Interleukin-4 therapy of psoriasis induces Th2 responses and

improves human autoimmune disease

KAMRANGHORESCHI1, PETERTHOMAS1, SUSANNEBREIT1, MARTINDUGAS2,

REINHARDMAILHAMMER4, WILLEMVANEDEN5, RUURDVANDERZEE5, TILOBIEDERMANN1,

JÖRGPRINZ1, MATTHIASMACK3, ULRICHMROWIETZ6, ENNOCHRISTOPHERS6, DETLEFSCHLÖNDORFF3, GERDPLEWIG1, CHRISTIANA. SANDER1& MARTINRÖCKEN1,7

Department of Dermatology and Allergology,

Institute for Biometrics and Department of Internal Medicine, Ludwig-Maximilians University Munich,

Munich, Germany

4

GSF-Forschungszentrum, Hämatologikum, Munich, Germany

5

Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine,

Utrecht University, The Netherlands

6

Department of Dermatology, Christian-Albrechts-University of Kiel, Kiel, Germany7

Department of Dermatology, Eberhard Karls University Tuebingen, Tuebingen, Germany

K.G. and P.T. contributed equally to this work.

Correspondence should be addressed to M.R.; email: mrocken@med.uni-tuebingen.de

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©2003 Nature Publishing Group www.51wendang.com

2

Published online 2 December 2002; doi:10.1038/nm804

Selective skewing of autoreactive interferon-γ(IFN-γ)-producing T helper cells (Th1) toward aninterleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoim-mune disease without inducing general immunosuppression. In a prospective dose escalationstudy, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. Thetherapy was well tolerated, and within six weeks all patients showed decreased clinical scoresand 15 improved more than 68%. Stable reduction of clinical scores was significantly better at0.2–0.5 µg rhuIL-4 than at ≤0.1 µg rhuIL-4 (P =0.009). In psoriatic lesions, treatment with 0.2–0.5µg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved inpsoriasis; the number of chemokine receptor CCR5+Th1 cells; and the IFN-γ/IL-4 ratio. In the cir-culation, 0.2–0.5 µg/kg rhuIL-4 increased the number of IL-4+CD4+T cells two- to three-fold.Thus, IL-4 therapy can induce Th2 differentiation in human CD4+T cells and has promise as a po-tential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

Psoriasis is an inflammatory disease of the skin and small jointsthat seriously impairs quality of life in 2% of the population1,2.Psoriasis plaques are infiltrated by oligoclonal T cells, and func-tional studies suggest that these are IFN-γ-producing T cells(Th1)3–7. Suppression of T-cell cytokine production8,9, inhibition ofT-cell activation10or deletion of activated T cells11,12can alleviatepsoriasis, indicating that activated T cells participate in diseasemanifestation. Psoriasis can also be attenuated by cytokines thatsuppress T-cell-mediated immune responses—such as IL-10,which induces T-cell anergy13–15, or IL-11, which attenuates Th1 re-actions16—or by neutralizing tumor necrosis factor (TNF)17.Although effective, these approaches carry the risks associatedwith general immunosuppression and may enhance susceptibilityto infectious agents, especially intracellular pathogens such as my-cobacteria. Therefore, therapies are needed that selectively targetpsoriasis-inducing T cells18.

T-cell-mediated inflammation depends on infiltrating pro-in-flammatory Th1 cells. In rodents, skewing CD4+T cells from anIFN-γ-producing Th1 phenotype toward an IL-4-producing phe-notype (Th2 cells) can antagonize Th1-mediated tissue destruc-tion and alleviate experimental organ-specific autoimmunedisease19–23. Induction of Th2 cells by simultaneous stimulation of

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CD4+T cells with antigen and IL-4 has been studied extensively invitroand, in the mouse, in vivo20–23. Even though IL-4 may alsocause immunosuppression, animal experiments show that IL-4can shift the differentiation of naive and probably even memory Tcells toward a Th2 phenotype in an antigen-specific fashion24,25.Once the in vivo biological actions of IL-4 and T-cell activation arebetter understood, it may therefore become possible to use IL-4therapy to induce a Th2 phenotype selectively in a targeted T-cellpopulation and to develop vaccination strategies against Th1-me-diated diseases.

In humans, neither the in vivoconditions necessary for induc-tion of Th2 cells nor the anti-inflammatory potential of IL-4 orTh2 cells have been studied. Analysis of T cells specifically in-volved in progressive infection by intracellular pathogens pro-vides strong evidence that Th2 cells also antagonize Th1-mediatedinflammation in humans26. Recombinant human IL-4 (rhuIL-4)was originally investigated in anticancer therapy, where it did notseem effective27–29. Occasionally, concomitant psoriasis improvedat rhuIL-4 concentrations that were well tolerated27. As IL-4 is theonly cytokine known to be capable of inducing a Th2 phenotypein human T cells in vitro30,31and in mouse T cells in vivo22–24,32, weinvestigated the effects of continuous rhuIL-4-treatment on the

NATURE MEDICINE VOLUME 9 NUMBER 1

JANUARY 2003