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C. Yu, R. Mahdi, C. Egwuagu; Daclizumab (Zenapax) Selectively Blocks Expansion of Human Th17, But Not Th1 Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2525.
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TH17 cells present in human PBMC are expanded by IL-2 and their numbers increased during active uveitis or scleritis and decreased following treatment, suggesting involvement of TH17 cells in etiology of these potentially blinding eye diseases. However, expansion of TH17 cells is inhibited by IFN-γ, suggesting that this TH1 cytokine may confer protection from TH17-mediated uveitis. In this study, we have investigated how IL-2 increases TH17 cells and whether efficacy of Daclizumab (anti-IL-2Rα antibody) in treating uveitis derives from its selective blockade of the expansion of TH17 but not TH1 cells.
Human PBMC and primary CD4+ cells were stimulated for 4 days with anti-CD3/-CD28 Abs in medium containing IL-2 or IL-6, IL-23 and IL-1β. Effects of Daclizumab and other drugs (Cyclosporine A, AG490, Wortamannin, PP2, PD89059, H7, Dexamethasone) on expansion of TH17 or TH1 cells were evaluated by CFSE labeling, intracellular cytokine staining, ELISA, RT-PCR and Western blotting assays.
We show that IL-2 is a more efficient inducer of TH17 expansion than a cocktail of IL-6, IL-23, and IL-1β. Cell-cycle analysis reveals that optimal expansion of TH17 cells occurs after the cells have experience 3 cycles of division. We further show that the expanding TH 17 cells are mostly memory CD4 T-cells characterized by their expression of high affinity IL-2R and secretion of copious amounts of IL-2 and TNF-α. Daclizumab or AG490 was found to selectively inhibit expansion of TH17 cells and inhibition of TH17 expansion by Daclizumab is correlated with its suppression of the activation of STAT pathways. In contrast to Daclizumab, drugs that inhibit TCR signals, such as Cyclosporine A and H7 inhibit both TH17 and TH1 cells.
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