Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

Remy Robert, Caroline Ang, Guizhi Sun, Laurent Juglair, Ee X. Lim, Linda J. Mason, Natalie L. Payne, Claude C.A. Bernard, Charles R. Mackay

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The chemokine receptor CCR6 marks subsets of T cells and innate lymphoid cells that produce IL-17 and IL-22, and as such may play a role in the recruitment of these cells to certain inflammatory sites. However, the precise role of CCR6 has been controversial, in part because no effective monoclonal antibody (mAb) inhibitors against this receptor exist for use in mouse models of inflammation. We circumvented this problem using transgenic mice expressing human CCR6 (hCCR6) under control of its native promoter (hCCR6-Tg/mCCR6–/–). We also developed a fully humanized mAb against hCCR6 with antagonistic activity. The expression pattern of hCCR6 in hCCR6-Tg/mCCR6–/– mice was consistent with the pattern observed in humans. In mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis, treatment with anti-hCCR6 mAb was remarkably effective in both preventive and therapeutic regimens. For instance, in the imiquimod model of psoriasis, anti-CCR6 completely abolished all signs of inflammation. Moreover, anti-hCCR6 attenuated clinical symptoms of myelin oligodendrocyte glycoprotein–induced (MOG-induced) EAE and reduced infiltration of inflammatory cells in the central nervous system. CCR6 plays a critical role in Th17 type inflammatory reactions, and CCR6 inhibition may offer an alternative approach for the treatment of these lesions.
Original languageEnglish
Number of pages16
JournalJCI Insight
Volume2
Issue number15
DOIs
Publication statusPublished - 3 Aug 2017

Cite this

@article{aa230c8eb90b49b099340d7747cabfe0,
title = "Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice",
abstract = "The chemokine receptor CCR6 marks subsets of T cells and innate lymphoid cells that produce IL-17 and IL-22, and as such may play a role in the recruitment of these cells to certain inflammatory sites. However, the precise role of CCR6 has been controversial, in part because no effective monoclonal antibody (mAb) inhibitors against this receptor exist for use in mouse models of inflammation. We circumvented this problem using transgenic mice expressing human CCR6 (hCCR6) under control of its native promoter (hCCR6-Tg/mCCR6–/–). We also developed a fully humanized mAb against hCCR6 with antagonistic activity. The expression pattern of hCCR6 in hCCR6-Tg/mCCR6–/– mice was consistent with the pattern observed in humans. In mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis, treatment with anti-hCCR6 mAb was remarkably effective in both preventive and therapeutic regimens. For instance, in the imiquimod model of psoriasis, anti-CCR6 completely abolished all signs of inflammation. Moreover, anti-hCCR6 attenuated clinical symptoms of myelin oligodendrocyte glycoprotein–induced (MOG-induced) EAE and reduced infiltration of inflammatory cells in the central nervous system. CCR6 plays a critical role in Th17 type inflammatory reactions, and CCR6 inhibition may offer an alternative approach for the treatment of these lesions.",
author = "Remy Robert and Caroline Ang and Guizhi Sun and Laurent Juglair and Lim, {Ee X.} and Mason, {Linda J.} and Payne, {Natalie L.} and Bernard, {Claude C.A.} and Mackay, {Charles R.}",
year = "2017",
month = "8",
day = "3",
doi = "10.1172/jci.insight.94821",
language = "English",
volume = "2",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "15",

}

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice. / Robert, Remy; Ang, Caroline; Sun, Guizhi; Juglair, Laurent; Lim, Ee X.; Mason, Linda J.; Payne, Natalie L.; Bernard, Claude C.A.; Mackay, Charles R.

In: JCI Insight, Vol. 2, No. 15, 03.08.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

AU - Robert, Remy

AU - Ang, Caroline

AU - Sun, Guizhi

AU - Juglair, Laurent

AU - Lim, Ee X.

AU - Mason, Linda J.

AU - Payne, Natalie L.

AU - Bernard, Claude C.A.

AU - Mackay, Charles R.

PY - 2017/8/3

Y1 - 2017/8/3

N2 - The chemokine receptor CCR6 marks subsets of T cells and innate lymphoid cells that produce IL-17 and IL-22, and as such may play a role in the recruitment of these cells to certain inflammatory sites. However, the precise role of CCR6 has been controversial, in part because no effective monoclonal antibody (mAb) inhibitors against this receptor exist for use in mouse models of inflammation. We circumvented this problem using transgenic mice expressing human CCR6 (hCCR6) under control of its native promoter (hCCR6-Tg/mCCR6–/–). We also developed a fully humanized mAb against hCCR6 with antagonistic activity. The expression pattern of hCCR6 in hCCR6-Tg/mCCR6–/– mice was consistent with the pattern observed in humans. In mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis, treatment with anti-hCCR6 mAb was remarkably effective in both preventive and therapeutic regimens. For instance, in the imiquimod model of psoriasis, anti-CCR6 completely abolished all signs of inflammation. Moreover, anti-hCCR6 attenuated clinical symptoms of myelin oligodendrocyte glycoprotein–induced (MOG-induced) EAE and reduced infiltration of inflammatory cells in the central nervous system. CCR6 plays a critical role in Th17 type inflammatory reactions, and CCR6 inhibition may offer an alternative approach for the treatment of these lesions.

AB - The chemokine receptor CCR6 marks subsets of T cells and innate lymphoid cells that produce IL-17 and IL-22, and as such may play a role in the recruitment of these cells to certain inflammatory sites. However, the precise role of CCR6 has been controversial, in part because no effective monoclonal antibody (mAb) inhibitors against this receptor exist for use in mouse models of inflammation. We circumvented this problem using transgenic mice expressing human CCR6 (hCCR6) under control of its native promoter (hCCR6-Tg/mCCR6–/–). We also developed a fully humanized mAb against hCCR6 with antagonistic activity. The expression pattern of hCCR6 in hCCR6-Tg/mCCR6–/– mice was consistent with the pattern observed in humans. In mouse models of experimental autoimmune encephalomyelitis (EAE) and psoriasis, treatment with anti-hCCR6 mAb was remarkably effective in both preventive and therapeutic regimens. For instance, in the imiquimod model of psoriasis, anti-CCR6 completely abolished all signs of inflammation. Moreover, anti-hCCR6 attenuated clinical symptoms of myelin oligodendrocyte glycoprotein–induced (MOG-induced) EAE and reduced infiltration of inflammatory cells in the central nervous system. CCR6 plays a critical role in Th17 type inflammatory reactions, and CCR6 inhibition may offer an alternative approach for the treatment of these lesions.

U2 - 10.1172/jci.insight.94821

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M3 - Article

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JO - JCI Insight

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SN - 2379-3708

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