
<lom:lom xmlns:lom="https://oer-repo.uibk.ac.at/lom" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="https://oer-repo.uibk.ac.at/lom/latest https://w3id.org/oerbase/profiles/lomuibk/latest/schemas/lom-uibk.xsd">
  
<lom:general>
  
<lom:identifier>
  
<lom:catalog>phaidra.vetmeduni.ac.at</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">o:3176</lom:langstring>

  
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</lom:identifier>

  
<lom:identifier>
  
<lom:catalog>DOI</lom:catalog>

  
<lom:entry>
  
<lom:langstring xml:lang="x-none">10.3389/fimmu.2024.1387945</lom:langstring>

  
</lom:entry>

  
</lom:identifier>

  
<lom:title>
  
<lom:langstring xml:lang="en">A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts</lom:langstring>

  
</lom:title>

  
<lom:description>
  
<lom:langstring xml:lang="en">The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection.To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus.Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus.Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.</lom:langstring>

  
</lom:description>

  
<lom:language>eng</lom:language>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">vascularized composite allotransplantation (VCA), transplantation immunology, tacrolimus, local immunosuppression, calcineurin inhibitors (CNIs), drug delivery systems (DDSs), porcine model, neutrophil extracellular traps (NETs)</lom:langstring>

  
</lom:keyword>

  
</lom:general>

  
<lom:lifecycle>
  
<lom:datetime>2024-07-03T07:40:48.889Z</lom:datetime>

  
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<lom:langstring xml:lang="x-none">LOMv1.0</lom:langstring>

  
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<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Arenas Hoyos;Isabel;
FN:Isabel Arenas Hoyos
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Olariu;Radu;
FN:Radu Olariu
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</lom:centity>

  
<lom:centity>
  
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VERSION:3.0
N:Sorvillo;Nicoletta;
FN:Nicoletta Sorvillo
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Rieben;Robert;
FN:Robert Rieben
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Luciani;Paola;
FN:Paola Luciani
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Taddeo;Adriano;
FN:Adriano Taddeo
END:VCARD</lom:vcard>

  
</lom:centity>

  
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<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Prost;Jean-Christophe;
FN:Jean-Christophe Prost
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Aleandri;Simone;
FN:Simone Aleandri
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Bordon;Gregor;
FN:Gregor Bordon
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Vögelin;Esther;
FN:Esther Vögelin
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Constantinescu;Mihai;
FN:Mihai Constantinescu
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Montani;Matteo;
FN:Matteo Montani
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Banz;Yara;
FN:Yara Banz
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Duckova;Tereza;
FN:Tereza Duckova
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Hammer;Sabine E.;
FN:Sabine E. Hammer
X-ORCID:https://orcid.org/0000-0003-1475-3938
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Petrucci;Maria Francesca;
FN:Maria Francesca Petrucci
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Garcia;Luisana;
FN:Luisana Garcia
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Casoni;Daniela;
FN:Daniela Casoni
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Zhang;Lei;
FN:Lei Zhang
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Hirsiger;Stefanie;
FN:Stefanie Hirsiger
END:VCARD</lom:vcard>

  
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<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Lese;Ioana;
FN:Ioana Lese
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Helmer;Anja;
FN:Anja Helmer
END:VCARD</lom:vcard>

  
</lom:centity>

  
<lom:centity>
  
<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Yerly;Anaïs;
FN:Anaïs Yerly
END:VCARD</lom:vcard>

  
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<lom:source>
  
<lom:langstring xml:lang="x-none">LOMv1.0</lom:langstring>

  
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<lom:format>application/pdf</lom:format>

  
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<lom:location>https://phaidra.vetmeduni.ac.at/o:3176</lom:location>

  
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