title: An epidermotypic model of interface dermatitis reveals individual functions of fas ligand and gamma interferon in hypergranulosis, cytoid body formation, and gene expression.
abstract: Analysis of complex cutaneous reactions using animal models allows for the identification of essential or modulatory participants, that is, cyto- and chemokines or adhesion molecules. However, complex whole animal modeling is bound to obscure some specific contributions of individual players. Mouse models suggest that expression of Fas ligand (FasL) by donor T cells is essential for the cutaneous acute graft-versus-host reaction (aGvHR), a major complication after allogeneic hematopoietic stem cell transplantation. The role of FasL/Fas in human cutaneous GvHR is not known. To understand the mechanisms of cytotoxicity and inflammation in human cutaneous GvHR, we developed an organotypic model using reconstructed human epidermis (RHE) that was exposed to FasL, gamma-interferon (IFNγ), or both. The model recapitulated key histological hallmarks of cutaneous aGvHR, including interface dermatitis, appearance of cytoid bodies, hypergranulosis, and expression of ICAM-1. Cytoid body formation and expression of ICAM-1 were attributable entirely to IFNγ, whereas hypergranulosis was triggered by FasL. Both FasL and IFNγ triggered vacuolar degeneration of keratinocytes. The validity of the RHE model of GvHR was demonstrated by histological correlation with biopsied skin from patients with acute graft-versus-host disease. FasL and IFNγ each elicited potent and specific proinflammatory genomic responses in RHE. Inhibition of caspase activity dramatically augmented the FasL-induced proinflammatory responses, suggesting an "apoptosis-versus-inflammation" antagonism in cutaneous aGvHR and other lichenoid dermatoses.
authors: Department of Cell and Developmental Biology, School of Nursing, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors: Sherry M
authors: SM
authors: Farley
authors: Lisa J
authors: LJ
authors: Wood
authors: Mihail S
authors: MS
authors: Iordanov
mesh_terms: D003872:Dermatitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053222:Fas Ligand Protein / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D009924:Organ Culture Techniques
chemical_list: D053222:Fas Ligand Protein; D007371:Interferon-gamma