Fast and Accurate Dynamic Simulations of Biological Systems

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is thought to result from a breakdown of self-tolerance that is characterized by T cell-mediated destruction of the insulin-producing -cells in the pancreas. Ultimately, glucose metabolism is interrupted, resulting in the development of life-threatening complications such as heart disease and renal failure. A number of factors are known to promote advantageous immune cell responses in experimental systems for T1D. However, systemic delivery of these agents often results in significant harmful off-target effects. We have pioneered a novel, biomaterial-based, particle vaccine system for in vivo delivery of pro- tolerance factors and insulin antigen, targeted to a key immune cell type, dendritic cells(DCs). Dendritic cells are professional antigen presenting cells (APCs), directly involved in T cell and B cell immunity, including the maintenance of tolerance to self-antigens. Moreover, exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro- tolerance DC phenotype as well as ameliorate T1D. Vaccination with DC-targeting microparticles (MPs) holds promise to correct T1D autoimmune responses, critically, without the costly ex vivo manipulations required of DC-based cellular therapy. Our long term goal is to develop an easily injectable, particle vaccine capable of prevention and reversal of T1D in humans. This approach greatly enhances the potential for widespread use. The objective of this Phase I proposal is tocomplete preclinical studies that demonstrate the feasibility of our most promising particle vaccine formulation for use in humans. More specifically, we want to assess biodistribution, bioavailability, toxicity and potentially harmful ff-target effects of the particle vaccine in preclinical models of T1D. Our preliminary data strongly suggests that this biomaterial-based, particle vaccine system holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Biomedical Engineering Department, College of Medicine and Diabetes Center of Excellence at the University of Florida boost our capability to complete the desired goals. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Type 1 diabetes is an autoimmune disease with enormous socioeconomic impact in the US. Therapeutic vaccination approaches for type-1 diabetes hold promise to correct these antigen- specific autoimmune responses. We seek to develop an easily injectable, polymeric biomaterial- based microparticle vaccine capable of targeted delivery of immuno-modulatory agents to immune cells, avoiding off-target effects that normally accompany systemic administration. The aim of this project is to initiate pre-clinical testing that demonstrates the translatability of this approach which addresses this unmet health need. We believe these studies are highly relevant to the mission of the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) and are designed to result in a significantimpact on public health.