title: Design of Polyelectrolyte Multilayers to Promote Immunological Tolerance.
abstract: Recent studies demonstrate that excess signaling through inflammatory pathways (e.g., toll-like receptors, TLRs) contributes to the pathogenesis of human autoimmune diseases, including lupus, diabetes, and multiple sclerosis (MS). We hypothesized that codelivery of a regulatory ligand of TLR9, GpG oligonucleotide, along with myelin-the "self" molecule attacked in MS-might restrain the pro-inflammatory signaling typically present during myelin presentation, redirecting T cell differentiation away from inflammatory populations and toward tolerogenic phenotypes such as regulatory T cells. Here we show that myelin peptide and GpG can be used as modular building blocks for co-assembly into immune polyelectrolyte multilayers (iPEMs). These nanostructured capsules mimic attractive features of biomaterials, including tunable cargo loading and codelivery, but eliminate all carriers and synthetic polymers, components that often exhibit intrinsic inflammatory properties that could exacerbate autoimmune disease. In vitro, iPEMs assembled from myelin and GpG oligonucleotide, but not myelin and a control oligonucleotide, restrain TLR9 signaling, reduce dendritic cell activation, and polarize myelin-specific T cells toward tolerogenic phenotype and function. In mice, iPEMs blunt myelin-triggered inflammatory responses, expand regulatory T cells, and eliminate disease in a common model of MS. Finally, in samples from human MS patients, iPEMs bias myelin-triggered immune cell function toward tolerance. This work represents a unique opportunity to use PEMs to regulate immune function and promote tolerance, supporting iPEMs as a carrier-free platform to alter TLR function to reduce inflammation and combat autoimmunity.
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.
authors: Lisa H
authors: LH
authors: Tostanoski
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.
authors: Yu-Chieh
authors: YC
authors: Chiu
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.
authors: James I
authors: JI
authors: Andorko
authors: Multiple Sclerosis Center of Excellence-East, United States Department of Veterans Affairs , 655 West Baltimore Street, Baltimore, Maryland 21201, United States.
authors: Ming
authors: M
authors: Guo
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.
authors: Xiangbin
authors: X
authors: Zeng
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.
authors: Peipei
authors: P
authors: Zhang
authors: Multiple Sclerosis Center of Excellence-East, United States Department of Veterans Affairs , 655 West Baltimore Street, Baltimore, Maryland 21201, United States.
authors: Walter
authors: W
authors: Royal
authors: Fischell Department of Bioengineering, University of Maryland , 8228 Paint Branch Drive, College Park, Maryland 20742, United States.|Department of Microbiology and Immunology, University of Maryland Medical School , 685 West Baltimore Street, HSF-I Suite 380, Baltimore, Maryland 21201, United States.|United States Department of Veterans Affairs , 10 North Greene Street, Baltimore, Maryland 21201, United States.|Marlene and Stewart Greenebaum Cancer Center , 22 South Greene Street, Baltimore, Maryland 21201, United States.
authors: Christopher M
authors: CM
authors: Jewell
keywords: autoimmunity and tolerance; biomaterials; human patients and clinical data; immunology and vaccines; nanotechnology; polyelectrolyte multilayers; self-assembly