(17e) Design of Self-Assembled Nanostructures Built from Immune Signals to Combat Autoimmune Disease

In multiple sclerosis (MS), myelin insulating neurons is attacked by the immune system. New studies in human MS patients reveal excess inflammation through toll like receptors (TLR) contribute to disease, and in animals, co-administration of self-antigens and regulatory cues can promote more specific tolerance. Biomaterials can enable this co-delivery and other attractive features (e.g., tunable loading, cargo protection), but can cause inflammation that exacerbates disease. Thus, we designed immune polyelectrolyte multilayers (iPEMs) mimicking attractive features of biomaterial, but assembled entirely from myelin-derived peptides and a macromolecular, regulatory TLR9 antagonist using a layer-by-layer strategy. We hypothesized these iPEMs would reduce TLR-driven inflammatory cues, biasing expanding myelin-reactive T cells away from effector cells (T_H1, T_H17) and toward regulatory T cells (T_REG) that control disease without broad immunosuppression. In culture, iPEMs co-deliver each signal to dendritic cells, attenuate TLR9 signaling, deactivate DCs, and polarize myelin-specific T cells toward T_REG. Importantly, these effects depend on integration of both myelin and the TLR antagonist. In mice, iPEMs reduce T_H17 and T_H1 cells, expand regulatory T cells, and eliminate MS-like disease in all mice. In samples from human MS patients, iPEMs also activate T cells, but polarize the cytokine profiles of these cells away from inflammation and toward tolerogenic function. This is the first time polyelectrolyte multilayers have been used to promote tolerance, representing a new platform for combatting autoimmunity by programming the combinations and relative concentrations of self-antigens and regulatory TLR ligands.