Project: B03

CD83-based immunomodulation in ocular surface inflammation such as dry eye

Ocular surface inflammation is involved in multiple ophthalmological diseases leading to corneal hem- and lymphangiogenesis and hence to corneal blindness. Previous studies on autoimmunity and transplantation have shown that the soluble form of the CD83 molecule (sCD83) ameliorates inflammation via the induction of tolerogenic dendritic cells (tDCs) and alternatively activated macrophages (AAMs), both inducing resolution of inflammation and establishing long-term immune tolerance. We have previously shown that sCD83 prolongs the survival of corneal transplants in a high-risk murine keratoplasty model, which is mechanistically mediated via the upregulation of the immune modulators IDO and TGF-ß, leading to the induction/expansion of regulatory T cells (Tregs). Thrombospondin-1 (TSP-1) as a key activator of latent TGF-ß serves as a regulator of inflammatory immune responses and corneal lymphangiogenesis.

Mice lacking TSP-1 develop an immune-mediated form of dry eye disease which involves the maturation of antigen-presenting cells such as dendritic cells (DCs), T cell activation, and secretion of proinflammatory cytokines. In addition, Herpes viruses such as the Herpes simplex virus type 1 (HSV-1) can induce strong proinflammatory immune responses in the corneal stroma via activation of mature proinflammatory DCs and classically activated macrophages (CAMs), leading to herpetic stromal keratitis (HSK). For both conditions (i.e. dry eye and HSK), there is a great unmet medical need for novel therapeutic treatment options targeting inflammatory immune responses. In this project, the candidate will investigate the hypothesis thatr sCD83 can ameliorate ocular surface inflammation and associated (lymph)angiogenesis and induce long-term resolution of inflammation in the immune-mediated Thrombospondin-1 deficient dry eye disease and herpetic stromal keratitis. The knowledge gained in this project will improve our understanding of the basic concept of inflammatory eye disorders and may open avenues for new therapeutic strategies to treat patients with severe ocular surface inflammation.

Key methods: in vivo model of dry eye disease and herpetic stromal keratitis, flow cytometry, cytokine bead array, cell culture, functional assays, IHC, IF, live cell imaging, qRT-PCR, scRNA-seq, bioinformatics, western blot