Examining the role of IFN-g+IL-17+ pathogenic Th17 cells in severe ocular allergy

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 DESCRIPTION (provided by applicant): Ocular allergy ranges from mild (i.e. seasonal and perennial allergic conjunctivitis (SAC and PAC, respectively)) to severe (i.e. atopic and vernal keratoconjunctivitis (AKC and VKC, respectively)). Current established models of ocular allergy predominantly mimic the mild forms; however, our lab has developed a novel mouse model that mimics more severe disease. Ocular allergy is classically a T helper (Th) 2-mediated disease; however, other Th cytokines, such as IFN-γ and IL-17, have been detected in AKC and VKC patients. While this suggests that Th1 and Th17 may be involved in severe ocular allergy, the cells responsible for the production of these cytokines have not been determined. My central hypothesis is that pathogenic IFN- γ+IL-17+ Th17 cells play a key role in the imunopathogenesis of severe ocular allergy, and they accomplish this via the recruitment of neutrophils. I have preliminary data comparing our model of severe ocular allergy with a model of mild allergy. My preliminary data demonstrates that mice with severe ocular allergy developed severe clinical manifestations consistent with what is seen in patients with AKC and VKC, specifically: white stringy discharge, anterior blepharitis, meibomitis, and corneal epitheliopathy, all of which are absent in the mild model. In addition, mice with severe ocular allergy have higher frequencies of pathogenic IFN-γ+IL-17+ Th17 cells compared to mice with mild disease. Interestingly, increased neutrophils were only detected in the conjunctiva of mice with severe ocular allergy, which is important because Th17 cells play a key role in neutrophil recruitment/activation. Thus, my preliminary data suggests that pathogenic IFN- γ+IL-17+ Th17 cells are important in the immunopathogenesis of severe ocular allergy, and may be doing so via recruitment and activation of effector neutrophils. I will test this with two aims. In my firstaim I will determine the role pathogenic IFN-γ+IL-17+ Th17 cells play in severe ocular allergy by depleting this population using anti- IL-23 and assessing how it affects the development of severe disease. In another experiment, I will also generate pathogenic IFN-γ+IL-17+ Th17 cells in vitro and determine if severe ocular allergy develops after adoptive transfer. In my second aim I will evaluate the role of IL-17-induced neutrophil infiltration into the conjunctiva in the pathogenicity of severe ocular allergy. I will do so by depleting neutrophils using anti-Ly6G and determining how severe ocular allergy is affected. In a subsequent experiment, I plan to test whether local transfer of neutrophils (via subconjunctival injection) can induce severe disease in the allergy setting. In summary, by the completion of these studies, my expectation is to have an understanding of the role of pathogenic IFN-γ+IL-17+ Th17 cells in severe ocular allergy. The successful completion of these studies has the potential to lead to creation of new therapies for this vision-threatening disease.