Mucosal tolerance disruption favors disease progression in an extraorbital lacrimal gland excision model of murine dry eye

Guzmán, Mauricio; Keitelman, Irene; Sabbione, Florencia; Trevani, Analía Silvina; Giordano, Mirta; Galletti, Jeremías Gastón

doi:10.1016/j.exer.2016.07.004

Cited by 28 publications

(48 citation statements)

References 19 publications

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“…One theory for the generation of autoreactive CD4 + T cells is that dry eye disrupts ocular surface immune tolerance. Loss of immune tolerance to antigens topically applied to the eye surface has been found in experimental models of dry eye induced by systemic cholinergic blockade and exposure to a desiccating environment, lacrimal gland excision, or topical administration of the detergent benzylkonium chloride (9)(10)(11). Similar to human dry eye, significant conjunctival GC loss has been documented in these mouse models (5,12).…”

Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

“…Loss of immune tolerance has been implicated in the immune-based conjunctival inflammation that develops in dry eye (10,11). Tolerance to antigens, such OVA, topically applied to the ocular surface has been reported to develop through anergy induction and generation of antigen-specific Tregs (10,11,24). Guzman and associates found that induction of tolerance to topically applied OVA antigen was lost after 3 days of experimental dry eye induced by pharmacological suppression of tear secretion and exposure to a desiccating environment, a model in which GC loss occurs (10).…”

Section: Discussionmentioning

confidence: 99%

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Goblet cell loss abrogates ocular surface immune tolerance

Ko¹,

Xiao²,

Barbosa³

et al. 2018

JCI Insight

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Goblet cell loss abrogates ocular surface immune tolerance

Ko¹,

Xiao²,

Barbosa³

et al. 2018

JCI Insight

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“…109 Goblet cell associated-passages that deliver surface antigens to the underlying dendritic cells and promote tolerance have been identified in both intestine and conjunctiva. 109, 110 Mice with deletion of the SAM pointed domain containing ETS transcription factor gene (Spdef knockout) are devoid of goblet cells, develop conjunctival inflammation and lose 111 immune tolerance to topically applied antigens, as has been found in other mouse dry eye models that are accompanied by goblet cell loss 109, 112–114 These studies indicate a critical role of goblet cell products in conditioning tolerogenic properties in conjunctival dendritic cells and maintaining ocular surface immune tolerance. 107, 108 …”

Section: Dry Eye – a Multifactorial And Self-perpetuating Inflammatormentioning

confidence: 77%

“…115–117 While the target autoantigen(s) in this autoimmune reaction have not been identified, members of the kallikrein family have been implicated as putative antigens in some studies. 118, 119 Disrupted immune tolerance in dry eye 112–114 elicits leads to dendritic cell maturation 120 and generation of autoreactive T effector cells 70, 101, 121–124 in mouse dry eye models. Human dry eye patients have an increased number of conjunctival dendritic cells 125, 126 and a higher percentage of cells expressing the dendritic cell maturation marker HLA-DR. 127–130 Depletion of dendritic cells prevented the development of dry eye disease in mice subjected to desiccating stress.…”

Section: Dry Eye – a Multifactorial And Self-perpetuating Inflammatormentioning

confidence: 99%

The Pathophysiology of Dry Eye Disease

2017

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Clinical and laboratory studies performed over the past few decades have discovered that dry eye is a chronic inflammatory disease that can be initiated by numerous extrinsic or intrinsic factors that promote an unstable and hyperosmolar tear film. These changes in tear composition, in some cases combined with systemic factors, lead to an inflammatory cycle that causes ocular surface epithelial disease and neural stimulation. Acute desiccation activates stress signaling pathways in the ocular surface epithelium and resident immune cells. This triggers production of innate inflammatory mediators that stimulate the production of matrix metalloprotease, inflammatory cell recruitment, and dendritic cell maturation. These mediators combined with exposure of autoantigens can lead to an adaptive T-cell mediated response. Cornea barrier disruption develops by protease-mediated lysis of epithelial tight junctions leading to accelerated cell death, desquamation, an irregular poorly lubricated cornea surface and exposure and sensitization of epithelial nociceptors. Conjunctival goblet cell dysfunction and death are promoted by the T helper 1 cytokine interferon gamma (IFN-γ). These epithelial changes further destabilize the tear film, amplify inflammation and create a vicious cycle. Cyclosporine and lifitegrast, the two FDA-approved therapies inhibit T cell activation and cytokine production. While these therapies represent a major advance in dry eye therapy, they are not effective in improving discomfort and corneal epithelial disease in all patients. Preclinical studies have identified other potential therapeutic targets, biomarkers and strategies to bolster endogenous immunoregulatory pathways. These discoveries will hopefully lead to further advances in diagnostic classification and treatment.

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Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development

et al. 2019

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Preclinical models of human diseases are critical to our understanding of disease etiology, pathology, and progression and enable the development of effective treatments. An ideal model of human disease should capture anatomical features and pathophysiological mechanisms, mimic the progression pattern, and should be amenable to evaluating translational endpoints and treatment approaches. Preclinical animal models have been developed for a variety of human ophthalmological diseases to mirror disease mechanisms, location of the affected region in the eye and severity. These models offer clues to aid in our fundamental understanding of disease pathogenesis and enable progression of new therapies to clinical development by providing an opportunity to gain proof of concept (POC). Here, we review preclinical animal models associated with development of new therapies for diseases of the ocular surface, glaucoma, presbyopia, and retinal diseases, including diabetic retinopathy and age-related macular degeneration (AMD). We have focused on summarizing the models critical to new drug development and described the translational features of the models that contributed to our understanding of disease pathogenesis and establishment of preclinical POC.

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Mucosal tolerance disruption favors disease progression in an extraorbital lacrimal gland excision model of murine dry eye

Cited by 28 publications

References 19 publications

Goblet cell loss abrogates ocular surface immune tolerance

Goblet cell loss abrogates ocular surface immune tolerance

The Pathophysiology of Dry Eye Disease

Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development

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