Single Dose Nasal Immunotherapy Rapidly Recruits NK Cell-Dependent Regulatory T (Treg) Cells into Central Nervous System (CNS) to Ameliorate Experimental Autoimmune Encephalomyelitis (EAE) (96.12)

Reovirus protein sigma 1 (pσ1), engineered to deliver OVA mucosally, induced tolerance in mice even with a single, low dose. To test the efficacy of pσ1-based therapy, the extracellular domain of myelin oligodendrocyte glycoprotein (MOG29-146) was genetically fused to pσ1 (MOG-pσ1). Susceptible C57BL/6 mice were nasally dosed with PBS, MOG-pσ1, or recombinant (r)MOG and 3 wks later were challenged with MOG35-55-induced EAE. MOG-pσ1, not rMOG or PBS, abrogated EAE incidence evidenced by >8-fold reductions in IFN-γ, IL-17, and IL-21, but greatly elevated IL-4 and IL-10. To test its therapeutic potential at the peak of MOG35-55-induced EAE (around day 15), mice were nasally treated with 50 μg of MOG-pσ1 or PBS. Strikingly, within 24 hrs of treatment with MOG-pσ1, >2-fold reduction in clinical symptoms were obtained. This improved clinical response was accompanied by a significant increase of at least 4-fold in FoxP3+ Treg cells in the spinal cords of treated mice; however, such increases were not evident in head and neck lymph nodes or the spleen. This increase in Treg cell infiltration into the CNS appears to be NK cell-dependent since this infiltration was abated in NK cell-depleted mice. Finally, enhanced apoptosis (30%) of infiltrating CD11c+ CD11b+ DCs was observed, underscoring the complexity of this system. * Authors contributed equally to the work; supported by NIH AI-78938.