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

  • Research Article
  • Theme: Nanoparticles in Vaccine Delivery
  • Published:
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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.

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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

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Acknowledgments

This work was supported by the NIH (1R56AI091996-01A1), KINBRE (P20 RR016475/P20 GM103418), American Foundation for Pharmaceutical Education (AFPE) Pre-Doctoral Fellowship in Clinical Pharmaceutical Science, and the Takeru Higuchi Graduate Fellowship (University of Kansas). In addition, the authors thank the laboratories of C. Russell Middaugh and David Volkin for use of laboratory equipment and Lorena Antunez, Cavan Kalonia, and Brian Kaiser for their contributions.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of Kansas, 2030 Becker Drive, 320E, Lawrence, Kansas, 66047, USA

    Laura Northrup, Joshua O. Sestak, Bradley P. Sullivan, Sharadvi Thati, Teruna J. Siahaan & Cory Berkland

  2. Bioengineering Graduate Program, University of Kansas, 1520 W 15th, Rm 1 Eaton Hall, Lawrence, Kansas, 66045, USA

    Brittany L. Hartwell & Cory Berkland

  3. Department of Biological Sciences, University of Texas at El Paso, 500 W University Ave, El Paso, Texas, 79968, USA

    Charlotte M. Vines

  4. Department of Chemical and Petroleum Engineering, University of Kansas, 1530 W 15th, Rm 4132 Learned Hall, Lawrence, Kansas, 66045, USA

    Cory Berkland

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  1. Laura Northrup
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Correspondence to Cory Berkland.

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Supplemental Figure 1

The 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)

Supplemental Figure 2

SAgAPLP: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)

Supplemental Figure 3

ICAM-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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Northrup, L., Sestak, J.O., Sullivan, B.P. et al. Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis. AAPS J 16, 1204–1213 (2014). https://doi.org/10.1208/s12248-014-9671-y

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  • DOI: https://doi.org/10.1208/s12248-014-9671-y

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