Dry eye disease (DED), an inflammatory autoimmune disorder affecting the ocular surface, degrades visual performance and the quality of life of >10 million people in the United States alone. The primary limitation in the effective treatment of DED is an incomplete understanding of its specific cellular and molecular pathogenic elements. Using a validated mouse model of DED, herein we functionally characterize the different T cell subsets, including regulatory T cells (Tregs) and pathogenic effector T cells, and determine their contribution to the pathogenesis of DED. Our data demonstrate the presence of dysfunctional Tregs and the resistance of pathogenic T cells, particularly Th17 cells, to Treg suppression in DED. In addition, we clearly show that in vivo blockade of IL-17 significantly reduces the severity and progression of disease, which is paralleled by a reduction in the expansion of Th17 cells and restoration of Treg function. Our findings elucidate involvement of a previously unknown pathogenic T cell subset (Th17) in DED that is associated specifically with Treg dysfunction and disease pathogenesis and suggest a new target for dry eye therapy.

The richly innervated corneal tissue is one of the most powerful pain generator in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain.

Neuropathic pain is caused by a primary lesion or dysfunction of the nervous system and can occur in the cornea. However, neuropathic corneal pain (NCP) is currently an ill-defined disease. Patients with NCP are extremely challenging to manage and evidence-based clinical recommendations for the management of patients with NCP are scarce. The objectives of this review are to provide guidelines for diagnosis and treatment of patients with NCP and to summarize current evidence-based literature in this area. We performed a systematic literature search of all relevant publications between 1966 and 2017. Treatment recommendations are, in part, based on methodologically sound randomized controlled trials (RCTs), demonstrating superiority to placebo or relevant control treatments, and on the consistency of evidence, degree of efficacy, and safety. In addition, the recommendations include our own extensive experience in the management of these patients over the past decade. A comprehensive algorithm, based on clinical evaluation and complementary tests, is presented for diagnosis and subcategorization of patients with NCP. Recommended first-line topical treatments include neuro-regenerative and anti-inflammatory agents, whilst first-line systemic pharmacotherapy includes tricyclic antidepressants and the anticonvulsant. Second line oral treatments recommended include the opioid-antagonist and opiate analgesics. Complementary and alternative treatments, such as cardio-exercise, acupuncture, omega-3 fatty acid, and gluten-free diet, may have additional benefits, as do potential non-invasive and invasive procedures in recalcitrant cases. Medication selection should be tailored on an individual basis, considering side effects, comorbidities, and levels of peripheral and centralized pain. Nevertheless, there is an urgent need for long-term studies and RCTs assessing the efficacy of treatments for NCP.

The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal graft has high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates due to a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered. However, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been employed for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments as well as tolerance-inducing methods show promising horizons in the management of high-risk corneal transplantation in near future.

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To determine the effect of desiccating stress on corneal angiogenic responses in dry eye disease (DED) using a murine model. Methods: Dry eye was induced in murine eyes using high-flow desiccated air. Corneas were double stained with CD31 (panendothelial marker) and LYVE-1 (lymphatic endothelial marker). Real-time polymerase chain reaction was performed to quantify expression of vascular endothelial growth factors (VEGF-A, VEGF-C, and VEGF-D) and their receptors (VEGFR-2 and VEGFR-3) in the cornea on days 6, 10, and 14. Enumeration of CD11b ϩ /LYVE-1 ϩ monocytic cells was performed in corneas with DED on day 14. Flow cytometric evaluation of the draining lymph nodes in normal mice and mice with DED was performed to determine whether DED is associated with homing of mature (major histocompatibility complex class II hi ) antigen-presenting cells to the lymphoid compartment.Results: Lymphatic vessels unaccompanied by blood vessels were seen growing toward the center of corneas with DED. Significant increases in lymphatic area (PϽ.001) and lymphatic caliber (PϽ.02) were seen on day 14 of disease. Lymphangiogenic-specific VEGF-D and VEGFR-3 levels increased earliest on day 6 followed by increased VEGF-C, VEGF-A, and VEGFR-2 levels. Increased recruitment of CD11b ϩ /LYVE-1 ϩ monocytic cells to the cornea and homing of mature CD11b ϩ antigen-presenting cells to the draining lymph nodes were also associated with DED. Conclusion:Low-grade inflammation associated with DED is an inducer of lymphangiogenesis without accompanying hemangiogenesis.

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Objective:To determine the effect of a topical antagonist to the chemokine receptor 2 (CCR2) in a murine model of dry eye disease. Methods:The effects of a topical CCR2 antagonist and a vehicle control treatment were studied in murine dry eyes. A controlled environment chamber induced dry eye by exposing mice to high-flow desiccated air. Corneal fluorescein staining and enumeration of corneal CD11b ϩ and conjunctival CD3 ϩ T cells were performed in the different groups. Real-time polymerase chain reaction was performed to quantify expression of different inflammatory cytokine transcripts in the cornea and conjunctiva.Results: Eyes receiving the formulation containing CCR2 antagonist showed a significant decrease in corneal fluorescein staining and decreased infiltration of corneal CD11b ϩ cells and conjunctival T cells compared with the vehicle-treated and untreated dry eye groups. The CCR2 antagonist also significantly decreased messenger RNA expression levels of interleukins 1␣ and 1␤ in the cornea, and tumor necrosis factor ␣ and interleukin 1␤ in the conjunctiva.Conclusion: Topical application of CCR2 antagonist is associated with significant improvement in dry eye disease and is reflected by a decrease in inflammation at the clinical, molecular, and cellular levels.Clinical Relevance: Topical application of CCR2 antagonist may hold promise as a therapeutic modality in dry eye disease.