Sunday, May 5, 2024
5/5/2024
SUMMARY The cornea is among the few tissues that enjoy immune privilege, however, corneal immune privilege is not absolute. In many corneal diseases, including infectious keratitis, dry eye disease, and corneal injuries, infiltrating leukocytes can advance disease progression. Our preliminary results suggest that plasmacytoid dendritic cells (PDCs), which reside in the cornea during steady state, actively participate in the maintenance of corneal immune homeostasis, as their depletion leads to enhanced corneal leukocyte infiltration and amplified adaptive immune responses in draining lymph nodes (dLNs). Thus, in this application, we propose to evaluate the significance of PDCs in the maintenance of tolerance and the mechanisms through which PDCs contribute to corneal immune homeostasis. We will identify potential candidates through single cell sequencing of PDCs. We aim to study the role of PDCs in mediating multiple steps involved in the process of inflammation, from leukocyte recruitment to the cornea, antigen uptake and processing by antigen presenting cells, their egress to, and antigen presentation in dLNs, and priming of T cells. Additionally, we have observed that PDCs interact directly with T cells in the dLNs, and support development and stabilization of regulatory T cell (Tregs), important immunosuppressive lymphocytes. We aim to analyze the molecular mechanisms by which PDCs induce and maintain Tregs, as well as examine the clinical utility of adoptive transfer of PDC- induced Tregs in infectious keratitis, dry eye disease and corneal transplantation. We also propose to study the feasibility, efficacy, and potential local and systemic side effects of local adoptive transfer of PDCs to the cornea for the treatment of immune and inflammatory diseases. Next, we aim to evaluate therapeutic efficacy of local adoptive transfer of PDCs or application of PDC secretome in limiting clinical severity of the disease, infiltration of leukocytes, disease progression, and complications in models of dry eye disease and herpes simplex keratitis. This application proposes a paradigm shift on how PDCs modulate immunity, and could result in the introduction of new immunomodulatory therapeutic avenues for ocular as well as systemic inflammatory, autoimmune, alloimmune and infectious diseases.
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