Solid organ and vascularized composite allotransplantation have distinct requirements for localized delivery of enhanced costimulation blockade to control rejection
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Le résumé fourni par la source
Abstract We recently demonstrated, in a mouse heart transplant model, the therapeutic effect of Enhanced Costimulation Blockade: the transient combination of CTLA4-Ig with the JAK inhibitor Tofacitinib (Tofa). In the same model, we also proved the efficacy of a graft-localized delivery by means of a Tofa releasing hydrogel (Tofa-Hydro). In this study, we implemented a mouse orthotopic hind-limb VCA model to delineate any differential drug delivery requirement. Moreover, we explored the potential of Tofa-containing lipid nanoparticles (LNp) in achieving selective targeting of immune cells and its therapeutic effect. Local injections of Tofa-Hydro combined with CTLA4-Ig promoted VCA survival, although with a smaller therapeutic benefit (MST=23 days vs CTLA4-Ig-only MST=14 days). We identified a LNp formulation with negligible toxicity and favorable Tofa encapsulation efficiency. Live animal imaging and flow analysis indicated these particles have the unique property of accumulating in draining lymphoid tissues, with minimal distribution to other tissues, and deliver their cargo to multiple immune cells. Four post-transplant SQ injections of Tofa-LNp (with CTLA4-Ig) promoted graft survival longer than Tofa-Hydro (MST>60 days). Our results reveal that SOT and VCA differ in the topography of inflammatory events that contribute to rejection. This novel observation suggests that different activatory mechanisms contribute to allopriming in the two systems, although they share utilization of JAK signaling pathways. Nevertheless, our study demonstrates the efficacy of localized actuation of enhanced costimulation blockade in achieving safer regulation of rejection. DOD Award # W81XWH-18-1-0789
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Solid organ and vascularized composite allotransplantation have distinct requirements for localized delivery of <i>enhanced costimulation blockade</i> to control rejection
- Date Crossref
- 01/05/2023
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Baltimore pays non établi dans la noticeUniversité ou école supérieure
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Cancer Institute (WIA) pays non établi dans la noticeÉtablissement de santé
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Frederick National Laboratory for Cancer Research pays non établi dans la noticeStructure de recherche
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Johns Hopkins University Applied Physics Laboratory pays non établi dans la noticeStructure de recherche
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Johns Hopkins School of Medicine pays non établi dans la noticeUniversité ou école supérieure
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National Cancer Institute at Frederick pays non établi dans la noticeStructure de recherche
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Johns Hopkins Applied Physics Laboratory pays non établi dans la noticeStructure de recherche
University of Baltimore, Cancer Institute (WIA) et Frederick National Laboratory for Cancer Research, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.