An Epidermotypic Model of Interface Dermatitis Reveals Individual Functions of Fas Ligand and Gamma Interferon in Hypergranulosis, Cytoid Body Formation, and Gene Expression
Analysis of complex cutaneous reactions using animal models allows for the identification of essential or modulatory participants, i.e. 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 following 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 was 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 aGvHD patients. FasL and IFNγ each elicited potent and specific pro-inflammatory genomic responses in RHE. Inhibition of caspase activity dramatically augmented the FasL-induced pro-inflammatory responses, suggesting an “apoptosis-versus-inflammation” antagonism in cutaneous aGvHR and other lichenoid dermatoses.
The American Journal of Dermatopathology
Farley, Sherry M.; Wood, Lisa J.; and Iordanov, Mihail S., "An Epidermotypic Model of Interface Dermatitis Reveals Individual Functions of Fas Ligand and Gamma Interferon in Hypergranulosis, Cytoid Body Formation, and Gene Expression" (2011). CUP Faculty Research. 121.
CU Commons -- Math and Science Department Faculty Research