Engineering the Skin Microenvironment to Promote Allergen Tolerance

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ABSTRACT Allergic contact dermatitis (ACD) is a destructive T-cell-mediated inflammation of the skin, resulting from repeated contact with allergens (e.g. nickel or poison ivy). ACD is one of the most common skin diseases, afflicting roughly 15-20 percent of the population, with annual costs in excess of $2 billion in the U.S. alone. Aside from avoiding known allergens when possible, current treatments involve non-specific anti-inflammatories that transiently suppress cutaneous inflammation, but fail to address the underlying immune dysfunction. In contrast, our bodies ordinarily employ highly specific mechanisms to suppress excessive inflammation, many of which are mediated by regulatory T cells (Tregs). Studies have shown that enhancing allergen or autoantigen-specific populations of Tregs can promote tolerance, or hyporesponsiveness, and ameliorate tissue-destructive inflammation. Information present in the local microenvironments where dendritic cells encounter or present allergen dictates whether T cells will become inflammatory effector T cells (Teff) or protective Tregs. The goal of the studies we propose is to develop an antigen specific strategy to prevent and treat contact dermatitis. We recently demonstrated that sustained local delivery of TReg- Inducing (“TRI”) factors and allergens with degradable, polymeric microparticles (MPs) or microneedle arrays (MNAs) expands allergen-specific Tregs and inhibits Teff differentiation during cutaneous allergen exposure, thereby promoting allergen-specific tolerance. In this proposal, we will induce tolerance by engineering local skin or lymph node microenvironments to promote Treg differentiation. To that end, we will leverage our multidisciplinary team’s combined experience and capabilities to specifically deliver Treg-inducing factors to defined microenvironments of the skin or skin draining lymph nodes using microneedle arrays and micro- sized controlled release systems. Importantly, our experiments include translational studies focusing on human skin that are designed to enable rapid translation of this strategy to clinical trials.