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ROR gamma t inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating gamma delta-T cells

Céline Mortier (UGent) , Eric Gracey (UGent) , Julie Coudenys (UGent) , Teddy Manuello (UGent) , Tine Decruy (UGent) , Margaux Maelegheer (UGent) , Flore Stappers (UGent) , Elisabeth Gilis (UGent) , Djoere Gaublomme (UGent) , Luc Van Hoorebeke (UGent) , et al.
(2023) RHEUMATOLOGY. 62(9). p.3169-3178
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Abstract
Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in PsA. Therefore, elucidating the role of ROR gamma t, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, ROR gamma t inhibition was assessed in combined skin, joint and gut inflammation in vivo, using a PsA model. Methods We tested the efficacy of a ROR gamma t antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results ROR gamma t-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, P < 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (P < 0.05 in calcaneus, P < 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (gamma delta)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by ROR gamma t inhibition (P < 0.001). Conclusion ROR gamma t-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by gamma delta-T cells and Th17 cells.
Keywords
PsA, ROR gamma-t, IL-23, IL-17, gamma-delta T cells, POTENTIAL ROLE, INTERLEUKIN-22, INFLAMMATION, EXPRESSION, HOMEOSTASIS

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MLA
Mortier, Céline, et al. “ROR Gamma t Inhibition Ameliorates IL-23 Driven Experimental Psoriatic Arthritis by Predominantly Modulating Gamma Delta-T Cells.” RHEUMATOLOGY, vol. 62, no. 9, 2023, pp. 3169–78, doi:10.1093/rheumatology/kead022.
APA
Mortier, C., Gracey, E., Coudenys, J., Manuello, T., Decruy, T., Maelegheer, M., … Venken, K. (2023). ROR gamma t inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating gamma delta-T cells. RHEUMATOLOGY, 62(9), 3169–3178. https://doi.org/10.1093/rheumatology/kead022
Chicago author-date
Mortier, Céline, Eric Gracey, Julie Coudenys, Teddy Manuello, Tine Decruy, Margaux Maelegheer, Flore Stappers, et al. 2023. “ROR Gamma t Inhibition Ameliorates IL-23 Driven Experimental Psoriatic Arthritis by Predominantly Modulating Gamma Delta-T Cells.” RHEUMATOLOGY 62 (9): 3169–78. https://doi.org/10.1093/rheumatology/kead022.
Chicago author-date (all authors)
Mortier, Céline, Eric Gracey, Julie Coudenys, Teddy Manuello, Tine Decruy, Margaux Maelegheer, Flore Stappers, Elisabeth Gilis, Djoere Gaublomme, Luc Van Hoorebeke, Sophie Van Welden, Catherine Ambler, Martin Hegen, Peter Symanowicz, Stefan Steyn, Gabriel Berstein, Dirk Elewaut, and Koen Venken. 2023. “ROR Gamma t Inhibition Ameliorates IL-23 Driven Experimental Psoriatic Arthritis by Predominantly Modulating Gamma Delta-T Cells.” RHEUMATOLOGY 62 (9): 3169–3178. doi:10.1093/rheumatology/kead022.
Vancouver
1.
Mortier C, Gracey E, Coudenys J, Manuello T, Decruy T, Maelegheer M, et al. ROR gamma t inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating gamma delta-T cells. RHEUMATOLOGY. 2023;62(9):3169–78.
IEEE
[1]
C. Mortier et al., “ROR gamma t inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating gamma delta-T cells,” RHEUMATOLOGY, vol. 62, no. 9, pp. 3169–3178, 2023.
@article{01GVNH7YQ2WTM2T2S9KZH07CEC,
  abstract     = {{Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in PsA. Therefore, elucidating the role of ROR gamma t, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, ROR gamma t inhibition was assessed in combined skin, joint and gut inflammation in vivo, using a PsA model. Methods We tested the efficacy of a ROR gamma t antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results ROR gamma t-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, P < 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (P < 0.05 in calcaneus, P < 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (gamma delta)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by ROR gamma t inhibition (P < 0.001). Conclusion ROR gamma t-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by gamma delta-T cells and Th17 cells.}},
  author       = {{Mortier, Céline and Gracey, Eric and Coudenys, Julie and Manuello, Teddy and Decruy, Tine and Maelegheer, Margaux and Stappers, Flore and Gilis, Elisabeth and Gaublomme, Djoere and Van Hoorebeke, Luc and Van Welden, Sophie and  Ambler, Catherine and  Hegen, Martin and  Symanowicz, Peter and  Steyn, Stefan and  Berstein, Gabriel and Elewaut, Dirk and Venken, Koen}},
  issn         = {{1462-0324}},
  journal      = {{RHEUMATOLOGY}},
  keywords     = {{PsA,ROR gamma-t,IL-23,IL-17,gamma-delta T cells,POTENTIAL ROLE,INTERLEUKIN-22,INFLAMMATION,EXPRESSION,HOMEOSTASIS}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{3169--3178}},
  title        = {{ROR gamma t inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating gamma delta-T cells}},
  url          = {{http://doi.org/10.1093/rheumatology/kead022}},
  volume       = {{62}},
  year         = {{2023}},
}
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