Mutant interleukin-4/13 signaling blockade successfully suppresses acute phase inflammation

Atopic dermatitis (AD) is a chronic disease with Th2-type-cytokine dominant profile. Several cytokines and related peptides had been tried for the treatment of AD but with unsuccessful results; a part of the reason is the limitation of their biological half time. We have recently developed a highly efficient mouse dominant negative IL-4/IL-13 DNA vaccine, which blocks both IL-4 and IL-13 signal transductions, resulting in the amelioration of atopic reaction. At the next step, the further consistent protein supplementation system is required for stable suppression of allergic reaction. To examine the effects of mutant IL-4/13 protein supplementation from skin, a keratinocyte-specific dominant negative IL-4-transgenic mouse line (IL-4DM) was established. The anti-inflammatory function was evaluated measuring ear thickness and analyzing histological change in mice AD model induced by repeated elicitation of oxazolone. In IL-4DM, ear thickness was suppressed significantly in the early phase of the elicitation schedule of contact hypersensitivity response. We next transplanted IL-4DM skin to normal control mice, and investigated effects in inflammatory reactions. In IL-4DM-skin-grafted mice, the inflammatory response was suppressed significantly similarly in the early phase accompanied with lesional suppressed Th2-type-cytokine signaling transduction. IL-4DM skin has the anti-inflammatory function especially in the acute phase of AD. Although there are several issues to be addressed for human application, the present results implicated that the gene manipulated skin transplantation is a potent therapeutic strategy to control allergic reactions.