Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis Axel Trautmann, MDa, Mübeccel Akdis, MDa, Peter.

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Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis Axel Trautmann, MDa, Mübeccel Akdis, MDa, Peter Schmid-Grendelmeier, MDa, Rainer Disch, MDb, Eva-B. Bröcker, MDc, Kurt Blaser, PhDa, Cezmi A. Akdis, MDa Journal of Allergy and Clinical Immunology Volume 108, Issue 5, Pages 839-846 (November 2001) DOI: 10.1067/mai.2001.118796 Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 1 T cell–induced keratinocyte apoptosis is mediated by IFN-γ and Fas triggering. Keratinocytes were cultured in Transwell plates with unstimulated (A) and stimulated (B) CD45RO+ T cells for 3 days (HOECHST staining; original magnification, ×200). C , Coculture of keratinocytes and CD45RO+ T cells for 3 days. Ke-ratinocyte viability was determined with ethidium bromide exclusion and flow cytometry. Control , Isotype control antibody. *P < .05. Results shown represent 3 experiments. Journal of Allergy and Clinical Immunology 2001 108, 839-846DOI: (10.1067/mai.2001.118796) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 2 Effect of immunomodulatory agents on T cell–induced keratinocyte apoptosis. A , Coculture of ke-ratinocytes and stimulated CD45RO+ T cells at day 3. *P < .05. B , Electrophoresis of keratinocyte DNA. Ke-ratinocytes were cultured in Transwell plates with unstimulated (lane 1) and stimulated (lanes 2 to 8 ) CD45RO+ T cells. At day 3, the keratinocytes were lysed, and the DNA was isolated. C , Coculture of ke-ratinocytes and stimulated CD45RO+ T cells in Transwell plates at day 1. Keratinocytes were stained with annexin V-FITC and subjected to flow cytometry. Histograms show fluorescence intensity (x-axis) versus cell number (y-axis) . Control , Keratinocytes alone. D , Levels of soluble Fas ligand and IFN-γ in supernatants of stimulated CD45RO+ T cells at day 3, as determined with ELISA. *P < .05. Results shown represent 3 (A-C ) and 2 (D ) experiments. Journal of Allergy and Clinical Immunology 2001 108, 839-846DOI: (10.1067/mai.2001.118796) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 3 Keratinocyte apoptosis induced by CD4 and CD8 T cells is inhibited by immunomodulatory agents. A and C , Stimulated type 1, but not type 2, CD4+/CD8+ T cells induced keratinocyte death. Stimulation of type 2 T cells in the presence of IL-12 enabled the induction of keratinocyte apoptosis. Control , Ke-ratinocytes alone. *P < .05. B and D , Coculture of keratinocytes and stimulated CD4+/CD8+ T cells at day 3. Control , Keratinocytes without immunosuppressants. *P < .05. Results shown represent 2 experiments. Journal of Allergy and Clinical Immunology 2001 108, 839-846DOI: (10.1067/mai.2001.118796) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 4 Direct effects of dexamethasone and IVIG on Fas-mediated keratinocyte apoptosis. A , IFN-γ– and Fas-induced keratinocyte apoptosis. Control , Keratinocytes alone. *P < .05. B , Keratinocyte culture at day 3. *P < .05. C , Different IVIG preparations (Sandoglobulin, Gammagard S/D, and Globhuman Berna) protect ke-ratinocytes from IFN-γ– and Fas-induced apoptosis at different concentrations. Results shown represent 4 (A and B ) and 2 (C ) experiments. Journal of Allergy and Clinical Immunology 2001 108, 839-846DOI: (10.1067/mai.2001.118796) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 5 Demonstration of apoptotic keratinocytes in lesional and treated AD and ACD. Representative histologic findings of acute eczematous dermatitis demonstrated with hematoxylin-eosin (HE) staining (original magnification, ×200). Skin sections were subjected to TUNEL (original magnification, ×400). A and D , Lesional skin of acute AD and ACD. B , C , and E , Previously eczematous AD and ACD skin lesions successfully treated topically with 0.25% prednicarbate and 0.1% tacrolimus. Results are representative of 11 specimens of AD (5 untreated and 6 treated) and 5 with ACD (3 untreated and 2 treated). Journal of Allergy and Clinical Immunology 2001 108, 839-846DOI: (10.1067/mai.2001.118796) Copyright © 2001 Mosby, Inc. Terms and Conditions