1. Abstract: The number of patients with autoimmunity and other antigen-specific immunoregulatory disorders is increasing worldwide at a rate of 4 to 8% per annum. Current therapies for autoimmunity only treat disease symptoms and are systemically immunosuppressive, resulting in an increased risk of infection and malignancy. The Holy Grail of autoimmune therapies would specifically abrogate pathogenic autoantigen-specific immune response. To this end, we propose the development of a novel biomaterial- based intranasal antigen-specific immunotherapy engineered to elicit auto-antigen specific regulatory T cells that control autoimmunity. Our in intranasal AIST is composed of autoantigens conjugated to a water- soluble polymer that binds to nasal mucus, facilitates paracellular transport across the nasal epithelium, and targets autoantigens and tolerance-programming small molecules (i.e., minocycline and dexamethasone) to underlying nasal DCs, resulting in the induction of autoantigen-specific regulatory T cells that suppress autoimmune responses. In this application, we propose: (1) the synthesis of our novel intranasal ASIT, (2) the demonstration of the ability of our platform to suppress antigen-specific immune responses, and (3) the use of our platform to treat and prevent experimental autoimmune myocarditis. Completion of this project will deliver a clinically viable treatment for autoimmune myocarditis and a therapeutic platform that can be easily tailored to treat other diseases driven by antigen-specific immune dysregulation, including diabetes, multiple sclerosis, transplant rejection, and numerous allergies.

Narrative: As many as 23.5 million Americans suffer from autoimmune dieses and current therapies are non-curative and often systemically immunosuppressive, increasing the risk of opportunistic infections and cancer. The aim of this proposal is to develop an antigen-specific immunotherapy that upon intranasal administration binds to nasal mucus, passes via paracellular transport to the nasal immune system, and actively programs dendritic cells to generate autoantigen-specific regulatory T cells that suppress autoimmunity. Completion of this project will demonstrate the efficacy of a clinically-viable cure for autoimmunity in a preclinical model of autoimmune myocarditis and establish a platform technology that can be easily modified to treat various autoimmune and allergic dieses as well as transplant rejection.