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Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis.

ABSTRACT: CCR7 plays a key role in mobilizing tissue dendritic cells (DCs) to the lymphoid compartment for consequent elicitation of adaptive immunity. Interfering with CCR7 function therapeutically would therefore be anticipated to inhibit the progression of atopic conditions, for example, allergic conjunctivitis (AC). However, the CCR7-CCL19/CCL21 system in the ocular surface is poorly understood as is the precise role of DCs in AC immunopathogenesis. T cells from ovalbumin (OVA)-primed mice were adoptively transferred into wild-type (WT) hosts. Exogenous WT (eGFP(+)) versus CCR7(-/-) DCs were engrafted subconjunctivally (SCJ), and hosts were challenged with OVA (Texas-Red+) eye drops. AC immunopathogenesis was evaluated via clinical examinations, infiltration of mast cells and eosinophils, Th2 reactivity, and serum IgE levels. AC was also assessed in actively immunized mice challenged with OVA eye drops containing 1% anti-CCR7 antibody or isotype control. In eye-draining lymph nodes (LNs), OVA(+) SCJ engrafted WT DCs conferred upregulated CCR7 and caused augmentation of clinical signs. This result was corroborated by increased conjunctival infiltration, Th2 cytokines in LNs, and serum OVA-specific IgE. Strikingly, this was completely reversed with SCJ engrafted CCR7(-/-) DCs in all parameters tested. Furthermore, topical antibody blockade of CCR7 in actively immunized mice significantly inhibited AC. Ocular surface DCs via CCR7 expression contribute to the immunopathogenesis of AC, thereby allowing significant inhibition of this experimental condition via topical CCR7 antibody blockade.

SUBMITTER: Schlereth S

PROVIDER: S-EPMC5691338 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis.

Schlereth Simona S Lee Hyun Soo HS Khandelwal Payal P Saban Daniel R DR

The American journal of pathology 20120414 6

CCR7 plays a key role in mobilizing tissue dendritic cells (DCs) to the lymphoid compartment for consequent elicitation of adaptive immunity. Interfering with CCR7 function therapeutically would therefore be anticipated to inhibit the progression of atopic conditions, for example, allergic conjunctivitis (AC). However, the CCR7-CCL19/CCL21 system in the ocular surface is poorly understood as is the precise role of DCs in AC immunopathogenesis. T cells from ovalbumin (OVA)-primed mice were adopti ...[more]

PMID: 22507838

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Project description:Based on previous findings that ozone can induce an inflammatory response in the ocular surface of an animal model and in cultured human conjunctival epithelial cells, we investigated whether exposure to ozone exacerbates symptoms of allergic conjunctivitis. We evaluated the effects of exposure to ozone on conjunctival chemosis, conjunctival injection, corneal and conjunctival fluorescein staining scores, production of inflammatory cytokines in tears, and aqueous tear production in a mouse model of allergic conjunctivitis. To validate our in vivo results, we used interleukin (IL)-1α-pretreated conjunctival epithelial cells as an in vitro substitute for the mouse model. We evaluated whether exposure to ozone increased the inflammatory response and altered oxidative status and mitochondrial function in IL-1α-pretreated conjunctival epithelial cells. In the in vivo study, ozone induced increases in conjunctival chemosis, conjunctival injection, corneal and conjunctival fluorescein staining scores, and production of inflammatory cytokines, accompanied by a decrease in tear volume. In the in vitro study, exposure to ozone led to additional increases in IL-6 and tumor necrosis factor-α mRNA levels, which were already induced by treatment with IL-1α. Ozone did not induce any changes in cell viability. Pretreatment with IL-1α increased the expression of manganese superoxide dismutase, and exposure to ozone led to additional increments in the expression of this antioxidant enzyme. Ozone did not induce any changes in mitochondrial activity or expression of mitochondrial enzymes and proteins related to mitochondrial function, with the exception of phosphor-mammalian target of rapamycin. Treatment with butylated hydroxyanisole, a free radical scavenger, attenuated the ozone-induced increases in IL-6 expression in IL-1α-pretreated conjunctival epithelial cells. Therefore, we conclude that exposure to ozone exacerbates the detrimental effects on the integrity of the ocular surface caused by conjunctival allergic reactions, and further increases the inflammatory response in IL-1α-pretreated conjunctival epithelial cells.

Project description:BackgroundClassical understanding of allergic conjunctivitis (ACJ) suggests that ocular itch results from a mast cell-dependent inflammatory process. However, treatments that target inflammatory mediators or immune cells are often unsatisfying in relieving the stubborn itch symptom. This suggests that additional mechanisms are responsible for ocular itch in ACJ. In this study, we aim to determine the role of neuronal FcεRIa in allergic ocular itch.MethodsCalcium imaging was applied to observe the effect of IgE-immune complex in trigeminal neurons. Genomic FcεRIa knockout mice and adeno-associated virus (AAV) mediated sensory neuron FcεRIa knockdown mice were used in conjunction with behavioral tests to determine ocular itch. In addition, immunohistochemistry, Western blot and quantitative RT-PCR were used for in vitro experiments.ResultsWe found that FcεRIα was expressed in a subpopulation of conjunctiva sensory neurons. IgE-IC directly activated trigeminal neurons and evoked acute ocular itch without detectible conjunctival inflammation. These effects were attenuated in both a global FcεRIa-knockout mice and after sensory neuronal-specific FcεRIa-knockdown in the mouse trigeminal ganglion. In an ovalbumin (OVA) induced murine ACJ model, FcεRIα was found upregulated in conjunctiva-innervating CGRP+ sensory neurons. Sensory neuronal-specific knockdown of FcεRIa significantly alleviated ocular itch in the ACJ mice without affecting the immune cell infiltration and mast cell activation in conjunctiva. Although FcεRIα mRNA expression was not increased by IgE in dissociated trigeminal ganglion neurons, FcεRIα protein level was enhanced by IgE in a cycloheximide-resistance manner, with concordant enhancement of neuronal responses to IgE-IC. In addition, incremental sensitization gradually enhanced the expression of FcεRIα in small-sized trigeminal neurons and aggravated OVA induced ocular itch.ConclusionsOur study demonstrates that FcεRIα in pruriceptive neurons directly mediates IgE-IC evoked itch and plays an important role in ocular itch in a mouse model of ACJ. These findings reveal another axis of neuroimmune interaction in allergic itch condition independent to the classical IgE-mast cell pathway, and might suggest novel therapeutic strategies for the treatment of pruritus in ACJ and other immune-related disorders.

Project description:IntroductionThe efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated.MethodsPooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score<1) and zero itch (itch score=0) was also assessed.ResultsA total of 284 subjects were enrolled in the two studies. At 3 min post-CAC and 16 h after treatment instillation, alcaftadine 0.25% achieved a significantly lower mean itch score compared with olopatadine 0.2% (0.50 vs. 0.87, respectively; P=0.0006). Alcaftadine demonstrated a significantly lower mean itch score over all time points compared with olopatadine (0.68 vs. 0.92, respectively; P=0.0390); both alcaftadine- and olopatadine-treated subjects achieved significantly lower overall mean ocular itching scores compared with placebo (2.10; P<0.0001 for both actives). Minimal itch over all time points was reported by 76.1% of alcaftadine-treated subjects compared with 58.1% of olopatadine-treated subjects (P=0.0121). Treatment with alcaftadine 0.25% and olopatadine 0.2% was safe and well tolerated; no serious adverse events were reported.ConclusionOnce-daily alcaftadine 0.25% ophthalmic solution demonstrated greater efficacy in prevention of ocular itching compared with olopatadine 0.2% at 3 min post-CAC (primary endpoint), and over all time points, 16 h post-treatment instillation. Alcaftadine and olopatadine both provided effective relief compared with placebo and were generally well tolerated.

Dataset Information

Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis.

Publications

Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis.

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