Autoimmune posterior uveitis is an inflammatory eye disease that causes vision loss in a majority of affected individuals. Immunosuppressive treatments may reduce the inflammation, but currently available drugs act non-specifically and are associated with considerable toxicity. The overall objective of this work is to improve the clinical outcomes of patients with autoimmune posterior uveitis. Studies in experimental models have identified CD4+ T cells as initiators of the inflammation. Helper T cell subsets move from the circulation into the posterior segment of the eye across the retinal vascular endothelium. Extravasation is mediated by a specific set of endothelial adhesion molecules. There are significant differences between the human and murine immune systems. Yet, in contrast to the extensive research on this process in the mouse, there has been little consideration of the basic mechanisms operating in human disease. This project is based on the hypothesis that adhesion molecules expressed on retinal endothelial cells participate critically in the development of human posterior autoimmune uveitis and represent novel targets for therapeutic intervention. Using primary endothelial cell cultures and profiling techniques, adhesion molecules warranting further investigation were identified on human retinal endothelial cells. The impact of these molecules on migration of Th1 and Th17 cells across human retinal endothelium will be studied in adhesion and transmigration assays. Intercellular adhesion molecule 1 (ICAM-1) is strongly implicated in leukocyte extravasation in many systems, but expression is cell- and stimulus-specific. Regulation of ICAM-1 transcription in the retinal endothelial cell will be evaluated using promoter reporter expression and electrophoretic mobility shift assays. Activated leukocyte-cell adhesion molecule (ALCAM) is a novel adhesion molecule never before identified on retinal endothelium. Expression and potential functions in relation to autoimmune posterior uveitis will be investigated.

Public Health Relevance

Posterior uveitis is an inflammation that occurs within the eye and may result in blindness. Present treatments are not directed specifically at the inflamed tissues, and consequently they cause toxicity. This work, which aims to identify the molecules that allow white blood cells to enter the human eye from the bloodstream at the onset of disease, should suggest new targets for safer drugs to treat patients with posterior uveitis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY019875-04
Application #
8658500
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2013-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$222,642
Indirect Cost
$16,492
Name
Flinders University of South Australia
Department
Type
DUNS #
756172482
City
Adelaide
State
Country
Australia
Zip Code
5001
Bharadwaj, Arpita S; Schewitz-Bowers, Lauren P; Wei, Lai et al. (2013) Intercellular adhesion molecule 1 mediates migration of Th1 and Th17 cells across human retinal vascular endothelium. Invest Ophthalmol Vis Sci 54:6917-25
Chipps, Timothy J; Appukuttan, Binoy; Pan, Yuzhen et al. (2013) CD44 isoforms in human retinal and choroidal endothelial cells. Graefes Arch Clin Exp Ophthalmol 251:1245-6
Bharadwaj, Arpita S; Appukuttan, Binoy; Wilmarth, Phillip A et al. (2013) Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res 32:102-80