Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis

Brittany L. Hartwell, Aaron Smalter Hall, David Swafford, Bradley P. Sullivan, Aaron Garza, Joshua O. Sestak, Laura Northrup, Cory Berkland

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)330-343
Number of pages14
JournalMolecular pharmaceutics
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
We gratefully acknowledge support from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (R56 AI091996), Kansas IDeA Network of Biomedical Research Excellence, American Foundation for Pharmaceutical Education (AFPE) PreDoctoral Fellowship in Clinical Pharmaceutical Science, and the Madison and Lila Self Graduate Fellowship at the University of Kansas. Additionally, we thank the Macromolecule and Vaccine Stabilization Center at the University of Kansas for instrument use.

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

  • antigen-specific immunotherapy
  • autoimmunity
  • co-delivery
  • molecular dynamics
  • nanomaterials

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