POS0048 LIPOPOLYSACCHARIDE ACTIVATED ENTHESEAL MYELOID CELL INHIBITION WITH UPADACITINIB PARADOXICALLY INCREASES MYELOID PRO-INFLAMMATORY CYTOKINES INCLUDING TNF AND IL-23 BY RESTRAINING AN IL-10 NEGATIVE FEEDBACK-BUT T-CELL TNFΑ AND IL-17 IS STRONGLY BLOCKED
Notice bibliographique
Résumé
Background Upadacitinib is effective in spondyloarthritis (SpA) associated arthropathy and is licensed for ankylosing spondylitis and psoriatic arthritis. Collectively SpA is linked to enthesitis with both myeloid lineage and T-lineage cells contributing to the IL-23/IL-17 and TNF axes that underscore disease. Objectives To investigate the effect of upadacitinib on an in vitro human enthesis model by focusing separately on the IL-23/IL-17 axis component myeloid and T-cells to better elucidate mechanisms of action in vivo. Methods Normal spinous process enthesis (n=26) was obtained from patients undergoing spinal decompression or surgery for scoliosis correction as previously described [1]. Enthesis cells were subsequently isolated by mechanical digestion. Entheseal myeloid cells were stimulated with LPS with and without upadacitinib. IL-23, TNFα and other proinflammatory cytokines in the supernatants were quantified using ELISA. IL-23 levels were measured after myeloid cell stimulation with LPS in the presence of upadacitinib and IL-10. IL-23 levels were also measured after stimulation with LPS in the presence of an IL-10Rα blocking antibody. Entheseal cells were stimulated with anti-CD3 with or without LPS, Th17-driving cytokines (IL-23 and IL-1β) and upadacitinib. Supernatants were measured by ELISA and cytokine-positive cell populations assessed by intracellular flow cytometry. Results Unexpectedly, upadacitinib significantly increased myeloid cell secretion of IL-23, TNFα and other proinflammatory cytokines after stimulation with LPS (Figure 1) (LPS = 51.2 pg/ml vs LPS + 1 µM Upa = 1048 pg/ml IL-23, n= 11). Addition of recombinant IL-10 attenuated such IL-23. Blockade of the IL-10 receptor with a blocking antibody increased IL-23 secretion from myeloid cells after stimulation with LPS (100 ng/ml IL-10 = 2.79 mean fold increase in IL-23, n=5). Despite this effect, upadacitinib strongly blocked TNFα and IL-17 from Th17 and Tc17 entheseal derived cells stimulated with exogenous IL-23 (138.19 pg/ml vs 14.2 pg/ml IL-17A after addition of 1 µM Upa to Th17 driving conditions, n = 5). Furthermore, addition of upadacitinib to LPS + anti-CD3 activated entheseal cells strongly downregulated T-cell derived IL-17 and TNFα despite a simultaneous increase in myeloid IL-23. Conclusion LPS activated myeloid cells, predominantly monocyte lineage further increase key cytokines IL-23 and TNFα post upadacitinib. This involves IL-10 pathway inhibition. However, in this system T-cell derived cytokine production is completely blocked despite elevation of myeloid IL-23 and TNFα. These unexpected findings highlight the pivotal role of T-cell derived cytokines in SpA given the known efficacy of JAK inhibition and these findings merit consideration in other domains such as intestinal inflammation that may have a greater innate immune driven component. Reference [1]Bridgewood, C., et al., Identification of myeloid cells in the human enthesis as the main source of local IL-23 production. Annals of the rheumatic diseases, 2019. 78(7): p. 929-933. Acknowledgements The study is funded by an Abbvie research grant. Disclosure of Interests Sami Giryes: None declared, Tom Macleod: None declared, Chi Wong: None declared, Mark Harland: None declared, Nicole McDermott: None declared, Charlie Bridgewood: None declared, Abhay S Rao: None declared, Almas Khan: None declared, Peter Loughenbury: None declared, Dennis McGonagle Grant/research support from: The study is funded by an Abbvie research grant.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,008 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».