Serum Th1 and Th2 Profile Cytokine Level Changes in Patients with Graves' Ophthalmopathy Treated with Corticosteroids

 

 Buy Article Permissions and Reprints

The aim of this study was to estimate the influence of corticosteroids on Th1 and Th2 serum cytokine balance in patients with GO: IFNγ, TNFα, IL-4 and IL-10. Further, we tested the hypothesis of an up-regulation of Th2 immune response during successful treatment with corticosteroids to explain their beneficial effect in Graves' ophthalmopathy. Serum cytokines were detected in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (Gd), 16 patients with clinical symptoms of ophthalmopathy (GO) (CAS over 3 points, last consultation record for GO less than a year old) and 16 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) (2 series, 3 g each time) and subsequent treatment with oral prednisone (60 mg per day) in a tapering schedule. The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and at the end of corticosteroid therapy. The levels of IFNγ, TNFα, IL-4 and IL-10 in the serum were determined using ELISA. Statistical significance was estimated by the Mann-Whitney U-test. Our findings show a deviation to systemic Th2 profile cytokines in Graves' disease. In patients with GO, we found a significantly increased serum IL-10 concentration. In corticosteroid-responsive patients, the balance of serum cytokines IL-4/IFNγ, IL-4/TNFα, IL-10/IFNγ and IL-10/TNFα increased and remained upregulated until the end of the study. In non-responders, the balance of serum cytokines studied increased after methylprednisolone but declined markedly during continuation of the therapy with prednisone. In summary, our results show that efficient corticosteroid therapy may be related to its influence on Th2/Th1 profile cytokine balance. The upregulation of serum IL-4 and IL-10 during successful treatment with corticosteroids indicate the possibility of using these cytokines as predictors of the beneficial effect of corticosteroids in Graves' ophthalmopathy.

References

• 1 Natt N, Bahn R S. Cytokines in the evolution of Graves' ophthalmopathy.  Autoimmunity. 1997;  26 129-136
  PubMedGoogle Scholar
• 2 Mossman T R, Cherwinski H, Bond M W, Giedlin M A, Coffman R L. Two types of murine helper T cell clone. Definition according to profiles of lyphokine activities and secreted proteins.  J Immunol. 1986;  123 2348-2357
  PubMedGoogle Scholar
• 3 de Carli M, D'Elios M, Maritti S, Marcocci C, Pinchera A, Ricci M. Cytolytic T cells with TH-1 like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy.  J Clin Endocrinol Metab. 1993;  77 1120-1124
  CrossrefPubMedGoogle Scholar
• 4 Grubeck-Loebenstein B, Trieb K, Sztankay A, Holter W, Anderl H, Wick G. Retrobulbar T cells from patients with Graves' ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts.  J Clin Invest. 1994;  3 2738-2743
  PubMedGoogle Scholar
• 5 Heufelder A E, Bahn R S. Detection and localization of cytokine immunoreactivity in retroocular connective tissue in Graves' ophthalmopathy.  Eur J Clin Invest. 1993;  23 10-17
  PubMedGoogle Scholar
• 6 Heufelder A E, Bahn R S. Modulation of Graves, orbital fibroblast proliferation by cytokines and corticosteroid receptor agonists.  Invest Ophthalmol Vis Sci. 1994;  35 120-127
  PubMedGoogle Scholar
• 7 Kazim M, Trokel S, Moore S. Treatment of acute Graves' orbitopathy.  Ophthalmology. 1991;  98 1443-1448
  PubMedGoogle Scholar
• 8 Nagayama Y, Izumi M, Kiriyama T. Treatment of Graves' ophthalmopathy with high-dose intravenous metylprednisolone pulse therapy.  Acta Endocrinologica (Copenh). 1987;  116 513-518
  PubMedGoogle Scholar
• 9 Guy J R, Fagien B, Donovan J, Rubin M L. Methylprednisolone pulse therapy in severe dysthyroid optic neuropathy.  Ophthalmology. 1989;  96 1048-1053
  PubMedGoogle Scholar
• 10 Mourits M, Koorneef L, Wiersinga W M, Prummel M F, Berghout A, Gaag R D. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.  Brit J Ophthalmol. 1989;  73 639-644
  PubMedGoogle Scholar
• 11 Moore K W, O'Garra A, Malefyt D W, Viera P, Mossman T R. Interleukin 10.  Ann Rev Immunol. 1993;  11 165-190
  CrossrefPubMedGoogle Scholar
• 12 de Waal Malefyt R, Haanen J, Spits H, Roncarolo M G, te Velde A, FiGdor C, Johnson K, Kastelein R, Yssel H, de Vries J E. Interleukin 10 and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via down-regulation class II major histocompatibility complex expression.  J Exp Med. 1991;  174 915-1001
  CrossrefPubMedGoogle Scholar
• 13 Koppelman B, Neefjes J J, de Vriesand R, DeWaal Malefyt R. Interleukin-10 down-regulates MHC class IIαβ peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling.  Immunity. 1997;  7 861-866
  CrossrefPubMedGoogle Scholar
• 14 Willems F, Marchant J P, Delville C, Gerard A, Delvaux T, Velu T, de Boer M, Goldman M. Interleukin 10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes.  Eur J Immunol. 1994;  24 1007-1010
  PubMedGoogle Scholar
• 15 de Waal Malefyt R, Abrams J, Benett B, FiGdor C G, de Vries J E. Interleukin 10 inhibits cytokines synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.  J Exp Med. 1991;  174 1209-1215
  CrossrefPubMedGoogle Scholar
• 16 Fiorentino D F, Zlotnik A, Mossman T R, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages.  J Immunol. 1991;  147 3815-3821
  PubMedGoogle Scholar
• 17 Dandona P, Aljada A, Garg R, Mohanty P. Increase in plasma interleukin-10 following hydrocortisone injection.  J Clin Endocrinol Metab. 1999;  84 1141-1144
  CrossrefPubMedGoogle Scholar
• 18 Kalmann B A, Hurter M, Tubes M, Feldkamp J, Bertrams J, Gries FA, Lampeter E F, Kolb H. Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease.  Diabetes. 1997;  46 237-243
  PubMedGoogle Scholar
• 19 Heufelder A E, Bahn R S. Elevated expression in situ of selectin and immunoglibulin superfamily adhesion molecules in retroocular connective tissues from patients with Graves' Ophthalmopathy.  Clin Exp Immunol. 1993;  91 381-389
  PubMedGoogle Scholar
• 20 Weetman A P, Cohen S, Gatter K C, Fells D, Shine B. Immunohistochemical analysis of the retrobulbar tissues in Graves' ophthalmopathy.  Clin Exp Immunol. 1989;  75 222-227
  PubMedGoogle Scholar
• 21 Bahn R, Heufelder A E. Mechanisms of disease: pathogenesis of Graves' ophthalmopathy.  N Engl J Med. 1993;  329 1468-1475
  CrossrefPubMedGoogle Scholar
• 22 Bahn R, Heufelder A E. Role of connective tissue autoimmunity in Graves' ophthalmopathy.  Autoimmunity. 1992;  13 75-79
  PubMedGoogle Scholar
• 23 Leonardi A, Borghesan F, DePaoli M, Plebani M, Secchi A G. Procollagens and inflammatory cytokine concentrations in tarsal and limbal vernal keratoconjunctivitis.  Exp Eye Res. 1998;  67 105-112
  CrossrefPubMedGoogle Scholar
• 24 Pleyer U, Milani J K, Ruckert D, Rieck P, Mondino B J. Determinations of serum tumor necrosis factor alpha in corneal allografts.  Ocul Immunol Inflamm. 1997;  5 149-155
  PubMedGoogle Scholar
• 25 Slepova O S, Gerasimenko V A, Makarov V P, Kushnir V N. Comparative study of the role of cytokines in different forms of eye diseases.  Vestn Oftalmol. 1998;  114 28-32
  PubMedGoogle Scholar
• 26 Barnes P J. Antiinflammatory actions of corticosteroids: molecular mechanisms.  Clin Sci. 1998;  84 557-572
  PubMedGoogle Scholar
• 27 Heufelder A E, Bahn R S, Smith T J. Regulation by corticosteroids of interferon gamma-induced HLA-DR antigen expression in cultured human orbital fibroblasts.  Clin Endocrinol. 1992;  37 659-643
  PubMedGoogle Scholar
• 28 Abbas A K, Murphy K M, Sher A. Functional diversity of helper T lymphocytes.  Nature. 1996;  383 787-793
  CrossrefPubMedGoogle Scholar

Janusz Myśliwiec, M.D.

Department of Endocrinology
Medical School Białystok

M. C. Skłodowskiej-Curie 24 A
15-267 Białystok
Poland


Fax: + 48 (85) 7447611