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Systemic Treatment with Either Cyclosporin A or Methotrexate Does Not Influence the T Helper 1/T Helper 2 Balance in Psoriatic Patients

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Abstract

Cyclosporin A and methotrexate are highly effective drugs in the treatment of psoriasis. It was hypothesized that these therapies might modulate T helper cell cytokine secretion patterns or T cell migration patterns. Flow cytometric determination of interferon-gamma (IFNγ) and interleukin 4 (IL4) producing T helper cell frequencies, as well as of cutaneous lymphocyte associated antigen (CLA) expressing T cell frequencies was performed in patients suffering from severe psoriasis, before, during, and after a scheduled immunosuppressive regimen with either cyclosporin A or methotrexate. Both cyclosporin A and methotrexate treatment reduced the psoriasis area severity index score after 12 weeks of treatment. Cyclosporin A treatment reduced the frequencies of IL4-producing CD4pos T cells, without significantly affecting the T helper 1 to T helper 2 (Th1/Th2) balance but in conjunction with the decreasing number of peripheral blood eosinophil counts. In methotrexate-treated patients, the Th1/Th2 balance was unaffected. Cessation of both therapies resulted in increased numbers of IFNγ- as well as IL4-producing CD4pos T cells as compared to before initiation of oral therapy. Methotrexate, but not cyclosporin A, treatment reduced the frequencies of circulating skin-homing CLApos T cells. This effect was reversed by 4 weeks after withdrawal of methotrexate therapy. We conclude that (1) neither cyclosporin A nor methotrexate affects the balance between Th1 and Th2 cells; (2) exaggerated cytokine production by T helper cells after cessation of oral cyclosporin A or methotrexate drug treatment may contribute to the reappearance of psoriatic skin lesions; and (3) decrease of circulating skin-homing T cells may be responsible for part of the therapeutic effect of methotrexate in severe psoriasis.

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REFERENCES

  1. Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, Krueger JG: Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1:442–447, 1995

    PubMed  Google Scholar 

  2. Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, Kapsenberg ML: Predominance of "memory" T cells (CD4 C, CDw29 C ) over "naive" T cells (CD4 C, CD45R C ) in both normal and diseased human skin. Arch Dermatol Res 281:24–30, 1989

    PubMed  Google Scholar 

  3. Bos JD, de Rie MA: The pathogenesis of psoriasis: Immunological facts and speculations. Immunol Today 20:40–46, 1999

    PubMed  Google Scholar 

  4. Robert C, Kupper TS: Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med 341:1817–1828, 1999

    Article  PubMed  Google Scholar 

  5. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG: The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necro-sis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: A type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113:752–759, 1999

    PubMed  Google Scholar 

  6. Mahmoud F, Abul H, Al-Seleh Q, Morgan G, Haines D, Al-Ramly M, Burleson J, Kreutzer D: Differential expression of interferon gamma by mitogen-stimulated peripheral blood mononuclear cells among Kuwaiti psoriasis patients. J Dermatol 26:23–28, 1999

    PubMed  Google Scholar 

  7. Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, Van Eden W, van der Zee R, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlondorff D, Plewig G, Sander CA, Rocken M: Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med 9:40–46, 2003

    PubMed  Google Scholar 

  8. Berg EL, Yoshino T, Rott LS, Robinson MK, Warnock RA, Kishimoto TK, Picker LJ, Butcher EC: The cutaneous lympho-cyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J Exp Med 174:1461–1466, 1991

    PubMed  Google Scholar 

  9. Picker LJ, Kishimoto TK, Smith CW, Warnock RA, Butcher EC: ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 349:796–799, 1991

    PubMed  Google Scholar 

  10. Picker LJ, Michie SA, Rott LS, Butcher EC: A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am J Pathol 136:1053–1068, 1990

    PubMed  Google Scholar 

  11. Ellis CN, Fradin MS, Messana JM, Brown MD, Siegel MT, Hartley AH, Rocher LL, Wheeler S, Hamilton TA, Parish TG: Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med 324:277–284, 1991

    PubMed  Google Scholar 

  12. Spuls PI, Witkamp L, Bossuyt PM, Bos JD: A systematic review of five systemic treatments for severe psoriasis. Br J Dermatol 137:943–949, 1997

    PubMed  Google Scholar 

  13. Heydendael VMR, Spuls PI, Opmeer BC, de Borgie CAJM, Reitsma JB, Goldschmidt WFM, Bossuyt PMM, Bos JD, de Rie MA: Metotrexate versus cyclosporine A in moderate to severe chronic plaque psoriasis: A randomized controlled trial. N Engl J Med, 349(7):658–665, 2003

    PubMed  Google Scholar 

  14. Baker BS, Griffiths CE, Lambert S, Powles AV, Leonard JN, Valdimarsson H, Fry L: The effects of cyclosporin A on T lympho-cyte and dendritic cell sub-populations in psoriasis. Br J Dermatol 116:503–510, 1987

    PubMed  Google Scholar 

  15. Gupta AK, Baadsgaard O, Ellis CN, Voorhees JJ, Cooper KD: Lym-phocytes and macrophages of the epidermis and dermis in lesional psoriatic skin, but not epidermal Langerhans cells, are depleted by treatment with cyclosporin A. Arch Dermatol Res 281:219–226, 1989

    PubMed  Google Scholar 

  16. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P, Revillard JP: Immunosuppressive properties of methotrexate: Apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 102:322–328, 1998

    PubMed  Google Scholar 

  17. Finlay AY, Kelly SE: Psoriasis–An index of disability. Clin Exp Dermatol 12:8–11, 1987

    PubMed  Google Scholar 

  18. Bollinger PB, Drewinko B, Brailas CD, Smeeton NA, Trujillo JM: The technicon H*1–An automated hematology analyzer for today and tomorrow. Complete blood count parameters. Am J Clin Pathol 87:71–78, 1987

    PubMed  Google Scholar 

  19. Duijvestijn AM, Horst E, Pals ST, Rouse BN, Steere AC, Picker LJ, Meijer CJ, Butcher EC: High endothelial differenti-ation in human lymphoid and inflammatory tissues defined by monoclonal antibody HECA-452. Am J Pathol 130:147–155, 1988

    PubMed  Google Scholar 

  20. Picker LJ, Singh MK, Zdraveski Z, Treer JR, Waldrop SL, Bergstresser PR, Maino VC: Direct demonstration of cytokine syn-thesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 86:1408–1419, 1995

    PubMed  Google Scholar 

  21. Ho VC, Griffiths CE, Albrecht G, Vanaclocha F, Leon-Dorantes G, Atakan N, Reitamo S, Ohannesson A, Mork NJ, Clarke P, Pfister P, Paul C: Intermittent short courses of cyclosporin (Neoral(R)) for pso-riasis unresponsive to topical therapy: A1-year multicentre, random-ized study. The PISCES Study Group. Br J Dermatol 141:283–291, 1999

    PubMed  Google Scholar 

  22. Jan V, Vaillant L, Bressieux JM, Barthelemy H, Legoux A, Steiner HG, Reigneau O: Short-term cyclosporin monotherapy for chronic severe plaque-type psoriasis. Eur J Dermatol 9:615–617, 1999

    PubMed  Google Scholar 

  23. Davison SC, Morris-Jones R, Powles AV, Fry L: Change of treatment from cyclosporin to mycophenolate mofetil in severe psoriasis. Br J Dermatol 143(2):405-407

  24. Wills-Karp M: Immunologic basis of antigen-induced airway hy-perresponsiveness. Annu Rev Immunol 17:255–281, 1999

    PubMed  Google Scholar 

  25. Cogan E, Schandene L, Crusiaux A, Cochaux P, Velu T, Goldman M: Brief report: Clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. N Engl J Med 330:535–538, 1994

    PubMed  Google Scholar 

  26. Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, Locksley RM: Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4 C T cells. Immunity 11:399–409, 1999

    PubMed  Google Scholar 

  27. Dong C, Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA: Defective T cell differentiation in the absence of Jnk1. Science 282:2092–2095, 1998

    PubMed  Google Scholar 

  28. Ranger AM, Oukka M, Rengarajan J, Glimcher LH: Inhibitory func-tion of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9:627–635, 1998

    PubMed  Google Scholar 

  29. Wierenga EA, Backx B, Snoek M, Koenderman L, Kapsenberg ML: Relative contributions of human types 1 and 2 T-helper cell-derived eosinophilotrophic cytokines to development of eosinophilia. Blood 82:1471–1479, 1993

    PubMed  Google Scholar 

  30. Jinquan T, Quan S, Jacobi HH, Reimert CM, Millner A, Hansen JB, Thygesen C, Ryder LP, Madsen HO, Malling HJ, Poulsen LK: Cutting edge: Expression of the NF of activated T cells in eosinophils: Regulation by IL-4 and IL-5. J Immunol 163:21–24, 1999

    PubMed  Google Scholar 

  31. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS: Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389:978–981, 1997

    PubMed  Google Scholar 

  32. de Graaf TW, van Ommen EC, Van der Stelt ME, Kerstens PJ, Boerbooms AM, van Dijk W: Effects of low dose methotrexate therapy on the concentration and the glycosylation of alpha 1-acid glycoprotein in the serum of patients with rheumatoid arthritis: A longitudinal study. J Rheumatol 21:2209–2216, 1994

    PubMed  Google Scholar 

  33. Sigmundsdottir H, Gudjonsson JE, Valdimarsson H: The effects of ultraviolet B treatment on the expression of adhesion molecules by circulating T lymphocytes in psoriasis. Br J Dermatol 148:996–1000, 2003

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Laboratory for Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands

    Rob J. Rentenaar, Frank N. J. Van Diepen & Ineke J. M. Ten Berge

  2. Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands

    Rob J. Rentenaar & Ineke J. M. Ten Berge

  3. Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands

    Vera M. R. Heydendael & Menno A. de Rie

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  1. Rob J. Rentenaar
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  2. Vera M. R. Heydendael
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  5. Ineke J. M. Ten Berge
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Rentenaar, R.J., Heydendael, V.M.R., Diepen, F.N.J.V. et al. Systemic Treatment with Either Cyclosporin A or Methotrexate Does Not Influence the T Helper 1/T Helper 2 Balance in Psoriatic Patients. J Clin Immunol 24, 361–369 (2004). https://doi.org/10.1023/B:JOCI.0000029107.47085.1b

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  • DOI: https://doi.org/10.1023/B:JOCI.0000029107.47085.1b

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