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A. Amadi-Obi, C.-R. Yu, R. Mahdi, X. Liu, G. Clarke, R. Nussenblatt, I. Gery, C. Egwuagu; Thil17 Plays a Role in Uveitis and Its Expansion Is Inhibited by Il-27. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1507.
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ThIL17 cells are implicated in pathogenesis of immune-mediated diseases. However, most of these studies have been in mice and involvement of ThIL17-cells in human diseases has not been firmly established. In this study, we show that ThIL17-cells may be involved in human uveitis or scleritis and have validated our findings in experimental autoimmune uveitis (EAU), a model of human uveitis.
Human PBMC was isolated by density gradient centrifugation. PBMC or mouse CD4+ cells were cultured in medium containing various combinations of IL-2, IL-23, TGF-ß1/IL-6, anti-CD3/-CD28 Abs or IRBP. For induction of EAU mice were immunized with IRBP in CFA and disease was characterized by fundoscopy and histology. Expression of transcription factors, lymphocyte effector molecules and cytokine secretion were assessed by Western blotting, RT-PCR, qRT-PCR or ELISA. Phenotype of lymph node or ocular pathogenic T-cells was analyzed by FACS and intracellular staining.
The major findings in this study are the following: (i) A major difference between mice and "men" is that ThIL17 cells are detected in normal PBMC of humans but not mice: (ii) IL-17 is elevated in uveitis, scleritis and EAU and we show that its induction of TNFα expression in retinal cells may contribute to the pathology of chronic inflammatory disease of the eye; (iii) We further show that IL-27 is constitutively expressed in ganglion cell and inner plexiform layers of the retina and that expression of IL-27 in retinal cells is upregulated by IFNγ. (iv) IL-27 inhibits the proliferation of ThIL-17 uveitogenic T-cells.
Taken together the data presented here suggest a novel mechanism by which Th1 cells may mitigate chronic inflammation by antagonizing ThIL17 phenotype through IFNγ-mediated STAT1-activation and induction of IL-27 in the target tissue. This first report that IL-2 promotes ThIL17-cells expansion provides explanations for efficacy of anti-IL2R therapy in uveitis and suggests that antagonism of ThIL17-cells by IFNγ/IL-27 maybe exploited in treating chronic inflammation.
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