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 eczema- tous 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 mecha- nisms 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.) Key words: Apoptosis, atopic dermatitis, allergic contact dermati- tis, cyclosporine A, dexamethasone, intravenous immunoglobulin, keratinocyte, rapamycine, tacrolimus/FK506, T cell Eczematous dermatitis is a distinctive pattern of skin inflammation that can be induced or maintained by a variety of environmental or intrinsic factors (eg, contact allergens, irritants, infective agents, and atopy). In the acute stage both atopic dermatitis (AD) and allergic con- tact dermatitis (ACD) are characterized by redness, edema, and papules, possibly with the formation of vesi- cles. In the upper dermis a perivascular T-cell infiltrate consisting predominantly of activated memory-effector T cells bearing cutaneous lymphocyte-associated antigen and CD45RO is an integral part of the observed response. 1-3 ACD is regarded as a type 1 T cell–mediat- ed phenomenon on the basis of a number of observa- tions. 2 A polarized type 2 T-cell cytokine pattern was pre- viously regarded as a specific feature reflecting immune dysregulation in AD, but current studies demonstrate that both type 1 and type 2 T-cell cytokines play important roles in the skin inflammatory response in AD. 4-7 Acti- vated T cells infiltrating the skin in AD and ACD induce keratinocyte apoptosis. 7 Induction of keratinocyte apop- tosis by skin-infiltrating T cells, subsequent cleavage of E-cadherin, and resisting demsosomal cadherins demon- strate molecular events in spongiosis formation. 8 Avoidance of exacerbating factors, such as contact allergens, infectious agents, and irritants, in conjunction with topical skin care is essential for effective manage- ment of eczematous dermatitis. With an increased under- standing of the immunopathogenesis, therapy directed at correcting specific immune abnormalities has been attempted. 5,9 Topical corticosteroids reduce inflammation and are widely used in controlling acute flares of eczema. 10,11 Several studies have demonstrated that patients with severe AD refractory to treatment with topi- cal corticosteroids can benefit from oral cyclosporine A. 12,13 Topical tacrolimus/FK506 can effectively reduce the clinical symptoms of AD. 14,15 There may also be a rationale for considering human intravenous immunoglob- ulin (IVIG) in the treatment of severe AD. 9,16 In this context we investigated the effects of different immunomodulatory agents in keratinocyte-T cell cocul- tures, which serve as an in vitro disease model of Dermatologic and ocular diseases Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis Axel Trautmann, MD, a Mübeccel Akdis, MD, a Peter Schmid-Grendelmeier, MD, a Rainer Disch, MD, b Eva-B. Bröcker, MD, c Kurt Blaser, PhD, a and Cezmi A. Akdis, MD a Davos, Switzerland, and Würzburg, Germany 839 From a the Swiss Institute of Allergy and Asthma Research (SIAF), Davos; b the Clinic of Dermatology and Allergy, Davos; and c the Department of Dermatology, University of Würzburg, Würzburg. Supported by grants from the Deutsche Forschungsgemeinschaft (TR460/1- 1) and the Swiss National Foundation (31.50590.97). Received for publication May 11, 2001; revised July 2, 2001; accepted for publication July 13, 2001. Reprint requests: Axel Trautmann, MD, Swiss Institute of Allergy and Asth- ma Research (SIAF), Obere Strasse 22, CH-7270 Davos, Switzerland. Copyright © 2001 by Mosby, Inc. 0091-6749/2001 $35.00 + 0 1/85/118796 doi:10.1067/mai.2001.118796