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Shilpa Kodati, Yihe Chen, Thomas H Dohlman, Sunil K Chauhan, Daniel R Saban, Reza Dana; CCR7 is critical in the induction and maintenance of Th17 immunity in dry eye disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3661.
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CC Chemokine receptor 7 (CCR7) has emerged as a critical mediator of antigen-presenting cell (APC) migration from the cornea to the draining lymph node (LN). In this study, we investigated the effect of topical CCR7 blockade on the induction and maintenance of dry eye disease (DED), including the effect on Th17 immunity.
DED was induced in 6 to 8 week old female C57BL/6 mice through exposure to a controlled environment chamber (CEC) and scopolamine injections. To determine the functional role of CCR7 in the induction of DED, mice (n=10) were treated topically with either anti-CCR7, isotype antibody or remained untreated. Corneal fluorescein staining (CFS) was performed and mice were sacrificed on day 9 for flow cytometric quantification of IL-17 secreting CD4+ (Th17 cells) within the draining LN and real-time PCR analyses of IL-17, MMP-3, IL-1β and TNF-α expression at the ocular surface. In order to evaluate the effect of topical CCR7 blockade on chronic DED, female C57BL/6 mice (n=10) were re-exposed to the CEC after an initial 12 days of exposure to the CEC and a subsequent 10 days of being housed in room air. On re-exposure, to the CEC mice were similarly treated topically with either anti-CCR7, isotype antibody or remained untreated and CFS was performed.
Decreased Th17 frequencies in the draining LN and reduced conjunctival expression of IL-17 were observed in mice treated with topical anti-CCR7 compared to isotype treated mice. Ocular surface expression of MMP-3 and DED associated pro-inflammatory cytokines IL-1β and TNF-α were significantly decreased in the anti-CCR7 treated group (p < 0.05). Furthermore, significantly lower clinical fluorescein scores (CFS) were observed in anti-CCR7 treated mice compared to isotype treated mice (p < 0.001). Finally, topical CCR7 blockade was effective in ameliorating chronic DED (p<0.001).
Our findings show that CCR7 blockade is highly effective in inhibiting the immunopathogenesis of DED. Furthermore, these results suggest that CCR7 mediated trafficking of APCs drives the induction and maintenance of Th17 immunity in DED.
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