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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Schools of Medicine
United States
Zip Code
Smith, Justine R; David, Larry L; Appukuttan, Binoy et al. (2018) Angiogenic and Immunologic Proteins Identified by Deep Proteomic Profiling of Human Retinal and Choroidal Vascular Endothelial Cells: Potential Targets for New Biologic Drugs. Am J Ophthalmol 193:197-229
Appukuttan, Binoy; Ashander, Liam M; Ma, Yuefang et al. (2018) Selection of Reference Genes for Studies of Human Retinal Endothelial Cell Gene Expression by Reverse Transcription-Quantitative Real-Time Polymerase Chain Reaction. Gene Rep 10:123-134
Ashander, Liam M; Appukuttan, Binoy; Ma, Yuefang et al. (2016) Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study. Mediators Inflamm 2016:7945848
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
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; 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
Smith, Justine R; Chipps, Timothy J; Ilias, Hoda et al. (2012) Expression and regulation of activated leukocyte cell adhesion molecule in human retinal vascular endothelial cells. Exp Eye Res 104:89-93
Furtado, Joao M; Bharadwaj, Arpita S; Ashander, Liam M et al. (2012) Migration of toxoplasma gondii-infected dendritic cells across human retinal vascular endothelium. Invest Ophthalmol Vis Sci 53:6856-62