Uveitis is a serious intraocular inflammatory disease. It is strongly associated with many systemic inflammatory disorders. Thus, the study of uveitis will potentially unravel the pathogenesis of other complex immune-mediated diseases. Most forms of uveitis are mediated by T lymphocytes that produce critical cytokines. IL-12 has been strongly implicated in uveitis. Only recently was it realized that many functions attributed to IL-12 are actually due to IL-23. IL-23 plays an important role in the development of pathogenic T cells and elicit IL-17-dependent inflammation. Using a T cell-dependent uveitis model, we demonstrated an enhanced expression of transcripts for IL-23 and its downstream cytokine IL-17 in uveitis. In addition, we have helped develop a novel IL-17 inhibitor. Based on the above findings, we hypothesize that 1) IL-23, the proximal mediator of inflammation, and ThlL-17 cells play an important role in the pathogenesis of T cell-dependent non-infectious uveitis, and 2) neutralization of IL-23 and IL-17 will attenuate ocular inflammation. This project has the following Specific Aims:
Specific Aim I. We will examine expression of IL-23 and IL-17 in different experimental uveitis models. Furthermore, we will identify the cellular sources of IL-23 and IL-17.
Specific Aim II. We propose to visualize IL-17 expression in the eye by generating a transgenic mouse model expressing enhanced green fluorescent protein (EGFP) under the control of mouse IL-17 promoter. Using EGFP as a surrogate marker for uveitis-specific IL-17 induction, we will characterize the kinetics and location of ThlL-17 cells and IL-17 expression.
Specific Aim III. We will test whether neutralizing IL 23 and/or IL-17 will alleviate the uveitis. We propose to compare the efficacies of monoclonal antibodies specifically against IL-23p19, IL-12/IL-23p40, or IL-17, and soluble IL-17 receptor/Fc fusion protein.
Specific Aim I V. We will further define the roles of IL-23 and ThlL-17 cells in uveitis by 1) determining whether adoptive transfer of IL-23-primed ThlL-17 cells augments the inflammation in the uveitis models; and 2) examining if co-transfer of T regulatory cells prevents or inhibits ThlL-17 cell-mediated uveitis. This study will enhance our knowledge of the underlying immunopathological mechanisms of uveitis. By targeting IL-23 or IL-17, we hope to develop a novel therapeutic strategy with more anti-inflammatory efficacy and less suppressive effect on host defense. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY016788-03
Application #
7473823
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Shen, Grace L
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$134,148
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Zhang, Zili; Wu, Xiumei; Duan, Jie et al. (2012) Low dose rapamycin exacerbates autoimmune experimental uveitis. PLoS One 7:e36589
Wu, Xiumei; Rosenbaum, James T; Adamus, Grazyna et al. (2011) Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis. Invest Ophthalmol Vis Sci 52:8520-6
Zhong, Wenwei; Zhang, Zili; Hinrichs, David et al. (2010) OX40 induces CCL20 expression in the context of antigen stimulation: an expanding role of co-stimulatory molecules in chemotaxis. Cytokine 50:253-9
Zhang, Zili; Rosenbaum, James T; Zhong, Wenwei et al. (2010) Costimulation of Th17 cells: Adding fuel or putting out the fire in the inflamed gut? Semin Immunopathol 32:55-70
Zhong, Wenwei; Xia, Zhenwei; Hinrichs, David et al. (2010) Hemin exerts multiple protective mechanisms and attenuates dextran sulfate sodium-induced colitis. J Pediatr Gastroenterol Nutr 50:132-9
Zhang, Zili; Zhong, Wenwei; Hinrichs, David et al. (2010) Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. Am J Pathol 177:2912-20
Zhang, Zili; Zhong, Wenwei; Spencer, Doran et al. (2009) Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice. Cytokine 46:79-91
Martin, Tammy M; Zhang, Zili; Kurz, Paul et al. (2009) The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum 60:611-8
Zhang, Zili; Zhong, Wenwei; Hall, Mark J et al. (2009) CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis. Exp Eye Res 89:522-31