The role of epigenetics in human biology is now far more studied that it used to. These reversible changes in the DNA affecting the expression of different set of genes have been involved in many pathologies. Moreover, epigenetic drugs such as HDAC inhibitors are now used in treatment of some cancer. To study the potential relevance of epigenetic drugs in uveitis treatment, we have treated cells (T cells and monocytes) isolated from uveitis patients and healthy donors with an HDAC inhibitor, Givinostat. Interestingly Givinostat was able to inhibit the production of IL-17 in T cells, and decrease the function of monocyte-derived DC. Moreover, in the EAU mouse model of IRBP-induced uveitis, Givinostat treatment lead to reduction of the severity of disease. We have reported epigenetic alterations the immune cells of AMD patients but this remains to be verified. In an animal model for uveitis, we have seen that epigenetic altering medication affects positively the expression of active disease, and changes were noted in vitro on human cells. In addition, an increase in the presence of immune markers such as IL-17 and its receptor in the eyes of AMD were noted, whatever their mechanism may be. In addition, patients with steroid refractory uveitis have a characteristic subpopulation of steroid refractory CD4+ T cells in their peripheral blood. Previously studies have demonstrated that this steroid refractory phenotype is restricted to the central memory pool of CD4+ cells which have the capacity to generate IL-17. We therefore compared transcriptomic responses of Th1 and Th17 cells to corticosteroids in order to identify novel biomarkers and targets for therapeutic intervention in steroid refractory disease. Steroid refractory patients have a greater propensity than sensitive patients to generate Th17 cells, and Th17 cells from either group of patients respond differently following exposure to Dex as compared with Th1 cells. Using gene expression profiling a restricted response to glucocorticoids was noticed. Of interest that there was a large genome shift in response to cyclosporine A. Since steroid resistance is an important clinical problem, this information would suggest strongly that new therapeutic which target either Th17 cells or the effector memory T helper cell population from which they are derived would be candidates for drug development. Of interest is the finding that in humans, glucocorticoid therapy affects the subtype of monocytes, inducing the subtype that is associated with the induction of T regulatory cells. Using additional techniques, we have identified that a subgroup of uveitis patients has markedly shortened telomere length. In addition, we have noted circulating IL-17 in sarcoidosis patients which is associated with active disease. Patients with sarcoidosis were noted to have an elevated IL-17RC expression on CD8+ cells. In addition, we have noted that CD8+ T cells, which are now designated as Tc17 cells, produce IL-17 and are characterized by CD146 expression. We have also studies dendritic cells in patients with ocular inflammatory disease. What was noted was the association of CD1c+mDCs with activity, and this appears to be regulated by TNF-alpha-p38 MAPK. We are pursuing the hypothesis that this could be a biomarker for activity before the disease becomes clinically apparent. We have performed whole transcriptome profiling of peripheral CD4+ T cells of AMD patients using RNA-Seq. These data show moderate but significant differences of gene expression levels between AMD patients and controls, with dysregulation of multiple pathways and biofunctions in CD4+ cells. These data support an immune dysregulation in AMD and the potential role of immunosenescence. We are currently extending these observations to a larger cohort of patient, to study both CD4 T cells and monocytes transcriptomes in patients at various stage of AMD versus age-matched controls, as well as deep immunophenotyping of the peripheral blood.

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National Eye Institute (NEI)
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Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A et al. (2015) Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A. Proc Natl Acad Sci U S A 112:4080-5
Liu, Baoying; Dhanda, Ashwin; Hirani, Sima et al. (2015) CD14++CD16+ Monocytes Are Enriched by Glucocorticoid Treatment and Are Functionally Attenuated in Driving Effector T Cell Responses. J Immunol 194:5150-60
Chen, Ping; Denniston, Alastair; Hannes, Susan et al. (2015) Increased CD1c+ mDC1 with mature phenotype regulated by TNF?-p38 MAPK in autoimmune ocular inflammatory disease. Clin Immunol 158:35-46
Dagur, Pradeep K; Biancotto, Angélique; Stansky, Elena et al. (2014) Secretion of interleukin-17 by CD8+ T cells expressing CD146 (MCAM). Clin Immunol 152:36-47
Wu, Wenting; Jin, Ming; Wang, Yujuan et al. (2014) Overexpression of IL-17RC associated with ocular sarcoidosis. J Transl Med 12:152
Thompson, Ian A; Liu, Baoying; Sen, H Nida et al. (2013) Association of complement factor H tyrosine 402 histidine genotype with posterior involvement in sarcoid-related uveitis. Am J Ophthalmol 155:1068-1074.e1
Wei, Lai; Chen, Ping; Lee, Joo Hyun et al. (2013) Genetic and Epigenetic Regulation in Age-related Macular Degeneration. Asia Pac J Ophthalmol (Phila) 2:269-74
Lima, Breno R; Nussenblatt, Robert B; Sen, H Nida (2013) Pharmacogenetics of drugs used in the treatment of ocular inflammatory diseases. Expert Opin Drug Metab Toxicol 9:875-82
Yeh, Steven; Albini, Thomas A; Moshfeghi, Andrew A et al. (2012) Uveitis, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), and intravitreal biologics for ocular inflammation. Am J Ophthalmol 154:429-435.e2
Wei, Lai; Liu, Baoying; Tuo, Jingsheng et al. (2012) Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell Rep 2:1151-8

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