Uveitis (intraocular inflammatory diseases) is the cause of approximately 10% of severe visual handicap in the United States. Current therapy is based on systemic corticosteroid, with or without second line agents such as cyclosporine A or anti-metabolites. Serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. Experimental autoimmune uveitis (EAU) is a well-characterized animal model of human uveitis and constitutes a unique experimental system for use in validating efficacy of treatment modalities against uveitis. Our efforts to develop effective anti-uveitis therapies have relied on 2 strategies: (i) Development of dendritic cell vaccine against uveitis: Studies of monkey and rodent EAU have led to identification of the retinal proteins, S-Antigen and IRBP, as putative autoantigen of uveitis. Our approach is to develop a therapeutic vaccine against uveitis based on tolerance induction to S-Antigen, IRBP and/or other putative uveitogens (recoverin, opsin). We had previously shown that STAT pathways are differentially activated as dendritic cells (DC) differentiate from precursor (pDC) to immature (iDC) and finally to mature DC (mDC). In this study, we have used wild-type, STAT1-deficient or STAT6-deficient DC to investigate the role of STAT1 and STAT6 in inducing DC to produce cytokines that promote inflammation (IL-12 and IL-23) or those that have anti-inflammatory functions (IL-10 and IL-27). Our studies reveal that while STAT1 is required for DC maturation and necessary for secretion of the anti-inflammatory cytokines IL-10 and IL-27 by mDC, STAT6 exerts negative regulatory constraints on DC maturation and promotes production of pro-inflammatory cytokines (IL-12 and IL-23). This new understanding now allows for a rational basis for generating DC that selectively produces tolerogenic or immunogenic cytokines. Our ultimate goal is to load highly enriched tolerogenic DCs with immunopathogenic epitopes of IRBP or S-Antigen for use as therapeutic vaccines against uveitis. (ii) Intracellular protein therapy for inhibition of uveitis: Our research over the past few years has documented potential role of SOCS proteins in protection of retinal cells from hypoxia, light damage and inflammation. However, therapeutic value of SOCS proteins is severely limited by technical difficulty of delivering these regulatory proteins inside the cell where their cognate target proteins reside. To circumvent this major huddle constraining therapeutic use of transcription factors and other soluble intracellular proteins, we exploited the new genetic engineering strategy by which proteins can be made deliverable into cells by fusing their coding sequences to 12 amino acid membrane-translocating sequences (MTS). Using this strategy we have generated a membrane-translocating SOCS1 protein, delivered it into macrophage cells and demonstrated its ability to inhibit STAT1 signaling pathway in these cells. We are now characterizing the efficiency of delivery of this protein into retinal cells and its eventual use to inhibit experimental uveitis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000350-10
Application #
7968318
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2009
Total Cost
$275,622
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Dambuza, Ivy M; He, Chang; Choi, Jin Kyeong et al. (2017) IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat Commun 8:719
Choi, Jin Kyeong; Dambuza, Ivy M; He, Chang et al. (2017) IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis. Front Immunol 8:1258
He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J et al. (2016) SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis). Mediators Inflamm 2016:2939370
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) Pre-existing CD19-independent GL7(-) Breg cells are expanded during inflammation and in mice with lupus-like disease. Mol Immunol 71:54-63
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur J Immunol 46:1343-50
Egwuagu, C E; Sun, L; Kim, S-H et al. (2015) Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. Curr Mol Med 15:517-28
He, Chang; Yu, Cheng-Rong; Sun, Lin et al. (2015) Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun 62:31-8
Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang et al. (2015) Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection. Inflammation 38:555-65
Egwuagu, Charles E; Yu, Cheng-Rong; Sun, Lin et al. (2015) Interleukin 35: Critical regulator of immunity and lymphocyte-mediated diseases. Cytokine Growth Factor Rev 26:587-93
Egwuagu, Charles E; Yu, Cheng-Rong (2015) Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol 35:49-57

Showing the most recent 10 out of 17 publications