Complexes assembled from myelin self-antigen and a toll-like receptor antagonist promote tolerance

Abstract

Abstract Myelin, a matrix that insulates the axons of neurons, is attacked by the immune system in multiple sclerosis (MS), leading to neurodegeneration. MS treatments are currently limited because they are non-curative and broadly-acting immunosuppressants that can leave patients immunocompromised. Recent reports show co-delivery of myelin peptides (MOG) along with regulatory signals can promote tolerance to myelin rather than cause inflammation. New studies reveal inflammatory toll-like receptors (TLRs) play a significant role in driving disease in both humans and mice. Further, several reports demonstrate that regular treatment with TLR9 antagonist, GpG, attenuates disease in mouse models of MS. We hypothesized that GpG DNA and cationic MOG peptide would electrostatically self-assemble into complexes, allowing co-delivery, increased cargo protection, and enhanced uptake by immune cells. These complexes might redirect the response against myelin through suppression of inflammatory TLR9 signaling during myelin presentation. Importantly, polyplexes significantly reduced inflammatory TLR9 signaling in a reporter cell line. Primary dendritic cells (DCs) internalized MOG-GpG complexes, resulting in a reduction of activation and decreased proliferation of myelin-reactive T cells. In a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), complex injection reduced disease severity more than 2-fold and incidence by 30%. This data demonstrates the ability of GpG to condense self-antigens while remaining an active immunomodulator. This work also suggests a new carrier-free platform for co-delivery of antigens and immune signals that still provides the more attractive features of biomaterials.