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

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RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma. / Lamb, David; De Sousa, Dorothy; Quast, Karsten; Fundel-Clemens, Katrin; Erjefält, Jonas S.; Sandén, Caroline; Hoffmann, Hans Jürgen; Kästle, Marc; Schmid, Ramona; Menden, Kevin; Delic, Denis.

I: Respiratory Research, Vol. 22, Nr. 1, 158, 01.12.2021.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Lamb, D, De Sousa, D, Quast, K, Fundel-Clemens, K, Erjefält, JS, Sandén, C, Hoffmann, HJ, Kästle, M, Schmid, R, Menden, K & Delic, D 2021, 'RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma', Respiratory Research, vol. 22, nr. 1, 158. https://doi.org/10.1186/s12931-021-01743-7

APA

Lamb, D., De Sousa, D., Quast, K., Fundel-Clemens, K., Erjefält, J. S., Sandén, C., Hoffmann, H. J., Kästle, M., Schmid, R., Menden, K., & Delic, D. (2021). RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma. Respiratory Research, 22(1), [158]. https://doi.org/10.1186/s12931-021-01743-7

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MLA

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Author

Lamb, David ; De Sousa, Dorothy ; Quast, Karsten ; Fundel-Clemens, Katrin ; Erjefält, Jonas S. ; Sandén, Caroline ; Hoffmann, Hans Jürgen ; Kästle, Marc ; Schmid, Ramona ; Menden, Kevin ; Delic, Denis. / RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma. I: Respiratory Research. 2021 ; Vol. 22, Nr. 1.

RIS

TY - JOUR

T1 - RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

AU - Lamb, David

AU - De Sousa, Dorothy

AU - Quast, Karsten

AU - Fundel-Clemens, Katrin

AU - Erjefält, Jonas S.

AU - Sandén, Caroline

AU - Hoffmann, Hans Jürgen

AU - Kästle, Marc

AU - Schmid, Ramona

AU - Menden, Kevin

AU - Delic, Denis

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

KW - Gene signature

KW - IL-17

KW - IL-22

KW - Inhibitor

KW - Mouse model

KW - RORgt

KW - Severe asthma

UR - http://www.scopus.com/inward/record.url?scp=85106709963&partnerID=8YFLogxK

U2 - 10.1186/s12931-021-01743-7

DO - 10.1186/s12931-021-01743-7

M3 - Article

C2 - 34022896

AN - SCOPUS:85106709963

VL - 22

JO - Respiratory Research

JF - Respiratory Research

SN - 1465-9921

IS - 1

M1 - 158

ER -