This project aims to develop new methods to stimulate dendritic cells by finding synergistic combinations of molecular agonists. The long-term goal is to improve vaccine performance using a chemical strategy of directing the immune system. Today, vaccines are still the most effective form of disease prevention. Vaccines for many diseases remain tantalizingly close to reality, but lack high enough effectiveness to be deployed. Until recently, rationally improving vaccines was considered impossible, as vaccine creation was largely an empirical process. The cellular pathway of vaccine activation, dendritic cells, have now been identified. These cells create immunity to vaccines using a series of receptors that are stimulated by molecular agonists carried in foreign pathogens. The most effective vaccines all stimulate these receptors in synergistic combinations. Using a selected combination of molecular agonists, some vaccines direct dendritic cells to elicit either a cytotoxi immune response or a sustained, humoral response. The placement and concentration of these molecular agonists on the most effective vaccines is the critical element in creating a strong immune response. Many weaker vaccines do not use these synergistic effects. Methods for determining synergies among agonists could potentially improve weak vaccines and reveal fundamental knowledge about immune system activation. Currently however, there are no chemical methods to manipulate these molecular signals, understand their cooperative effects or attach them to potential vaccines to enhance immunity. We propose to develop a method of combining molecular agonists on inert polymeric scaffolds using a series of bio-conjugation reactions. We will use these combinations of agonists to study and understand their synergistic activity in stimulating dendritic cells. Our hypothesis is that facilitated by our scaffold, differnt combinations of agonist will direct the immune system toward greater humoral or cytotoxic immunity. We will also develop methods of coupling our immune-directing polymers onto developed vaccines, such as Enterotoxigenic E. Coli, that were not effective enough for commercial deployment. We will use hetero-telechelic polymer synthesis and an array of bio- conjugation reactions to create a combinatorial library of agonists that target many of the Toll-like and NOD-like receptors on dendritic cells responsible for immune stimulation. We will determine the effect of these combinations using colorimetric, cellular, and immunohistochemical assays of stimulation. Our final effort will be in determining immune direction via T-cell expansion assays. The project is risky, but if successful, could both improve researchers understanding of the stimulation of the immune system and create a method of directing the immune response for strengthening many potential vaccines.

DP2AI112194

2013-09-24

2018-08-31