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* Institute of Medical Immunology, Charité University Medicine Berlin Campus Mitte, Germany;
Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charite, Berlin, Germany;
Clinic for Dermatology, Venerology and Allergology, Charité University Medicine Berlin Campus Mitte, Germany; and
Institute of Cell and Neurobiology, Charité University Medicine Berlin Campus Mitte, Germany
Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137+ cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft SFB650 and TR52 to B.S. and H.-D.V. Procedure number: 1862/Si. 262 EK-Vorg.: 1310/2000.
2 Address correspondence and reprint requests to: Dr. Birgit Sawitzki, Charite University Medicine, Monbijoustr. 2a, Berlin, Germany. E-mail address: birgit.sawitzki{at}charite.de
3 Abbreviations used in this paper: PASI, Psoriasis Area and Severity Index; TOAG-1, tolerance associated gene-1; RHAMM, receptor for hyaluronic acid mediated migration; HPRT, hypoxanthin-phosphoribosyl-transferase; TMRM, tetramethylrodamine methyl ester; AUC, area under the curve; 7-AAD, 7-amino-actinomycin; HA, hyaluronan.
4 The online version of this article contains supplemental material.
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