THE ERΒ AGONIST, WT-IV-012, SUPPRESSES THE INFLAMMATORY RESPONSE IN SYSTEMIC LUPUS ERYTHEMATOSUS
Notice bibliographique
Résumé
PV007 / #645 Poster Topic: AS02 - Animal Models Background/Purpose Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that causes inflammation in many of the body’s tissues, including the skin, joints, lungs, kidneys and heart. This inflammation causes damage to these tissues and produces significant mortality, with most complications in the early stages of the disease involving direct effects on various organs. SLE affects young women between the ages of 15 and 45 years at a 9:1 rate as compared to men. The etiology is complex and remains elusive, however the susceptibility of women during the years in which estrogen levels are at their highest may suggest a significant and critical contribution to the development of SLE. Estrogens are known to have pleiotropic effects on the immune system which is mediated through either estrogen receptor α (ERα), estrogen receptor β (ERβ) or the cell surface G-protein coupled receptor GPER1. ERα has been studied extensively in this context, however ERβ and GPER1 have received much less attention. Previously, our group and others have shown that ERα carrying immune cells are mediators of proinflammatory effects of estrogen more so than cells that lack this receptor. In the pursuit of a drug that is tailored to have a favorable selective estrogenic effect, the OSU Drug Development Institute discovered a novel carborane-based selective estrogen receptor modulator (SERM), WT-IV-012. This ERβ agonist exhibits potent binding of human ERβ (Ki = 2.0 nM) and functional selectivity for ERβ over ERα of at least 200-fold. The work presented herein describes the potential utility of WT-IV-012 in treating SLE in a humanized mouse model of the disease. Methods PBMC isolated from patients with active SLE were adoptively transferred into NSG mice and allowed to expand in vivo for 1 week. The mice were divided into 3 cohorts receiving either vehicle control, prednisone or WT-IV-012 via oral gavage on a daily basis for 5 weeks. Blood samples were taken at baseline, 3 and 5 weeks. Serum was analyzed for circulating cytokines using the MSD human V-PLEX Proinflammatory Panel. At 5 weeks, mice were euthanized, kidneys and hearts were harvested and processed for H&E and IHC histology and urine was collected and tested for proteinuria. Lupus patient PBMCs were isolated and stimulated under various conditions and then flow cytometry was used to identify specific cell types affected by WT-IV-012 and cytokine ELISAs were used to evaluate the cell culture supernatants. Results WT-IV-012 was as effective as prednisone in suppressing immune cell invasion of the kidney as well as inflammation of the heart. Furthermore, the ERβ agonist demonstrated superior effectiveness in suppressing proinflammatory cytokines as compared to prednisone as well as reducing the proteinuria seen in the vehicle-treated control mice. The in vitro effect of WT-IV-012 confirmed the suppression of IFNγ and TNFα and revealed the cell type specific effects of the drug. Conclusions WT-IV-012 is an effective inhibitor of the SLE inflammatory process and warrants additional study as a potential therapeutic in patients with SLE.
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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) | 0,000 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».