Response to Clark and Kupper

Department of Dermatology, University of Cologne, Cologne, Germany.

Address correspondence to: Ingo Haase, Department of Dermatology and Center for Molecular Medicine, University of Cologne (CMMC), Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany. Phone: 49-221-478-86360; Fax: 49-221-478-5949; E-mail: Ingo.Haase@uni-koeln.de.

I read with great interest the commentary by Clark and Kupper titled Misbehaving macrophages in the pathogenesis of psoriasis (1) regarding our recently published articles in the JCI (2, 3). I very much appreciate this instructive commentary, but I feel that it should be put in perspective, in particular for readers who are not specialists in the field of psoriasis.

First, to date, only 2 of the 8 mouse models cited in the commentary have shown conclusively that T cells are required in order for the psoriasis-like skin phenotype to develop in the respective model. In these 2 models, elimination of human CD3+ T cells from transplanted skin of 3 psoriatic individuals (4) or depletion of CD4+ T cells from CD18 hypomorphic mice (5) led to an improvement of the phenotype. Three of the other mouse models have shown that injection of in vitro–activated T cells/CD4+ T cells into skin grafts (6, 7) or of MHC-mismatched CD4+ T lymphocytes into SCID mice (8) reproduces or produces a psoriasis-like skin phenotype. This indicates that T cells can be sufficient but does not prove that they are required for the development of the psoriasis-like changes in the skin.

Second, not all psoriasis patients respond sufficiently to cyclosporine A treatment. The amenability of psoriasis to cyclosporine treatment is used as an argument in favor of a pathogenic function of T cells. Although cyclosporine A is one of the most efficient drugs in the treatment of psoriasis, trials and clinical experience indicate that a subset of patients does not sufficiently respond to this treatment. For example, a meta-analysis of 3 controlled studies in 597 patients with severe psoriasis (9) demonstrated that only about half of the patients achieved a 70% or better improvement of their skin symptoms with cyclosporine A. Moreover, cyclosporine A not only affects T cells but also affects many other cell types, e.g., monocytes/macrophages, in which it can inhibit the production of TNF- (10), a cytokine with a known function in the development of psoriasis.

Third, the T cell–depleting agent denileukin diftitox (ONTAK) has poor efficacy in the treatment of psoriasis. DAB389IL-2 is a fusion protein consisting of IL-2 fused to diphtheria toxin. It binds to cells expressing the high-affinity IL-2 receptor and causes their destruction. In a double-blind, placebo-controlled phase II multicenter trial in patients with psoriasis, the efficacy of DAB389IL-2 as compared with placebo was minimal, and no dose-response relationship could be established (11).

Finally, although it is likely that T lymphocytes have important functions in the development of psoriasis, it seems too early to conclude upon their pathogenic role. While a contribution of T cells may be critical for the development of psoriasis in a number of cases, any generalization of this concept would be premature at present. Instead, it should be considered that pathogenic pathways leading to the multifaceted clinical picture of psoriasis could be heterogeneous and may not necessarily depend on 1 single cell type.

References

Clark R.A. and Kupper T.S. 2006. Misbehaving macrophages in the pathogenesis of psoriasis. J. Clin. Invest. 116:2084–2087 doi: 10.1172/JCI29441.

Stratis A., et al. 2006. Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation. J. Clin. Invest. 116:2094–2104 doi: 10.1172/JCI27179.

Wang H., et al. 2006. Activated macrophages are essential in a murine model for T cell–mediated chronic psoriasiform skin inflammation. J. Clin. Invest. 116:2105–2114 doi: 10.1172/JCI27180.

Boyman O., et al. 2004. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J. Exp. Med. 199:731–736.

Kess D., et al. 2003. CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis. J. Immunol. 171:5697–5706.

Sano S., et al. 2005. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat. Med. 11:43–49.

Nickoloff B.J. and Wrone-Smith T. 1999. Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis. Am. J. Pathol. 155:145–158.

Schon M.P., Detmar M., Parker C.M. 1997. Murine psoriasis-like disorder induced by naive CD4+ T cells. Nat. Med. 3:183–188.

Faerber L., et al. 2001. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. Am. J. Clin. Dermatol. 2:41–47.

Nguyen D.T., et al. 1990. Cyclosporin a modulation of tumor necrosis factor gene expression and effects in vitro and in vivo. J. Immunol. 144:3822–3828.

Bagel J., et al. 1998. Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial. J. Am. Acad. Dermatol. 38:938–944.