The AAPS Journal

, Volume 16, Issue 6, pp 1204–1213 | Cite as

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

  • Laura Northrup
  • Joshua O. Sestak
  • Bradley P. Sullivan
  • Sharadvi Thati
  • Brittany L. Hartwell
  • Teruna J. Siahaan
  • Charlotte M. Vines
  • Cory Berkland
Research Article Theme: Nanoparticles in Vaccine Delivery
Part of the following topical collections:
  1. Theme: Nanoparticles in Vaccine Delivery

Abstract

Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.

KEY WORDS

antigen-specific immunotherapy B7/CD28:CTLA-4 co-stimulatory pathway experimental autoimmune encephalomyelitis (EAE) proteolipid peptide soluble antigen array 

Abbreviations

HA

Hyaluronic acid

SAgA

Soluble antigen array

PLP

Proteolipid peptide

B7AP

B7 antisense peptide

CD80-CAP

CD80 competitive antagonist peptide

SAgAPLP:LABL

Soluble antigen array co-grafted with PLP and LABL peptides

SAgAPLP:B7AP

Soluble antigen array co-grafted with PLP and B7AP peptides

SAgAPLP:CD80-CAP

Soluble antigen array co-grafted with PLP and CD80-CAP peptides

SAgAPLP:sF2

Soluble antigen array co-grafted with PLP and sF2 peptides

Supplementary material

12248_2014_9671_MOESM1_ESM.docx (33 kb)
Supplemental Figure 1The molecular weight of each SAgA was calculated from GPC data. (A) The retention time of each SAgA was used to determine the molecular weight as compared to a (B) pullulan polymer standard curve. Results shown are an average from triplicate injections of a single batch preparation. All samples had a RSD ≤ 0.01. (DOCX 32 kb)
12248_2014_9671_MOESM2_ESM.docx (1.5 mb)
Supplemental Figure 2SAgAPLP:sF2 was analyzed for subvisible particulate formation at a concentration of 0.1 mg/ml in PBS using micoflow imaging (MFI). Representative images of insoluble aggregates from 25 to 70 μm equivalent circular diameter are shown. (DOCX 1558 kb)
12248_2014_9671_MOESM3_ESM.docx (153 kb)
Supplemental Figure 3ICAM-1 and B7-targeted SAgAs were found to reduce disease incidence in EAE mice. EAE was induced on day zero, and mice were treated on days four, seven, and ten with a dose of SAgA equivaent to 200 nMol PLP. Treatments of HA were administered at a dose equivalent of the SAgAs, 29 nMol. EAE disease incidence was evaluated such that disease free animals maintained a clinical score <1. In all the SAgA treatment groups, over half of the animals remained disease free over the course of the study, while in both negative control groups all animals became diseased. (n = 6 mice per group) (DOCX 152 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Laura Northrup
    • 1
  • Joshua O. Sestak
    • 1
  • Bradley P. Sullivan
    • 1
  • Sharadvi Thati
    • 1
  • Brittany L. Hartwell
    • 2
  • Teruna J. Siahaan
    • 1
  • Charlotte M. Vines
    • 3
  • Cory Berkland
    • 1
    • 2
    • 4
  1. 1.Department of Pharmaceutical ChemistryUniversity of KansasLawrenceUSA
  2. 2.Bioengineering Graduate ProgramUniversity of KansasLawrenceUSA
  3. 3.Department of Biological SciencesUniversity of Texas at El PasoEl PasoUSA
  4. 4.Department of Chemical and Petroleum EngineeringUniversity of KansasLawrenceUSA

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