Experimental models of autoimmune inflammatory ocular diseases

Gasparin, Fabio; Takahashi, Beatriz Sayuri; Scolari, Mariana Ramos; Gasparin, Filipe; Pedral, Lycia Sampaio; Damico, Francisco Max

doi:10.1590/s0004-27492012000200016

Cited by 24 publications

(18 citation statements)

References 57 publications

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“…To this date, several animal models have been used to study AIU (reviewed in [35,36] ). In the next sections we review the most frequently used models to study the immunopathogenesis as well as some promising systems for evaluation of novel therapies.…”

Section: Animal Models Of Autoimmune Uveitismentioning

confidence: 99%

Immunotherapeutic strategies in autoimmune uveitis

Papotto

Marengo

Sardinha

et al. 2014

Autoimmunity Reviews

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Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab′ antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results.

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Section: Animal Models Of Autoimmune Uveitismentioning

confidence: 99%

Immunotherapeutic strategies in autoimmune uveitis

Papotto

Marengo

Sardinha

et al. 2014

Autoimmunity Reviews

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“…The phenotype seen in the eyes of Asah1 P361R/P361R mice shares some similarities with the rodent models of experimental autoimmune uveoretinitis. 34 During the early phase after experimental autoimmune uveoretinitis induction, cellular infiltrates can be observed in the vitreous and optic nerve head of mice eyes. 35 As mice transition into the acute phase of experimental autoimmune uveoretinitis, inflammation is more severe, and retinal folding and edema might occur.…”

Section: Discussionmentioning

confidence: 99%

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Sajdak

Sikora

et al. 2019

The American Journal of Pathology

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Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1 P361R/P361R mice. Asah1 P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1 P361R/ P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment. (Am J Pathol 2019, 189: 320e338; https://doi.

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“…Studies in EAU models suggest that IL-2 is one of the predominant cytokines produced in the early phases of the disease. [239] One example of anti-IL-2 therapy is represented by daclizumab, a humanized blocking monoclonal antibody acting against an epitope of the alpha subunit of the IL-2 receptor (CD25), which is located on activated T-cells and other immune cells. [240] Daclizumab has been used in patients experiencing acute reaction episodes following organ transplantation, including heart, [241,242] pancreas, [243] liver, [244] and lung.…”

Section: Ocular Diseasesmentioning

confidence: 99%

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

Ratay

Bellotti

Gottardi³

et al. 2017

Adv Healthcare Materials

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Dry eye disease (DED), age-related macular degeneration (AMD), and Uveitis are ocular diseases that significantly affect the quality of life of millions of people each year. In these diseases, the action of chemokines, pro-inflammatory cytokines, and immune cells drives a local inflammatory response that results in ocular tissue damage. Multiple therapeutic strategies have been developed to either address the symptoms or abate the underlying cause of these diseases. Herein, we will review the challenges to deliver drugs to the relevant location in the eye for each of these diseases as well as current and innovative therapeutic approaches that attempt to restore homeostasis within the ocular microenvironment.

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Experimental models of autoimmune inflammatory ocular diseases

Cited by 24 publications

References 57 publications

Immunotherapeutic strategies in autoimmune uveitis

Immunotherapeutic strategies in autoimmune uveitis

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

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