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

Abstract

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 antigenspecific 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.

Pulmonary Administration of Soluble Antigen Arrays Is Superior to Antigen in Treatment of Experimental Autoimmune Encephalomyelitis

“…But, no change was seen in these cytokines, as we have shown in literature 3,28 . All three cytokine levels, however, seem to be similar to previous studies 21 . One major reason for the variation in cytokine levels reported in literature is because of comparisons made between differing time points of the study.…”

“…Antigen-specific immunotherapies in the form of ‘allergy shots’ are traditionally administered via subcutaneous injections 13,20,21 . Injections of antigens can potentially transport by two mechanisms: via diffusion from the injection site to regional lymph nodes or into systemic circulation or via active cellular transport to lymph nodes 1–5 .…”

Immune Tolerance for Autoimmune Disease and Cell Transplantation

“…Strategies have also been developed to conjugate antigen onto larger polymers or proteins (86). Hyaluronic acid polymers grafted with antigen- and B7-inhibiting peptides decreased disease scores in the EAE model with three subcutaneous injections, a result that is hypothesized to result from inhibition of costimulation in the context of TCR engagement.…”

Co-delivery of autoantigen and dexamethasone in incomplete Freund's adjuvant ameliorates experimental autoimmune encephalomyelitis

“…Co-delivery of autoantigen and immunomodulator has been successful in animal models of autoimmunity [7-14]. These promising results may be attributed to the spatial and temporal combination of the components in order to elicit the appropriate antigen-specific immune response.…”