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January '11 Paper of the Month Share This OHSU Content

01/24/11  Portland, Ore.

OX40, a co-stimulatory molecule critical for T cell activation during the pathogenesis of uveitis


Drs. Zhang & RosenbaumThis month's featured paper is from the American Journal of Pathology, and is titled “Activation of OX40 Augments Th17 Cytokine Expression and Antigen-Specific Uveitis.” The research was conducted by an investigative collaboration led by Zili Zhang, MD, PhD, Associate Professor, Department of Pediatrics, and James T. Rosenbaum, MD, Professor, Department of Ophthalmology, and colleagues.* 

Uveitis is a common eye disorder which can be characterized by chronic and serious inflammation. Symptoms include light sensitivity, loss of vision, pain, and redness of the eye. Many systemic diseases including sarcoidosis, ankylosing spondylitis, and juvenile idiopathic arthritis are frequently associated with uveitis. The disorder affects more than 280,000 people in the United States each year. **

Numerous studies show that aberrant T cells play a central role in the pathogenesis of uveitis. However, the molecular mechanism of uveitogenic T cell activation remains to be fully elucidated. Of the various receptor/ligand pairs that are involved in lymphocyte stimulation, ligation of the membrane receptor OX40 appears to be an important co-stimulatory interaction that contributes to T cell activation, proliferation and enhances memory survival.

This research demonstrates that OX40 is up-regulated during uveitis in animal models.  Activation of OX40 not only exaggerates antigen-induced uveitis but also enhances T cell effector function.  In addition, OX40 augments the production of IL-21, a novel yc cytokine essential for the proliferation of T cell subsets.

Therefore, these data suggest that OX40 signaling is critical in the pathogenesis of T cell-mediated uveitis. This study enhances knowledge of the underlying immunopathological mechanisms of uveitis and further tests the feasibility of targeting OX40 as a novel therapeutic strategy for the control and regulation of ocular inflammation.

Because T cell-mediated uveitis is a major cause of visual loss, and contributes to significant economic and other health-related burdens, research into the role OX40 plays in uveitis is crucial to the health and welfare of society. “Through studying OX40, scientists will better understand the mechanism of uveitis, and begin to pinpoint novel potential therapeutic targets. Therefore, this project is significant with a potential to transition from basic science to clinical application,” said Dr. Zhang.

Down the road, the team plans to investigate the regulatory mechanism of OX40 at a molecular level during T cell activation and expansion, as well as testing the efficacy of OX40-targeting therapy for treating uveitis.

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Intravital microscopy reveals inflammatory cell infiltration in a unique mouse uveitis model recently developed in Zhang and Rosenbaum laboratories (A and C).  Blocking OX40 signaling by anti-OX40L antibody attenuated the ocular inflammation (B and D).

 
Pictured: (left) Zili Zhang, MD, PhD; (right) James T. Rosenbaum, MD

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ABOUT THE PAPER OF THE MONTH

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD, and reviewed by Dean Mark Richardson, MD, MBA, and Vice President/Senior Associate Dean for Research Dan Dorsa, PhD.

This paper was selected because of its scientific value with the identification of a promising new therapeutic target for the treatment of a common eye disorder, uvetis. The research is emblematic of collaborative science both within OHSU and inter-institutionally.

 

* PAPER AUTHORS
From the Department of Pediatrics: Zili Zhang, Wenwei Zhong, Xiumei Wu, Mark Hall; From the Department of Internal Medicine and Ophthalmology: Doran Spencer, James T. Rosenbaum; From the Earle A. Chiles Research Institute, Providence Portland Medical Center: Andrew Weinberg; From the Portland VA Medical Center: David Hinrichs, Keith Wegmann. 

** "Incidence and prevalence of uveitis in Northern California: the Northern California Epidemiology of Uveitis Study." Ophthalmology. March 2004.