425.5: Achieving Localized Immunosuppression Through Ex Vivo Engineering of Organ Blood Vessels
Notice bibliographique
Résumé
Introduction: Classic immunosuppressants lead to systemic immune shutdown, though necessary to mediate transplant rejection, it may lead to various complications. To reduce off-target immunosuppression while retaining increased organ survival, we propose direct modification of the endothelium of vascular transplants ex vivo to achieve localized immunomodulation. The glycocalyx (eGcx), made up of membrane-bound glycoproteins, is of particular interest due to its ability to control cell to cell communication and the activation of immune response through cell recognition. During organ transplantation, inflammation and oxidative damage occurs and can lead to the shedding and damage of the eGcx layer; this has been linked to organ failure and rejection. We developed an enzymatic approach to modify the surface of the endothelium with immunosuppressive polymers to induce immunomodulatory effects locally. We tested the efficacy of this approach in murine transplants.Method: We developed a method using tissue transglutaminase (tTGase) as the surface immobilizing enzyme and polyglycerol polymers containing sialic acid or sulfate moieties that is compatible with UW organ preservation solution at 4°C. In vitro mechanistic studies were performed using EaHy.926 cells to replicate the endothelium and PBMCs and CAR-T cells were used to test immune cytotoxicity. In vivo efficacy of graft rejection was assessed through aortic vessel or renal grafts from BALB/c donor mice into C57BL/6 recipient mice. Polymer treated and untreated grafts were assessed by serology and histology at various timepoints (day 2, 15 and 42 for vessel grafts and day 30 for renal grafts). Results: In vitro, polymer modified endothelial cells were able to evade CAR-T cell induced cytoxicity and reduced oxidative stress. Moreover, polymer treatment reduced TNF release in M1 macrophages. In vivo, modified grafts showed reduced medial thickening and leukocyte infiltration in vessel transplants; further confirmed in the reduction of pro-inflammatory cytokines in serum. In 42 day studies, donor-specific antibody was reduced in polymer-treated grafts compared to untreated. Finally, histological analysis of polymer-treated renal grafts revealed less infiltration and mesangial expansion relating to a healthier graft after 30 days.Conclusion: Here, the use of a polymer-mediated organ engineering approach leads to vascular protection that prevents immune-mediated rejection of organ transplants. Ex-vivo delivery of these immune cloaking polymers that engineer the blood vessel lumen allow for localized immune protection, making this an enticing and viable strategy for the reduction in the use of broad-active immunosuppressants post-transplantation. The protocol remains simple and easy to deliver, thereby enhancing its potential clinical applicability. To further validate this novel approach, studies in larger animal models that more closely replicate human transplant conditions are being planned. Canadian Institutes of Health Research. Natural Sciences and Engineering Council of Canada. Heart and Stroke Foundation of Canada. Canadian Glycomics Network, GlycoNet.
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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 | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».