Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis
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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 WORDSantigen-specific immunotherapy B7/CD28:CTLA-4 co-stimulatory pathway experimental autoimmune encephalomyelitis (EAE) proteolipid peptide soluble antigen array
Soluble antigen array
B7 antisense peptide
CD80 competitive antagonist peptide
Soluble antigen array co-grafted with PLP and LABL peptides
Soluble antigen array co-grafted with PLP and B7AP peptides
Soluble antigen array co-grafted with PLP and CD80-CAP peptides
Soluble antigen array co-grafted with PLP and sF2 peptides
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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