Low dose tolerance vaccine platform, reovirus protein sigma 1 and treatment of autoimmunity

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Montana State University - Bozeman, College of Agriculture


Effective treatments for multiple sclerosis (MS) are problematic due to its unknown etiology. Experimental autoimmune encephalomyelitis (EAE) in rodents mimics MS. Mucosal treatment of EAE with antigens to induce tolerance is effective, but requires large and/or multiple administrations, which introduces an allergy risk. We utilized reovirus adhesin, protein sigma 1 (p sigma1), to improve mucosal auto-antigen delivery and show that a single low-dose of p sigma1-based vaccines induces tolerance and prevents autoimmunity when administered nasally. We engineered three p sigma1-based vaccines carrying chicken ovalbumin (OVA-p sigma1) and/or myelin antigens (PLP:OVA-p sigma1, MOG-p sigma1). When mice were nasally immunized with OVA-p sigma1, tolerance to OVA was established. This tolerance resisted co-administration of mucosal adjuvants and peripheral challenge with OVA. P sigma1-mediated tolerance relied upon specific IL-10- producing regulatory T (T reg) cells, which inhibited OVA-specific CD4+ T cell proliferation. OVA-p sigma1 did not generate tolerance in IL-10-deficient mice presumably by a failure to induce T reg cells. Mucosal, but not systemic p sigma1 delivery, induced tolerance, while mice lacking mucosal inductive tissues were resistant to p sigma1-mediated tolerance. Likewise, PLP:OVA-p sigma1 and MOG-p sigma1 protected mice against relapsing-remitting or acute EAE, respectively. Protection against PLP139-151-induced EAE was accomplished by PLP:OVA-p sigma1, but not OVA-p sigma1, implicating antigen-specificity of p sigma1-mediated tolerance. Moreover, MOG-p sigma1, but not PLP:OVA-p sigma1, ameliorated MOG35-55-induced EAE via apoptosis of encephalitogenic CD4+ T cells. The PLP:OVA-p sigma1- or MOG-p sigma1-mediated protection against EAE depends on specific IL-10+ T reg cells and is supported by IL-4+ Th2-type cells. Adoptive transfer of PLP:OVA-p sigma1-primed T reg cells entirely prevented EAE development in mice; however, transfer of PLP:OVA-p sigma1-specific CD25- CD4+ Th2 cells significantly reduced and delayed clinical EAE. Aggressive EAE, due to the TGF-beta which induced activation of Th17 cells, was observed in mice dosed with PLP:OVA-p sigma1 and were functionally depleted of T reg cells. Concomitant inactivation of TGF-beta and T reg cells induced Th2 cells bias and re-established PLP:OVA-p sigma1-mediated protection against EAE. IL-10-producing B cells supported MOG-p sigma1-mediated protection against EAE, as MOG-p sigma1-dosed B cell-deficient mice developed attenuated disease. Adoptive transfer of T reg cells, but not Th2 or B cells from MOG-p sigma1-dosed B6 mice to diseased IL-10-/- mice, significantly accelerated recovery from EAE. These data demonstrate the feasibility of using p sigma1-based single-dose delivery system to prevent and/or treat autoimmunity.




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