Immunopathogenic Mechanisms of Dry Eye Disease

Schepens Eye Research Institute, Boston MA

Investigators

Linked publications & trials

Abstract

Dry eye disease (DED) is a chronic immune-mediated disorder of the ocular surface, characterized by disruption of the epithelial barrier and sustained ocular surface inflammation, which in severe cases results in corneal ulceration and scarring. The impact of DED is significant: it is the most common ophthalmic condition for which patients visit eye care providers, with more than 16 million US adults affected. While several treatments have been approved by the FDA, none are ideal; all suffer from limited efficacy and/or tolerability, reflected by the fact that less than 15% of patients with DED are using any of the approved therapeutics and over 60% of those who start using them cease their use within 6 months due to various side effects. The financial burden of DED is vast, with costs from productivity losses in the US exceeding $3.5 billion annually. The work of several laboratories, including the PI’s, has revealed key insights concerning the immunopathogenesis of DED. There is now strong evidence that T helper-17 (Th17) cells are critical promoters of immune-mediated damage to the ocular surface. The PI’s laboratory has shown that memory Th17 (mTh17) cells maintain disease chronicity, resulting in ocular surface epitheliopathy that persists for many months after exposure to desiccating stress. Moreover, data from the PI’s lab show that regulatory T cells (Treg) are defective in suppressing the Th17 response in DED. In addition, the PI’s lab has shown that Th17 cell activation is also associated with recruitment of macrophages, critical cells of the innate immune system, in DED; however, the mechanisms that underlie Th17-mediated recruitment of macrophages remain incompletely understood. Despite the substantial progress that we and others have made in unraveling the underlying immunopathogenic mechanisms of DED important questions remain unanswered. We hypothesize that (1) T17 cells mediate ocular surface damage both directly, via secretion of effector cytokines, and indirectly by promoting recruitment of macrophages to the ocular surface, principally through their key effector cytokines IL-17A and IL-17F, and (2) mTh17 cells, which persist long-term, are inadequately controlled by Treg, enabling them to induce exacerbation of disease upon reactivation. The principal objectives of this project, as captured by our three specific aims, are to answer the following questions: (1) What are the precise mechanisms that mediate Th17-mediated ocular surface epithelial damage? (2) How exactly do IL-7 and IL-15 contribute to the long-term persistence of memory Th17 cells in DED? and (3) What exactly is the interplay between Treg (dys)function and memory Th17 reactivation that contributes to disease exacerbation in chronic DED? Finally, (4) Can low-dose interleukin-2, which can enhance Treg function, significantly suppress mTh17 function in chronic DED? It is anticipated that this research will have significant translational impact given the high prevalence of DED, the still limited knowledge we have regarding its immunopathogenesis, and the scarcity of effective and well-tolerated treatments.