Abstract

A critical step in the development of autoimmune diseases is the stimulation of immune cells against endogenous antigen. Here, we investigate soluble antigen arrays (SAgAs) capable of suppressing autoimmune response to antigen. When properly designed, these nanomaterials facilitate: 1) drainage to lymph nodes (site of antigen priming) and 2) multivalent presentation of both antigen and an immune cell adhesion inhibitor (to suppress immune response to the co- grafted antigen). Compelling preliminary data show that SAgAs significantly attenuated disease progression in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The objective of this study is to systematically study how the nanomaterial properties of SAgAs affect the local biodistribution and in vivo outcomes. Our central hypothesis is that, Targeted-SAgAs from 20-100 kDa will compartmentalize to regional lymph nodes and will significantly improve clinical outcomes and shift biomarkers towards immune tolerance. We propose four Specific Aims:
Specific Aim #1 : Synthesize and characterize Soluble Antigen Arrays (SAgAs).
Specific Aim #2 : Evaluate the therapeutic performance of SAgAs in EAE mice.
Specific Aim #3 : Identify the local biodistribution of SAgAs.
Specific Aim #4 : Define immune cells and soluble mediators that control EAE following treatment with the SAgAs. Nanomaterials that localize to lymph nodes and present antigens to induce immune tolerance represent an unexplored therapeutic approach for treating autoimmune diseases. This unique therapeutic approach addresses national health interests by firmly establishing the potential for innovative nanomaterial immunotherapies capable of inducing immune tolerance and extendable to novel vaccination schemes.

Public Health Relevance

A critical need exists to identify key properties of nanomaterials to influence immune response. This proposal aims study progression of multiple sclerosis in animals that have been treated with nanomaterials specifically designed to interfere with immune signaling.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI091996-01A1
Application #
8513574
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Rothermel, Annette L
Project Start
2012-08-15
Project End
2014-07-31
Budget Start
2012-08-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$381,304
Indirect Cost
$118,804

  Institution

Name
University of Kansas Lawrence
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045

  Publications

Hartwell, Brittany L; Pickens, Chad J; Leon, Martin et al. (2018) Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis. J Autoimmun 93:76-88
Kuehl, Christopher; Thati, Sharadvi; Sullivan, Bradley et al. (2017) Pulmonary Administration of Soluble Antigen Arrays Is Superior to Antigen in Treatment of Experimental Autoimmune Encephalomyelitis. J Pharm Sci 106:3293-3302
Hartwell, Brittany L; Smalter Hall, Aaron; Swafford, David et al. (2016) Molecular Dynamics of Multivalent Soluble Antigen Arrays Support a Two-Signal Co-delivery Mechanism in the Treatment of Experimental Autoimmune Encephalomyelitis. Mol Pharm 13:330-43
Hartwell, Brittany L; Martinez-Becerra, Francisco J; Chen, Jun et al. (2016) Antigen-Specific Binding of Multivalent Soluble Antigen Arrays Induces Receptor Clustering and Impedes B Cell Receptor Mediated Signaling. Biomacromolecules 17:710-22
Hartwell, Brittany L; Antunez, Lorena; Sullivan, Bradley P et al. (2015) Multivalent nanomaterials: learning from vaccines and progressing to antigen-specific immunotherapies. J Pharm Sci 104:346-61
Thati, Sharadvi; Kuehl, Christopher; Hartwell, Brittany et al. (2015) Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis. J Pharm Sci 104:714-21
Northrup, Laura; Sestak, Joshua O; Sullivan, Bradley P et al. (2014) Co-delivery of autoantigen and b7 pathway modulators suppresses experimental autoimmune encephalomyelitis. AAPS J 16:1204-13
Chittasupho, Chuda; Sestak, Joshua; Shannon, Laura et al. (2014) Hyaluronic acid graft polymers displaying peptide antigen modulate dendritic cell response in vitro. Mol Pharm 11:367-73
Sestak, Joshua O; Sullivan, Bradley P; Thati, Sharadvi et al. (2014) Codelivery of antigen and an immune cell adhesion inhibitor is necessary for efficacy of soluble antigen arrays in experimental autoimmune encephalomyelitis. Mol Ther Methods Clin Dev 1:14008
Sestak, Joshua O; Fakhari, Amir; Badawi, Ahmed H et al. (2014) Structure, size, and solubility of antigen arrays determines efficacy in experimental autoimmune encephalomyelitis. AAPS J 16:1185-93

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