Development of a novel platform for the delivery of AhR antagonists to DCs and T cells

University Of Montana, Missoula MT

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Abstract

? DESCRIPTION (provided by applicant): Environmentally induced immunosuppression contributes to increased susceptibility to infectious diseases and cancer and is responsible for significant morbidity and mortality in people throughout the world. Recently, the Aryl hydrocarbon Receptor (AhR) signaling pathway has been identified in playing a significant role in mediating the effects of a large number of environmental pollutants and subsequent immune-related disease. To this end, blocking AhR activation by environmental chemicals (ie TCDD and dioxin-like compounds) can effectively be used to treat environmentally induced, immunologic dysfunction, primarily by inhibiting the generation of immunoregulatory dendritic cells (DCs), and regulatory T cells (Tregs). However, because AhR activation plays a major role in xenobiotic metabolism and immunoregulation, many adverse side effects (ie increased inflammation and enhanced oxidative stress) are associated with systemic administration of AhR antagonistic compounds. In contrast, the development of novel technological approaches to selectively deliver an highly efficacious AhR antagonist in a tissue- or cell-specific manner has the potential to generate localized therapies to treat and possibly cure environmentally induced immune deficiencies, dramatically enhancing the level of care for patients suffering from the adverse effects of exposure to AhR-activating contaminants such as smoke and urban air pollution. We propose to: (1) generate novel PEGylated liposomal nanoparticles (LNPs) to selectively deliver potent AhR antagonists to dendritic cells and CD4+ T cells using targeting molecules (i.e. monoclonal antibodies and defined peptides); (2) define optimal route(s) of administration, bio-distribution, and therapeutic effects of targeted LNPs in vivo, and (3) evaluate the effects of blocking AhR activation with targeted LNPs in virally-infected animals. This translational and highly collaborative approach will effectively block AhR activation in tissue-specific DCs and T cells, inhibiting the development of immunosuppression, and ultimately leading to a novel and significant therapeutic platform for the treatment of environmentally-induced immune suppression.