OVEREXPRESSION OF VASCULAR-PERMEABILITY FACTOR (VPF VEGF) AND ITS ENDOTHELIAL-CELL RECEPTORS IN DELAYED-HYPERSENSITIVITY SKIN REACTIONS/

Delayed hypersensitivity (DH) is a T cell-mediated form of immune resp onse characterized by a predominantly perivascular, mononuclear cell i nfiltrate. The venules in DH reactions are hyperpermeable to plasma pr oteins, leading to extravasation of plasma fibrinogen and its extravas cular clotting to form a fibrin gel that promotes induration and angio genesis. The mechanisms responsible for microvascular hyperpermeabilit y in DH are unknown. Recently, a cytokine named vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF) has been implicated in the chronic vascular hyperpermeability and ang iogenesis of solid and ascites tumors, healing wounds, rheumatoid arth ritis, and psoriasis. These findings suggested that VPF/VEGF might als o have a role in the pathogenesis of DH. Two model systems were studie d: allergic contact dermatitis to poison ivy in human volunteers and c lassical tuberculin hypersensitivity in rats. In both, in situ hybridi zation revealed that the mRNAs encoding VPF/VEGF were strikingly overe xpressed in keratinocytes of the epidermis; scattered mononuclear cell s infiltrating the dermis also overexpressed VPF/VEGF mRNA, to a great er extent in rat tuberculin than in human contact reactions. In contac t reactions, mRNAs for two VPF/VEGF vascular endothelial cell receptor s, flt-1 and KDR, were also strikingly overexpressed. Abundant fibrin deposition in both models confirmed that dermal microvessels were inde ed hyperpermeable to plasma fibrinogen. These results implicate VPF/VE GF as a potentially important mediator in the pathogenesis of cell-med iated immunity and provide further evidence that products of epithelia l cells may regulate the inflammatory response.