SwePub
Sök i LIBRIS databas

  Extended search

WFRF:(Delic Denis)
 

Search: WFRF:(Delic Denis) > (2021) > RORγt inhibitors bl...

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist
  • Lamb, DavidBoehringer Ingelheim GmbH (author)

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-05-22
  • Springer Science and Business Media LLC,2021

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:80d4b9c7-9a24-4b17-a835-10a6455fc0e8
  • https://lup.lub.lu.se/record/80d4b9c7-9a24-4b17-a835-10a6455fc0e8URI
  • https://doi.org/10.1186/s12931-021-01743-7DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Background: RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma. Methods: IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Results: We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells. Conclusion: These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • De Sousa, DorothyBoehringer Ingelheim (Canada) Ltd. (author)
  • Quast, KarstenBoehringer Ingelheim GmbH (author)
  • Fundel-Clemens, KatrinBoehringer Ingelheim GmbH (author)
  • Erjefält, Jonas S.Lund University,Lunds universitet,Luftvägsinflammation,Forskargrupper vid Lunds universitet,Airway Inflammation and Immunology,Lund University Research Groups,Medetect AB(Swepub:lu)mphy-jer (author)
  • Sandén, CarolineMedetect AB(Swepub:lu)mphy-cgu (author)
  • Hoffmann, Hans JürgenAarhus University (author)
  • Kästle, MarcBoehringer Ingelheim GmbH (author)
  • Schmid, RamonaBoehringer Ingelheim GmbH (author)
  • Menden, KevinBoehringer Ingelheim GmbH (author)
  • Delic, DenisBoehringer Ingelheim GmbH (author)
  • Boehringer Ingelheim GmbHBoehringer Ingelheim (Canada) Ltd. (creator_code:org_t)

Related titles

  • In:Respiratory Research: Springer Science and Business Media LLC22:11465-99211465-993X

Internet link

Find in a library

To the university's database

  • 1 of 1
  • Previous record
  • Next record
  •    To hitlist

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view