Project Details
Projekt
The role of interleukin (IL)-10 in the pathogenesis of autoimmune uveitis in mice and man
Subject Area
Ophthalmology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 257498687
Intraocular inflammation (uveitis) is a common cause of blindness. Etiologically, uveitis can be divided into infectious and autoimmune forms, with some associations between both forms, as in the case of HLA-B27 positive uveitis. Since there is a release of self antigens during every infection, the body prevents the development of subsequent autoimmune reactions by peripheral tolerance mechanisms including regulatory cell populations and cytokines such as interleukin (IL)-10. Failure of this network may explain the known association between autoimmune disorders and preceding infections. Our preliminary work in the murine model of human uveitis, experimental autoimmune uveitis (EAU), has shown that pre-exposure with bacterial products (analogous to a preceding infection) in form of complete freund´s adjuvant (CFA) ameliorates EAU. This protective feature critically depends on IL-10 and is associated with an expansion of myeloid derived suppressor cells (MDSC). The aim of this project now is to elucidate the mechanisms of this protective effect, particularly the role of MDSC and the cellular source of IL-10. Based on these findings we want to explore the hypothesis that dysregulation of IL-10 production, especially during infections, predisposes to subsequent autoimmune uveitis. Our initial findings support that in the EAU model, uveitis develops in IL-10 deficient mice after pre-exposure with bacterial products followed by EAU induction, but not in wild-type mice that are protected through bacteria-induced IL-10. In addition to peripheral MDSC, resident macrophages in the retina are present as microglia and aquire an activated state during EAU. The contribution of this population to immunoregulation of EAU via IL-10 will be analyzed. Local delivery by intravitreal application of IL-10 will be evaluated in EAU as a novel therapeutical means for uveitis, enabling a local immunosuppression without potential systemic side-effect due to the pleiotropic profile of this cytokine. Finally, secretion patterns of IL-10 in serum and peripheral blood monocytes and lymphocytes as putative markers of susceptibility for developing uveitis will be examined in patients with HLA-B27 positive uveitis.
DFG Programme
Research Units
