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Barbara P. Vistica, Guangpu Shi, Lindsey Nugent, Amnon Altman, Igal Gery; SLAT/Def6 Knock-Out (KO) Mice Exhibit Profoundly Reduced Capacity to Develop Experimental Autoimmune Uveitis (EAU). Invest. Ophthalmol. Vis. Sci. 2011;52(14):2926.
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SWAP 70-like adapter of T cells (SLAT; aka Def6) is a novel guanine nucleotide exchange factor for Rho GTPases that has been previously shown to play a role in CD4+ T cell activation, Th1/Th2 differentiation and development of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE) (Canonigo-Balancio et al., J. Immunol., 183:7259, 2009). Here, we investigated the role of SLAT/Def6 in the development of EAU, an animal model for several uveitic conditions in humans.
SLAT/Def6 KO mice and C57Bl/6 controls were immunized with Interphotoreceptor-Retinoid Binding Protein (IRBP), emulsified with complete Freund’s adjuvant, administered subcutaneously along with pertussis toxin, injected intraperitoneally. The development of ocular inflammation was determined by fundoscopy on day 12 post-immunization and by histological examination on day 14, following euthanization. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of IFN-gamma and IL-17 in response to IRBP, using conventional methods. Antibody response to IRBP was measured by ELISA. qPCR was used to compare the transcript levels of immune-related molecules in inflamed eyes.
(i) SLAT/Def6 KO mice had markedly reduced EAU compared to controls. (ii) Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (IFN-gamma and IL-17, respectively) when compared with cells isolated from control mice. (iii) In contrast, serum antibody to IRBP was only slightly reduced in SLAT/Def6 KO mice when compared to control mice. (iv) qPCR of inflamed eyes detected similar levels of IFN-gamma transcript in control and SLAT/Def6 KO mice whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were strikingly lower than in eyes of the controls.
SLAT/Def6 KO mice exhibit reduced ocular inflammation when immunized with IRBP. Our study provides new data showing that SLAT/Def6 is a regulator of inflammatory response in controlling the T cell-mediated autoimmune disease, EAU.
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