Through studies proposed here, we will develop a strategy for antigen-specific negative immunization to prevent and treat contact dermatitis. Further, the studies proposed will establish a model approach that could be extended for the development of therapies to prevent or treat a broad range of T-cell mediated inflammatory skin diseases. We propose to manipulate neuroinflammatory responses in the skin at the moment of antigen challenge to prevent the development of antigen-specific T-cell responses including prevention of the development of T-cell memory. Further, we will extend this strategy to mitigate/abrogate established memory T-cell responses that underlie chronic inflammatory skin diseases. To accomplish this we will utilize novel microneedle array (MNA) technology developed in our laboratory. These MNAs have been formulated to achieve simultaneous delivery of antigen (Ag) and neuroimmunomodulatory small molecules to a specific skin stratus. By combining this innovative immune-regulatory approach with our novel MNA delivery technology, we will engineer the cutaneous microenvironment in vivo. The purpose of our approach is to generate Ag specific anti-inflammatory antigen presenting cells (APCs) capable of presenting Ag to T cells in a tolerogenic fashion. This strategy will enable, for the first time an Ag-specific therapy for the prevention and treatment of T-cell mediated skin diseases. We will evaluate the effects of this strategy on the prevention of Ag-specific effector and memory T-cells (Aim 1), and the mitigation/abrogation of preexisting memory responses (Aim 2). We will determine mechanisms that prevent immune induction, including effects on skin APC function, and memory T-cell induction, function, and survival. Importantly, our experiments include translational studies focusing on human skin (Aims 1 and 2) that are specifically designed to enable rapid translation of this strategy to clinical trials.
Chronic inflammatory skin disorders are common incapacitating diseases with increasing incidence and high socioeconomic impact. In particular, contact dermatitis (CD) is a substantial health problem, which, as result of increased exposure to skin sensitizers in modern domestic and working environments, has escalated across age and gender differences. A recent joint study by the Society of Investigative Dermatology and the American Academy of Dermatologists concludes that the prevalence of allergic CD is 18% Allergic CD is the second highest cause of work-related diseases in the USA and an annual cost of in the USA up to 1.4 billion dollars. The onset and relapses of CD involve neuro-immunologic networks not addressed by current therapies. In this project we designed a therapeutic strategy that considers recent advances in immunology, neurology, and bioengineering. We will test a of a newly engineered neuro-immune regulation device based on a delivery platform unique to our laboratories. Our therapeutic system integrates a highly regulated skin-targeting strategy to inhibit CD and other antigen specific chronic inflammatory skin disorders. Importantly, our approach includes translational studies focusing on human skin that are specifically designed to enable rapid translation to clinical trials.
| Mathers, A R; Carey, C D; Killeen, M E et al. (2017) Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice. Allergy 72:656-664 |
| Brand, Rhonda M; Epperly, Michael W; Stottlemyer, J Mark et al. (2017) A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage. J Invest Dermatol 137:576-586 |
| Balmert, Stephen C; Donahue, Cara; Vu, John R et al. (2017) In vivo induction of regulatory T cells promotes allergen tolerance and suppresses allergic contact dermatitis. J Control Release 261:223-233 |
| Morelli, Adrian E; Larregina, Adriana T (2016) Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease. Stem Cells 34:1142-50 |
| Liu, Quan; Rojas-Canales, Darling M; Divito, Sherrie J et al. (2016) Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J Clin Invest 126:2805-20 |
