The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation

Copland, David A; Wertheim, M. S.; Armitage, W. John; Nicholson, Lindsay B.; Raveney, Ben J. E.; Dick, Andrew D.

doi:10.1167/iovs.08-2348

Cited by 65 publications

(78 citation statements)

References 22 publications

(31 reference statements)

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“…This is consistent with our finding of substantial numbers of Th17-DP cells persisting in blood and retina of mice with EAU ( Fig. 2D) and in line with a recent study showing that during the resolution phase of acute uveitis, neither the clinical appearance nor the number of infiltrating leukocytes returned to pre-disease levels [27]. Physiological relevance of IL-2-expressing Th17 (Th17-DP) is suggested by our finding that substantial percentage of autoreactive T cells that mediate EAU was Th17-DP cells.…”

Section: Discussionsupporting

confidence: 94%

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Golestaneh

et al. 2011

Eur J Immunol

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Compared with other T‐helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL‐2 levels during Ag‐priming and this correlated with their decreased susceptibility to activation‐induced cell death (AICD). However, complete depletion of IL‐2 with IL‐2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL‐2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL‐2 (Th17‐DP). The Th17‐DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17‐DP and are targets of daclizumab, an IL‐2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL‐2 production to levels that cannot provoke IL‐2‐induced AICD yet are sufficient to promote Th17 homeostatic expansion.

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Section: Discussionsupporting

confidence: 94%

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Golestaneh

et al. 2011

Eur J Immunol

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“…Dex was administered subcutaneously and CsA was administered by oral gavage. TEFI was used to assess the clinical score of EAU (Table S3) (18). A single-cell suspension of tissues was isolated using a tissue dissociation method.…”

Section: Methodsmentioning

confidence: 99%

“…For comparison of the effect of CsA and Dex on T-cell subsets, drug concentrations were titrated to establish the minimum dose at which equivalent suppression of inflammation was achieved, as measured by direct visualization of the organ-specific immune response in the eye using topical endoscopic fundal imaging (TEFI) (Fig. S4A) (18). We then treated EAU mice with either Dex or CsA and evaluated their effects by a combination of TEFI and histology (Fig.…”

Section: Human Th17 Cells Exhibit a Restricted Genome-wide Response Tomentioning

confidence: 99%

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Schewitz-Bowers

Lait

Copland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

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“…35 The animal models, such as experimental autoimmune uveoretinitis (EAU), support a role for autoimmunity with clinical-pathological features bearing remarkable similarity to man. 7,8,36,37 The currently held notion is that of a CD4 + T helper cell-driven process and supported in man by the association of sympathetic ophthalmia and Vogt-Koyanagi-Harada disease with specific HLA class II alleles as well as the identification of ocular antigen-responsive T cells in both the peripheral blood and eyes of patients. [38][39][40] When T cells are activated, they assume different functional phenotypes directed through canonical transcription factors 41,42 and characterised by the secretion of signature cytokines.…”

Section: Understanding Uveitismentioning

confidence: 99%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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The Clinical Time-Course of Experimental Autoimmune Uveoretinitis Using Topical Endoscopic Fundal Imaging with Histologic and Cellular Infiltrate Correlation

Cited by 65 publications

References 22 publications

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Doyne lecture 2016: intraocular health and the many faces of inflammation

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