Self-assembly of immune signals to induce and control tolerance

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune disease in which myelin insulating neurons is attacked. New research in humans shows excess inflammation through toll like receptors (TLR) contribute to disease. In animals, co-administration of self-antigens and regulatory cues leads to more specific tolerance. Polymers and other biomaterials can enable this co-delivery, along with attractive features such as tunable cargo loading, targeting, and cargo protection. However, these materials often exhibit intrinsic properties that can cause inflammation; features that might exacerbate disease. Thus, we designed immune polyelectrolyte multilayers (iPEMs) mimicking attractive features of biomaterial, but constructed entirely from immune signals. iPEMs were built by electrostatic interactions between myelin-derived, cationic peptides with an anionic, regulatory TLR9 antagonist (GpG). We hypothesized iPEMs would reduce TLR-driven inflammation during T cell differentiation, biasing expanding myelin-reactive T cells away from effector cells (TH1, TH17) and toward regulatory T cells (TREG) that control disease specifically. In culture, iPEMs co-deliver each signal to dendritic cells, reduce TLR9 levels, deactivate DCs, and promote myelin-specific TREG. These results depend on the presence of both GpG and myelin. In mice, iPEMs reduce TH17 and TH1 cells, expand TREG, and reverse MS-like disease (EAE). In samples from human MS patients, iPEMs also activate T cells, but polarize cytokine profiles toward tolerance and away from inflammation. This approach represents a simple, modular platform for combatting autoimmunity by programming the combinations and relative concentrations of self-antigens and regulatory TLR ligands.