Utilizing the immune system to combat dry eye disease

Image Credit: AdobeStock/Jennifer Toomey/MJH Life Sciences

Dry eye disease (DED) is a chronic and often progressive condition that can be a source of frustration for patients and clinicians.¹ Finding the right combination of treatments that effectively alleviate symptoms can be demanding, and the chronic nature of the condition typically requires ongoing management to maintain ocular health and comfort.

Managing DED presents unique challenges due to its diverse presentation and multifaceted etiology, which complicate both diagnosis and treatment strategies. With symptoms spanning mild to severe dryness, irritation, redness, light sensitivity, and vision loss, DED imposes a substantial burden on the quality of life of individuals affected.² A study in 2017 estimated there were 16 million patients diagnosed with DED in the US alone—a number likely to be higher today, given the progressively aging population.³

Inflammation in DED

In recent years, a definition of DED has emerged that facilitates the discussion and management of DED.⁴ In a pivotal report published in 2017, the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) group defined dry eye as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”⁵ This definition of DED underscores the crucial role that inflammation plays in the disease’s pathogenesis, highlighting the immune system as an appealing target for therapeutic intervention.

Inflammation in DED manifests as a persistent activation of the innate and adaptive immune systems, perpetuating ocular surface damage and disease progression.⁶ Although the exact mechanisms remain unclear, exposure to environmental stress, intrinsic dysfunction of immunoregulatory pathways, desensitization of corneal nerves, and changes in tear fluid composition are considered important drivers of ocular surface inflammation.⁷ These triggers promote the accumulation of immune cells at the ocular surface, where they release cytokines and induce epithelial damage.

Although inflammation is a physiological process that facilitates a return to homeostasis in normal circumstances, dysregulation of the inflammatory response can lead to a vicious cycle that perpetuates the disruption of the immune system and exacerbates damage to the ocular surface.⁷ In 2 clinical studies that evaluated large populations of subjects with DED, elevated levels of the inflammatory cytokine metalloproteinase-9 (MMP-9) was detected in more than 80% of subjects.^8,9 To combat DED-associated inflammation, various immunosuppressive therapies have been explored to disrupt the inflammatory cycle.

Current treatments of DED

In recent years, the FDA has approved several novel pharmacological agents for DED, marking significant progress in the treatment landscape. These treatments encompass a broad spectrum of mechanisms, including a corticosteroid with enhanced safety (loteprednol etabonate [Eysuvis] in 2020),10 a nasal spray that stimulates basal tear production (varenicline solution [Tyrvaya] in 2021),¹¹ a water-free cyclosporine 0.1% ophthalmic solution (Vevye in 2023) approved to treat signs and symptoms of DED,¹² and an ophthalmic solution that reduces tear evaporation (perfluorohexyloctane [Miebo] in 2023).¹³ These additions complement existing treatments, including cyclosporine 0.05% (Restasis), cyclosporine 0.09% (Cequa), and lifitegrast (Xiidra).

Among the FDA-approved therapies for DED, cyclosporine, lifitegrast, and loteprednol etabonate are medications designed to target inflammation and modulate the immune system. As the first FDA-approved medication for the treatment of DED, cyclosporine is an effective immunosuppressive agent that inhibits IL-2 expression and T-cell activation.¹⁴ Lifitegrast, the second anti-inflammatory agent approved by the FDA, is a competitive antagonist of specific leukocyte integrins that are associated with T-cell activation, cytokine release, and ocular inflammation.¹⁵

In addition to cyclosporine and lifitegrast, clinicians routinely prescribe immunosuppressive corticosteroids to treat DED, despite heightened risks of ocular infection, glaucoma, and cataracts.¹⁶ Among corticosteroids, loteprednol etabonate is the preferred choice, as it is designed to rapidly metabolize into inactive metabolites after exerting its effect, thereby minimizing the risk of adverse effects.¹⁷

The approval of these therapies represents meaningful advances in our approach to DED management. However, a considerable number of patients continue to suffer from the condition despite extended pharmacological intervention. Some of these patients may exhibit advanced ocular surface damages that remain inadequately addressed by first-line therapies, whereas others may experience neurotrophic keratitis (NK)–related nerve desensitization that requires alternative interventions.

Treating advanced ocular surface damage in DED with amniotic membranes

In addition to the aforementioned therapies, comprehensive DED management also consists of artificial tears, proper eyelid hygiene, warm compresses, and nutritional supplements such as ω-3 and ω-6 fatty acids.¹⁸ For more advanced cases, treatments may consist of scleral lenses, autologous serum, punctal plugs, cenegermin (Oxervate), punctal plugs, and amniotic membranes (AMs). Despite the broad array of treatments available for DED, there is still a pressing need for innovative therapeutic approaches due to the highly diverse disease etiologies and challenges in disease management.

For patients with extensive epithelial damage or NK, cenegermin and AMs can be effective options that promote wound healing and reduce inflammation. Cenegermin is a recombinant form of human nerve growth factor (NGF) structurally identical to natural NGF.^19,20 Studies have shown that NGF helps corneal epithelial cells and corneal nerves survive.^21-23

AMs can play an integral role in repairing ocular surface damage and rehabilitation, as they have unique anti-inflammatory, antifibrotic, antiangiogenic, and prohealing properties for acute and chronic ocular surface disease.²⁴ AMs are generally prepared for ophthalmic use via dehydration (various companies, such as IOP Ophthalmics and BioDOptix) or cryopreservation (BioTissue). Although there are several differences between dehydrated and cryopreserved AMs, these are due to the preservation process.

The dehydrated AM preservation process is performed with heat or chemicals and is indicated for wound covering but should not be used for active ocular infection. The cryopreservation technique retains the extracellular matrix components, such as heavy-chain hyaluronic acids, growth factors, fibronectin, and collagen, all of which promote anti-inflammatory effects and healing. Cryopreserved AM (CAM) consists of a highly biocompatible natural scaffold derived from the placenta that contains a rich source of regenerative stem cells, anti-inflammatory cytokines, and growth factors.²⁵ For advanced ocular surface damage, either due to dry eye or NK, the appropriate AM should be considered for treatment.

The application of CAM on the corneal surface suppresses inflammation, reduces scarring or fibrosis, and accelerates epithelial wound healing and corneal nerve regeneration.²⁶ These effects were demonstrated in the DREAM study, in which patients with severe refractory DED showed significant improvements on the ocular surface and reductions in DEWS scores after approximately 5 days of CAM therapy.²⁷ Remarkably, 2 days of CAM therapy are sufficient to improve DEWS scores, corneal staining, visual symptoms, and ocular discomfort for up to 3 months.²⁸

Mesenchymal stem cells in the treatments of DED

In recent years, mesenchymal stromal cells (MSCs) and MSC-derived exosomes have received considerable research attention in the treatment of DED due to their anti-inflammatory, tissue repair, and immune regulatory effects.²⁹ MSCs are pluripotent cells isolated from donor tissues and can interact directly with target tissue through intercellular contact or indirectly via paracrine secretion mechanisms. When placed in an environment with proinflammatory factors, MSCs differentiate into an immunosuppressive phenotype that regulates various immune cells and exerts anti-inflammatory effects.

In the past decade, a number of preclinical studies in animal models of DED found adipose-derived MSCs reduced inflammation and neovascularization and improved epithelial cell marker expressions.^29,30 In a clinical study of patients with severe DED secondary to Sjögren syndrome, an injection of allogenic adipose-derived MSCs into the lacrimal gland demonstrated promising clinical results.³¹ A single injection of MSCs significantly reduced Ocular Surface Disease Index (OSDI) scores and improved noninvasive tear breakup time.³²

Although MSCs hold promise as a viable treatment option for DED, there is a considerable risk of allograft and cell rejection associated with MSC transplantation. In contrast, MSC-derived exosomes offer a cell-free therapy option that avoids these potential risks.

Preclinical studies of MSC-derived exosomes found that treatment decreased cytokine levels, promoted corneal epithelial repair, and increased tear secretion in a murine model of dry eye.³³ In a group of eyes with refractory graft-vs-host disease, exosomes substantially reduced corneal staining, improved tear breakup time, increased tear secretion, and lowered OSDI scores.³⁴ These effects were attributed to the presence of miR-204, a microRNA which was shown to reprogram proinflammatory macrophages toward an immunosuppressive state.

For MSC transplantation, additional research is warranted to minimize the risk of rejection. Meanwhile, MSC-derived exosomes face considerable difficulty in purification and characterization, which hinder the academic and clinical studies needed to bring these therapies to market.³⁵

Targeting the immune system in practice

Recognizing the central role of inflammation in DED, many contemporary treatments aim to modulate the immune response, thereby disrupting the inflammatory cascade and facilitating epithelial healing. Although these anti-inflammatory therapies effectively alleviate symptoms and enhance the quality of life for a substantial number of patients, a significant portion still experience suboptimal outcomes, underscoring the need for innovative treatment approaches.

Many practitioners can be reluctant to manage DED due to the multifaceted etiologies and diverse sequelae. Yet, the expanding landscape of available therapeutics and their varied mechanisms present a compelling opportunity to effectively manage even the most refractory cases. With novel therapies such as varenicline, perfluorohexyloctane, and AM at our disposal, we are entering an exciting era in the treatment of ocular surface diseases, including DED and NK.

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