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Jessica Wei, Reiko Horai, Rachel R Caspi, Karsten Gronert; Lipoxin A4 Dampens T Effector Cell Responses in Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2540. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Lipid mediators are bioactive small signaling molecules that maintain homeostasis by initiating inflammatory responses under healthy conditions to prevent chronic inflammation. However, the role of lipid mediators in autoimmunity has been minimally explored. Thus we sought to examine whether and how lipid mediator lipoxin A4 (LXA4) regulates the development of autoimmune uveitis.
Experimental autoimmune uveitis (EAU) was induced by active immunization with IRBP651-670 peptide in C57BL/6 mice. Eyes and lymph nodes were collected at peak inflammation for flow cytometry, immunohistochemistry and lipidomic analyses. Effects on induction of T cell responses were assayed in vitro by antigen-specific proliferation ( 3H- thymidine incorporation) and activation assays. Treatment efficacy of LXA4 was addressed under conditions of adoptive transfer of in vitro-activated, retina-specific T cells from IRBP T cell receptor transgenic mice into naïve B10.RIII wild-type recipients treated, or not, with LXA4. Treatment started from day 0 of immunization or adoptive transfer. Disease progression was monitored by fundus examination.
Flow cytometry and immunohistochemistry analyses showed that LXA4 treatment attenuated disease and altered the adaptive immune responses in EAU.In mice immunized for uveitis, endogenous LXA4 formation, quantified by LC-MS/MS, was impaired in the draining lymph nodes during peak EAU inflammation. Antigen recall responses were suppressed in EAU immunized mice treated with LXA4 in comparison to those treated with vehicle. Uveitis induced by adoptive transfer of pathogenic effector T cells was also attenuated in vivo with the administration of LXA4. Mechanisms appeared to involve effects on T cell migration and reducing uveitogenic effector T cell infiltration into the eye.
Our findings demonstrate an immunomodulatory role of LXA4 in autoimmune uveitis. The results indicate that endogenous LXA4 modulates adaptive immune responses involved in disease pathogenesis, and that systemic LXA4 treatment curbs ocular inflammation through effects including activation, proliferation and migration of uveitogenic effector T cells. Amplifying the endogenous anti-inflammatory lipid mediator circuit could improve the immunosuppressive treatment regimen by ameliorating symptoms and slowing disease progression.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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