Design of Polyelectrolyte Multilayers to Promote Immune Tolerance

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 further, that co-administration of self-antigens and regulatory signals 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 could exacerbate autoimmunity. Thus, we designed immune polyelectrolyte multilayers (iPEMs) mimicking attractive features of biomaterial, but self-assembled entirely from myelin-derived peptides and a macromolecular, regulatory TLR9 antagonist. We hypothesized these iPEMs would reduce TLR-driven inflammatory cues that expand self-reactive T cells, promoting regulatory T cells that control disease without broad immunosuppression. We show iPEMs co-deliver each signal to dendritic cells, attenuate TLR9 signaling, deactivate DCs, and polarize antigen-specific T cells toward regulatory T cell function. Importantly, these effects depend on integration of both myelin and the TLR antagonist. In mice, iPEMs reduce inflammatory T_H17 and T_H1 cells, expand regulatory T cells, and eliminate MS-like disease. In samples from human MS patient, 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 and could represent a new platform for combatting autoimmune disease by programming the combinations and relative combinations of self-antigens and regulatory TLR ligands.