title: Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis.
abstract: 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-gamma 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.
  
  
  CONCLUSIONS
  These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications.
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Trautmann
authors.forename: M
authors.initials: M
authors.lastname: Akdis
authors.forename: P
authors.initials: P
authors.lastname: Schmid-Grendelmeier
authors.forename: R
authors.initials: R
authors.lastname: Disch
authors.forename: E B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: K
authors.initials: K
authors.lastname: Blaser
authors.forename: C A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D000208:Acute Disease; D017209:Apoptosis; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology*; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D013806:Theophylline / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology
chemical_list: D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D019014:fas Receptor; D018664:Interleukin-12; D003907:Dexamethasone; D016572:Cyclosporine; D013806:Theophylline; D020123:Sirolimus; D016559:Tacrolimus