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- W2343156982 abstract "Dysregulated expression of IL17 is a major hallmark of psoriasis, and targeting the IL17 pathway is an effective treatment for psoriatic inflammation. The chemokine receptor CCR6 is expressed on Th17+ T cells. The ligand for CCR6 CCL20, is upregulated in both psoriatic lesions of patients and in skin lesions in murine pre-clinical models of psoriasis. We have previously reported that CCX9664, a small molecule inhibitor of CCR6, reduced skin inflammation in murine models of psoriasis and reduced the numbers of skin Vγ3-negative dermal γδ T cells, a population known to contain IL17-secreting T cells. Here we report data using a novel series of orally available, small molecule CCR6 antagonists from a chemical class different from CCX9664. These novel CCR6 antagonists, which have improved potency and pharmacokinetic properties have efficacy in pre-clinical mouse models equivalent to that achieved with antibody to IL-17RA. In the imiquimod induced model of psoriasiform lesions, prophylactic dosing led to a reduction in all features contributing to the PASI (Psoriasis Activity Severity Index) score, with less than 20% of the mice scoring as severe (score ≥3) for scaling and erythema, compared with 80% scoring in vehicle treated mice. In the IL-23 mediated model of psoriasis, therapeutic dosing led to a complete reduction in ear swelling (p<0.0001 vs vehicle treated mice). In addition to the effect on Th17+ T cell migration shown in our earlier studies, we now demonstrate that CCR6 antagonism is also associated with blockade of the migration of CD11c+ CCR6+ Langerhans cells from the skin to the draining inguinal lymph nodes (p<0.01 vs vehicle treated mice). Taken together, our studies suggest that inhibition of CCR6 may provide an important new therapeutic modality for the treatment of psoriasis." @default.
- W2343156982 created "2016-06-24" @default.
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- W2343156982 date "2016-05-01" @default.
- W2343156982 modified "2023-09-26" @default.
- W2343156982 title "521 Chemokine receptor inhibition as a novel therapeutic approach for psoriasis" @default.
- W2343156982 doi "https://doi.org/10.1016/j.jid.2016.02.559" @default.
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