Keratoconjunctitivitis sicca (KCS), or dry eye disease, is one of the most common conditions seen by ophthalmologists and affects 15% of those from 65-84 years of age, or 4.3 million Americans. The pathophysiology of dry eye includes immune-mediated inflammation involving both the ocular surface and the lacrimal gland. While knowledge of the pathology of dry eye disease has improved significantly during recent years, the mainstay of treatment, ocular lubrication, provides only palliative relief at best to patients with severe dry eye disease. Therefore, attention has turned to immunomodulation as a therapeutic approach for I severe dry eye disease, especially for that seen in autoimmune diseases like Sjogren's syndrome, I rheumatoid arthritis, and systemic lupus erythematosus (SLE). Available agents such as corticosteroids have I considerable side effects that render them therapeutically impotent in a number of patients. Recently, the FDA approved Cyclosporine A (CSA), 0.5% (Restasis) for the treatment of moderate to severe dry eye. However, 85% of CSA-treated patients did not experience a significant increase in tear production. Therefore, a therapeutic agent that could reliably decrease immune-mediated ocular surface damage without significant adverse effects in a large proportion of affected patients would constitute a major therapeutic advance, particularly for dry eye disease. Thymosin beta 4 (Tb4) promotes corneal wound healing and reduces inflammation in mice after chemical injury to the eye. Since Tb4 has both anti-inflammatory and wound healing properties, it is an ideal candidate for evaluation in an autoimmune model of dry eye.
Two specific aims are proposed to test the overall hypothesis of this application that Tb4 modulates lacrimal gland, corneal and conjunctival inflammation in an animal model of autoimmune dry eye disease. 1) To test the hypothesis that Tb4 alters production of cytokines, chemokines and specific matrix metalloproteinases (MMPs) in a murine model of Sjogren's syndrome; 2) To test the hypothesis that Tb4 alters autoimmune ocular surface damage in the MRL/Ipr mouse by decreasing lacrimal gland inflammation and conjunctival squamous metaplasia. By identifying Tb4 as a novel wound healing and anti-inflammatory agent to protect the ocular surface from inflammatory and immune tissue injury, it is aimed to substantiate the potential clinical usage of Tb4 for the majority of patients who are not relieved by currently available therapies.
