Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis

• Published in: Journal of allergy and clinical immunology 2001-11, Vol.108 (5), p.839-846
• Main Authors: Trautmann, Axel, Akdis, Mübeccel, Schmid-Grendelmeier, Peter, Disch, Rainer, Bröcker, Eva-B., Blaser, Kurt, Akdis, Cezmi A.
• Format: Article
• Language: English
• Subjects: Acute Disease; allergic contact dermatitis; Apoptosis; atopic dermatitis; Biological and medical sciences; Cells, Cultured; Cyclosporine - pharmacology; cyclosporine A; Dermatitis, Allergic Contact - drug therapy; Dermatitis, Allergic Contact - immunology; Dermatitis, Allergic Contact - pathology; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - immunology; Dermatitis, Atopic - pathology; dexamethasone; Dexamethasone - pharmacology; fas Receptor - physiology; Histamine and antagonists. Allergy; Humans; Immunoglobulins, Intravenous - pharmacology; Immunosuppressive Agents - pharmacology; Interleukin-12 - pharmacology; intravenous immunoglobulin; keratinocyte; Keratinocytes - drug effects; Keratinocytes - pathology; Medical sciences; Pharmacology. Drug treatments; rapamycine; Sirolimus - pharmacology; T cell; T-Lymphocytes - immunology; Tacrolimus - pharmacology; tacrolimus/FK506; Th1 Cells - immunology; Theophylline - pharmacology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1067/mai.2001.118796

Background: Activation and skin-selective homing of T cells and effector functions in the skin represent sequential events in the pathogenesis of atopic dermatitis and allergic contact dermatitis. Objective: T cell–mediated keratinocyte apoptosis plays a key pathogenetic role in the formation of eczematous dermatitis. IFN-γ released from activated T cells upregulates Fas on ke-ratinocytes, which renders them susceptible to apoptosis. The lethal hit is given to keratinocytes by means of Fas ligand expressed on the T-cell surface or released to the inflammatory microenvironment. We sought to investigate whether drugs used for the treatment of eczematous disorders interfere with this pathogenic pathway. Methods: T cell–mediated, Fas-induced keratinocyte apoptosis in a keratinocyte-T cell coculture system serves as an in vitro model of eczematous dermatitis. We tested, in this model, whether immunomodulatory agents (dexamethasone, cyclosporine A, rapamycine, tacrolimus/FK506, intravenous immunoglobulin [IVIG], and theophylline) are able to inhibit apoptosis of keratinocytes. Additionally, skin biopsy specimens from patients with untreated and successfully treated eczematous dermatitis were evaluated for keratinocyte apoptosis. Results: Dexamethasone, cyclosporine A, FK506, rapamycine, and IVIG are inhibitors of keratinocyte apoptosis induced by activated T cells. This effect is mediated by 2 major mechanisms directed on T cells or keratinocytes. T-cell activation was mainly inhibited by dexamethasone, FK506, cyclosporine A, and rapamycine. Interestingly, high-dose dexamethasone and IVIG directly inhibited Fas-mediated keratinocyte apoptosis. In vivo keratinocyte apoptosis was significantly reduced after successful topical treatment of eczematous lesions. Conclusion: These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications. (J Allergy Clin Immunol 2001;108:839-46.)