Evidence for Extrathymic Generation of Regulatory T Cells Specific for a Retinal Antigen

Gregerson, Dale S.; Heuss, Neal D.; Lehmann, Ute; McPherson, Scott W.

doi:10.1159/000119868

Cited by 8 publications

(12 citation statements)

References 35 publications

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“…Previously, we found that an ONC reversed the inhibitory activity of the endogenous regulatory response to retinal βgal in the ear-swelling assay for DTH (38). The ONC injures a small fraction of retinal neurons, stimulating an increase in the number of retinal GFP + DC and their activation, as detected by upregulation of MHC class II expression.…”

Section: Resultsmentioning

confidence: 88%

Local Activation of Dendritic Cells Alters the Pathogenesis of Autoimmune Disease in the Retina

Heuss

Lehmann

Norbury

et al. 2012

The Journal of Immunology

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Interest in the identities, properties, functions and origins of local antigen presenting cells (APC) in CNS tissues is growing. We recently reported that dendritic cells (DC) distinct from microglia were present in quiescent retina, and rapidly responded to injured neurons. In this study, the disease-promoting and regulatory contributions of these APC in experimental autoimmune uveoretinitis (EAU) were examined. Local delivery of purified, exogenous DC or monocytes from bone marrow substantially increased the incidence and severity of EAU induced by adoptive transfer of activated, autoreactive CD4 or CD8 T cells that was limited to the manipulated eye. In vitro assays of antigen presenting cell activity of DC from quiescent retina showed that they promoted generation of Foxp3+ T cells, and inhibited activation of naive T cells by splenic DC and antigen. Conversely, in vitro assays of DC purified from injured retina revealed an enhanced ability to activate T cells, and reduced induction of Foxp3+ T cells. These findings were supported by the observation that in situ activation of DC prior to adoptive transfer of β-galactosidase-specific T cells dramatically increased severity and incidence of EAU. Recruitment of T cells into retina by local delivery of antigen in vivo showed that quiescent retina promoted development of parenchymal Foxp3+ T cells, but assays of pre-injured retina did not. Together, these results demonstrated that local conditions in the retina determined APC function, and affected the pathogenesis of EAU by both CD4 and CD8 T cells.

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Section: Resultsmentioning

confidence: 88%

Local Activation of Dendritic Cells Alters the Pathogenesis of Autoimmune Disease in the Retina

Heuss

Lehmann

Norbury

et al. 2012

The Journal of Immunology

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“…However, this DTH response was inhibited in naïve arrβgal × βgalTCR double Tg mice, but the inhibition could be overcome in these mice by antibody depletion of CD25 + cells prior to ear testing (Fig. 2A ) [41]. We have also obtained similar results with a CD4 + TCR Tg and a CD8 + TCR Tg (both specific for distinct βgal epitopes) crossed with arrβgal mice, all on the B6 background (unpublished observations).…”

Section: Retinal Ags Induce a Distinct Immunoregulation Mediated By Cmentioning

confidence: 57%

“…This differs from ACAID immunoregulation which is associated with increased levels of all three cytokines. Further, splenocytes from B10.A and arrβgal mice that were subjected to βgal-induced ACAID and then βgal immunized were blocked in their production of IL-2 and IFN-γ upon antigenic challenge, whereas βgal immunized arrβgal mice could only induce a partial reduction in IFN-γ levels compared to B10.A controls [41]. Second, the expression of βgal in photoreceptors is different than the placement of a bolus of Ag.…”

Section: Retinal Ags Induce a Distinct Immunoregulation Mediated By Cmentioning

confidence: 99%

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Generation of Regulatory T Cells to Antigen Expressed in the Retina

McPherson¹,

Heuss²,

Lehman³

et al. 2011

CIR

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Regulatory T cells (Tregs) are generated to antigens (Ag) found in the retina. Some Tregs are the result of ectopic expression of the retinal Ags in the thymus, where developing T cells are committed to enter the regulatory lineage. However, the generation of retinal Ag-specific Tregs independent of the thymus was uncertain. Our studies show that Tregs can be generated from mature, peripheral T cells based on exposure to retinal Ags. These peripherally induced Tregs limited immune responses and experimental autoimmune disease induced by retinal Ags and thus constitute a crucial component of retinal immune privilege.

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“…• Can we expect that intravitreal therapy will control an immune-mediated disorder – when specific (circulating) immune cells are considered to be important [1]?…”

Section: Introductionmentioning

confidence: 99%

Think Global – Act Local: Intravitreal Drug Delivery Systems in Chronic Noninfectious Uveitis

Hazırolan

Pleyer

2012

Ophthalmic Res

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The eye is probably the most attractive site of the body for treatment using locally delivered therapeutic agents. An ideal indication for such an approach is noninfectious posterior uveitis. Since intraocular structures of the posterior segment are difficult to reach and are otherwise accessible only by systemic treatment, current interest is focused on the pros and cons of intravitreal drug delivery. Because of its chronic and recurrent nature, the long-term release of anti-inflammatory agents is a major treatment goal. Intravitreal injections, intravitreal implants and biodegradable devices are the most commonly used and approved approaches to deliver various agents to the vitreous. Because of their broad and potent effects, corticosteroids (CS) have been the first-line candidates for intraocular delivery. An increasing spectrum of CS preparations including nondegradable and biodegradable devices is currently available. Since repeated and long-term applications bear the risk of steroid-related complications such as increased intraocular pressure and cataract, alternative agents are currently being tested. Intravitreal injection of methotrexate, anti-VEGF (vascular endothelial growth factor), anti-TNFα (tumor necrosis factor α) and sirolimus have also been applied in patients with conflicting results. Intravitreal treatment has significantly reduced the incidence of adverse effects compared to systemic application, but due to greater ocular side effects there are still some limitations.

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Evidence for Extrathymic Generation of Regulatory T Cells Specific for a Retinal Antigen

Cited by 8 publications

References 35 publications

Local Activation of Dendritic Cells Alters the Pathogenesis of Autoimmune Disease in the Retina

Local Activation of Dendritic Cells Alters the Pathogenesis of Autoimmune Disease in the Retina

Generation of Regulatory T Cells to Antigen Expressed in the Retina

Think Global – Act Local: Intravitreal Drug Delivery Systems in Chronic Noninfectious Uveitis

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