Immune-mediated diseases such as autoimmunity, allergic diseases and chronic inflammatory diseases are increasing annually and are responsible for significant morbidity and mortality in people in the U.S. and throughout the world. Recently, the Aryl hydrocarbon Receptor (AhR) signaling pathway has been successfully utilized to treat immune-mediated diseases in mice. To this end, activation of the AhR using various novel and relatively non-toxic ligands (i.e. ITE, VAF347, etc.) have effectively been used in a prophylactic and therapeutic manner to treat immune-mediated diseases, primarily by generating immunoregulatory dendritic cells (DCs), regulatory T cells (Tregs), and immunomodulation. However, because of the immunosuppressive nature of AhR agonists, many adverse side effects are associated with systemic administration of these compounds. In contrast, novel technological approaches to selectively deliver high-affinity AhR ligands in a tissue- and/or cell- specific manner have the potential to generate localized and/or antigen-specific therapies to treat and even cure immune-mediated diseases--dramatically enhancing the level of care for patients suffering from these conditions. In this proposal, we will develop and validate a novel, non-toxic method to deliver select AhR ligands to murine DCs using PEGylated liposomal based nanoparticles (LNPs), with/without monoclonal antibodies (for targeting delivery to CD11c+ murine DCs) and peptide antigen (for antigen- and disease-related specificity). This approach will generate immunoregulatory DCs, antigen-specific Tregs, and highly selective immunosuppression, ultimately leading to a significant advancement in the treatment of immune-mediated diseases.
This proposal will determine the optimal methods for delivery of a potent novel AhR agonist (plus antigen) specifically to DCs using liposomal based nanoparticles. The ultimate objective of this proposal is to develop a novel treatment for immune-mediated diseases based upon the generation of disease-specific immunoregulatory cells to induce localized and highly specific immune suppression.
| Kreitinger, Joanna M; Beamer, Celine A; Shepherd, David M (2016) Environmental Immunology: Lessons Learned from Exposure to a Select Panel of Immunotoxicants. J Immunol 196:3217-25 |
