A NOVEL HUMAN IL23A-DRIVEN MOUSE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS
Notice bibliographique
Résumé
PV009 / #339 Poster Topic: AS02 - Animal Models Background/Purpose Interleukin 23, a member of the IL12 cytokine family, has been implicated in the reprogramming of immune cells by inducing and maintaining their proinflammatory state. It acts as a heterodimer composed of 2 subunits IL23A and IL12B and it has been shown to play a lead role in pathogenic mechanisms involved in the development of immune-mediated inflammatory diseases like psoriasis, inflammatory bowel disease etc. To further explore the contribution of IL23A in disease pathogenesis we generated a transgenic mouse expressing deregulated levels of the human IL23A subunit (TghIL23A) and characterized the phenotypes developed. Methods To achieve deregulated levels of expression of the human IL23A subunit, we designed the TghIL23A transgene containing the complete intron-exon sequence of human IL23A gene under the human IL23A promoter, with its 3’UTR replaced with the human-beta-globin in order to abolish all posttranscriptional regulation. Signs of overt pathology included skin lesions which were assessed clinically and all affected organs, including skin, liver, lungs, spleen and lymph nodes were examined histopathologically. Biochemical and hematological analyses were used for the evaluation of blood and urine samples, while biomarkers of pathology including cytokines and antinuclear antibodies, were assessed at different ages by ELISA and molecular analyses. Both overt pathology signs and biological fluids analyses were assessed in crosses of TghIL23A to IL12BKO and Rag1KO mice. The response of the TghIL23A mice to human therapeutics was assessed by treating them twice weekly with guselkumab. Results The human IL23A subunit in the transgenic mice that we generated could form active IL23 entities by forming heterodimers with its mouse partner and resulted in the development of clinical phenotypes that involved chronic inflammatory lesions in the skin, kidney and lungs as well as enlargement of the spleen and local lymph nodes. Signs of the developing pathology also included the development of proteinuria, circulating anti-dsDNA antibodies, increased levels of circulating IgGs that were gradually found deposited in kidney glomeruli and skin. The formation of human-mouse heterodimers was supported by the abolishment of the phenotypes upon crossing the TghIL23A to IL12BKO, while the autoimmune nature of the developing pathologies was supported by the abolishment of the pathologies upon crossing to Rag1KO mice that lack a functional immune system. The above-described pathological features exhibit significant similarities to those observed in human SLE patients supporting that the transgenic mouse that we developed can serve as novel mouse model of lupus erythematosus with cutaneous implications. Interestingly, our preliminary evidence indicates that equally to IL23A, mice expressing the human IL12B subunit show similar signs of lupus. Conclusions We have generated and characterized a novel genetic mouse model of SLE, providing proof of concept for the etiopathogenic role of hIL-23A. This new model integrate several characteristics of the human disease complexity and chronicity making it attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and for the evaluation of human therapeutics targeting the human IL23 pathway.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».