title: Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity.
abstract: Autoimmune diseases occur when the immune system incorrectly recognizes self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLRs), pathways usually involved in generating immune responses against pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR signaling, and in primary dendritic cell and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
authors.forename: Krystina L
authors.initials: KL
authors.lastname: Hess
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Andorko
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Tostanoski
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, 8228 Paint Branch Drive, College Park, MD 20742, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA; United States Department of Veterans Affairs, 10 North Greene Street, Baltimore, Maryland 21201, USA. Electronic address: cmjewell@umd.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jewell
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy*; D009696:Nucleic Acids; D020135:Peptide Nucleic Acids / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D001324:Autoantigens; D009696:Nucleic Acids; D020135:Peptide Nucleic Acids; D051193:Toll-Like Receptors
keywords: Immunology; Nanoparticle; Polyplex; Self-assembly; Tolerance and autoimmunity; Toll-like receptor