title: Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis.
abstract: Many current therapies for autoimmune diseases such as multiple sclerosis (MS) result in global immunosuppression, rendering insufficient efficacy with increased risk of adverse side effects. Multivalent soluble antigen arrays, nanomaterials presenting both autoantigen and secondary inhibitory signals on a flexible polymer backbone, are hypothesized to shift the immune response toward selective autoantigenic tolerance to repress autoimmune disease. Two-signal co-delivery of both autoantigen and secondary signal were deemed necessary for therapeutic efficacy against experimental autoimmune encephalomyelitis, a murine model of MS. Dynamic light scattering and in silico molecular dynamics simulations complemented these studies to illuminate the role of two-signal co-delivery in determining therapeutic potential. Physicochemical characteristics such as particle size and molecular affinity for intermolecular interactions and chain entanglement likely facilitated cotransport of two signals to produce efficacy. These findings elucidate potential mechanisms whereby soluble antigen arrays enact their therapeutic effect and help to guide the development of future multivalent antigen-specific immunotherapies.
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Hartwell
authors.affiliation: Molecular Graphics and Modeling Laboratory, University of Kansas , 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smalter Hall
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: David
authors.initials: D
authors.lastname: Swafford
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.|Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Avenue, Lawrence, Kansas 66047, United States.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.forename: Aaron
authors.initials: A
authors.lastname: Garza
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.|Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Avenue, Lawrence, Kansas 66047, United States.
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Sestak
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.|Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Avenue, Lawrence, Kansas 66047, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Northrup
authors.affiliation: Therapeutic Particles and Biomaterials Technology Laboratory, University of Kansas , 2030 Becker Drive, Lawrence, Kansas 66047, United States.|Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Avenue, Lawrence, Kansas 66047, United States.
authors.forename: Cory
authors.initials: C
authors.lastname: Berkland
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy; D051379:Mice; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D040081:Protein Array Analysis
chemical_list: D001324:Autoantigens; D011108:Polymers
keywords: antigen-specific immunotherapy; autoimmunity; co-delivery; molecular dynamics; nanomaterials