221.1: ABO-incompatible transplantation following enzymatic A-antigen removal in a mouse model: A-antigen re-expression and prevention of early antibody-mediated rejection.
Notice bibliographique
Résumé
Introduction: The ABO histo-blood group barrier challenges equitable organ allocation due to high risk of rapid antibody-mediated rejection (AMR) of ABO-incompatible transplants (ABOi Tx). Enzymatic reduction of graft ABO-A-antigen (Ag) using FpGalNAc deacetylase and FpGalactosaminidase, termed Azymes, has demonstrated efficacy in converting human ABO-A lungs to ABO-O via ex vivo perfusion. The timing of A-Ag re-expression in the donor organ and the effectiveness of Azymes treatment in preventing early AMR remain unclear. A-transgenic (A-Tg) mice constitutively express A-Ag on vascular endothelium and can be used to model ABOi Tx and AMR. Herein, we used this model to evaluate A-Ag re-expression kinetics after Azyme treatment and determine whether early AMR is prevented by pre-transplant donor organ Azyme treatment. Methods: After i.v. administration of 0.8mg/kg Azyme (or control), heart and lung from A-Tg C57BL/6 (B6) mice (male/female, n=5/6; 15-19 weeks of age) were harvested. To assess A-Ag removal, organs were stored in organ preservation (UW) solution at 4°C for 4 or 24 hrs then placed in fixative for microscopy. To analyze A-Ag re-expression, hearts were stored in UW solution at 4°C for 4 hrs then heterotopically Tx’d into sex-matched wild-type (WT) B6 recipients and harvested 1, 4 or 7 days later. To model AMR, WT recipients were Tx’d with A-Tg heart (±Azyme treatment) followed by i.v. administration of mouse IgM anti-A monoclonal antibody and rabbit complement. Graft function was assessed by palpation 24 hrs post-Tx; A- and H-Ag expression and C4d deposition were assessed by immunohistochemistry. Results: After in vivo Azyme/4 hrs cold storage, vascular endothelium of A-Tg heart and lung showed marked reduction in A-Ag and were H-Ag positive (Fig 1). Further reduction in A-Ag was observed after 24 hrs cold storage. 24 hours post-Tx, Azyme-treated A-Tg grafts remained H-antigen positive with only very weak/diffuse A-Ag staining (Fig 2A). Azyme-treated hearts at 4 days post-Tx showed weak A-Ag staining primarily localized to outer myocardial microvasculature; at 7 days post-Tx, A-Ag expression was similar to non-Azyme-treated grafts. In the AMR model, the Azyme-treated graft showed no evidence of AMR after 24 hrs, whereas grafts without treatment had reduced graft function, C4d deposition (Fig 2B), and lymphocyte infiltration.Conclusion: Azyme treatment rapidly depleted A-Ag in A-Tg mouse heart and lung. A-Ag re-expression was minimal in heart grafts 4 days post-Tx, but fully visible 7 days post-Tx. Preliminary findings showed that A-Ag removal by Azyme treatment prevented early AMR. Longer term AMR studies will offer further insight into the effectiveness of temporary A-Ag depletion in avoiding AMR. Clinical application of Azymes may permit additional ABOi Tx, offering lifesaving treatment for individuals for whom compatible organs may not be found and utilizing organs otherwise discarded. This work was funded by the Collaborative Health Research Project funds from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC). TE was supported through a NSERC Undergraduate Student Research Award.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».