Delovitch, T.L. Interleukin-4. Clin. Immunother. 6, 251–260 (1996). https://doi.org/10.1007/BF03259087

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