Tacrolimus before CTLA4Ig and rapamycin promotes vascularized composite allograft survival in MGH miniature swine.

Animals Swine Tacrolimus / therapeutic use Swine, Miniature Composite Tissue Allografts Sirolimus / therapeutic use Graft Survival Abatacept / therapeutic use Graft Rejection Immunosuppressive Agents / therapeutic use
Immunosuppression Miniature swine Vascularized composite allotransplantation

Journal

Transplant immunology
ISSN: 1878-5492
Titre abrégé: Transpl Immunol
Pays: Netherlands
ID NLM: 9309923

Informations de publication

Date de publication:
12 2022
Historique:
received: 31 05 2022
revised: 11 08 2022
accepted: 11 08 2022
pubmed: 21 8 2022
medline: 30 11 2022
entrez: 20 8 2022
Statut: ppublish

Résumé

We evaluated the outcome of vertical rectus abdominus myocutaneous flap (VRAM) allotransplantation in a mini-pig model, using a combined co-stimulation blockade (Co-SB) and mechanistic target of rapamycin inhibition (mTORi)-based regimen, with or without preceding calcineurin inhibition (CNI). VRAM allotransplants were performed between SLA-mismatched MGH miniature swine. Group A (n = 2) was treated continuously with the mTOR inhibitor rapamycin from day -1 in combination with the Co-SB agent cytotoxic T lymphocyte antigen 4-Ig (CTLA4-Ig) from post-operative day (POD) 0. In group B (n = 3), animals received tacrolimus daily from POD 0 to POD 13, followed by rapamycin daily from POD 7 and CTLA4-Ig weekly from POD 7-28. Graft rejection was determined by Banff criteria and host cellular and humoral immunity monitored. In group A, allografts developed grade-I acute rejection by POD 2 and POD 7, and reached grade-IV by POD 17 and POD 20, respectively. By contrast, in group B, two allografts demonstrated grade-I rejection on POD 30 and grade-IV on POD 74, while the third exhibited grade-I rejection starting on POD 50, though this animal had to be euthanized on POD 58 due to Pneumocystis jirovecii infection. Time-to-event incidence of grade-I rejection was significantly lower in group A compared to group B. During the first 3 weeks post-transplant, no significant differences in anti-donor immunity were observed between the groups. A short course of CNI, followed by combined Co-SB and mTORi significantly delays acute rejection of VRAM allografts in SLA-mismatched miniature swine.

Sections du résumé

BACKGROUND
We evaluated the outcome of vertical rectus abdominus myocutaneous flap (VRAM) allotransplantation in a mini-pig model, using a combined co-stimulation blockade (Co-SB) and mechanistic target of rapamycin inhibition (mTORi)-based regimen, with or without preceding calcineurin inhibition (CNI).
MATERIALS AND METHODS
VRAM allotransplants were performed between SLA-mismatched MGH miniature swine. Group A (n = 2) was treated continuously with the mTOR inhibitor rapamycin from day -1 in combination with the Co-SB agent cytotoxic T lymphocyte antigen 4-Ig (CTLA4-Ig) from post-operative day (POD) 0. In group B (n = 3), animals received tacrolimus daily from POD 0 to POD 13, followed by rapamycin daily from POD 7 and CTLA4-Ig weekly from POD 7-28. Graft rejection was determined by Banff criteria and host cellular and humoral immunity monitored.
RESULTS
In group A, allografts developed grade-I acute rejection by POD 2 and POD 7, and reached grade-IV by POD 17 and POD 20, respectively. By contrast, in group B, two allografts demonstrated grade-I rejection on POD 30 and grade-IV on POD 74, while the third exhibited grade-I rejection starting on POD 50, though this animal had to be euthanized on POD 58 due to Pneumocystis jirovecii infection. Time-to-event incidence of grade-I rejection was significantly lower in group A compared to group B. During the first 3 weeks post-transplant, no significant differences in anti-donor immunity were observed between the groups.
CONCLUSION
A short course of CNI, followed by combined Co-SB and mTORi significantly delays acute rejection of VRAM allografts in SLA-mismatched miniature swine.

Identifiants

DOI: 10.1016/j.trim.2022.101696 PMID: 35987329
pubmed: 35987329
pii: S0966-3274(22)00170-8
doi: 10.1016/j.trim.2022.101696
pii:
doi:

Substances chimiques

Tacrolimus WM0HAQ4WNM
Sirolimus W36ZG6FT64
Abatacept 7D0YB67S97
Immunosuppressive Agents 0

Types de publication

Journal Article Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

101696

Informations de copyright

Copyright © 2022 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest No author of this manuscript has any financial or personal relationships with other people or organizations that could potentially and inappropriately influence (bias) their work and conclusions.

Auteurs

Tarek Y Elgendy (TY)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: tarek.y.elgendy@gmail.com.

Matthias Waldner (M)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, ZH, Switzerland. Electronic address: matthias.waldner@gmail.com.

Wensheng Zhang (W)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; 59(th) Medical Wing Office of Science and Technology, JBSA Lackland, TX, USA; Department of Surgery, Uniformed Service University of the Health Sciences, Bethesda, MD, USA. Electronic address: wensheng.zhang.ctr@mail.mil.

Deokyeol Y Kim (DY)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dr.dykim@gmail.com.

Marta I Minervini (MI)

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: minervinimi@upmc.edu.

Chiaki Komatsu (C)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: komatsuc2@upmc.edu.

Yalcin Kulahci (Y)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA. Electronic address: yakulahci@yahoo.com.

Kia M Washington (KM)

Division of Plastic Surgery, Department of Surgery, University of Colorado, Denver, CO, USA. Electronic address: kia.washington@cuanschutz.edu.

Vijay S Gorantla (VS)

Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA. Electronic address: vgorantl@wakehealth.edu.

Mohamed B Ezzelarab (MB)

Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: ezzemb@upmc.edu.

Mario G Solari (MG)

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: solarimg@upmc.edu.

Angus W Thomson (AW)

Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: thomsonaw@upmc.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Artiodactyla › Suidae › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Tacrolimus › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Artiodactyla › Suidae › Sus scrofa › Porc miniature › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Régions du corps › Transplants › Allogreffes de tissus composites › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Sirolimus › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunologie en transplantation › Réaction de l'hôte contre le greffon › Survie du greffon › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Abatacept › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunologie en transplantation › Réaction de l'hôte contre le greffon › Rejet du greffon › Tacrolimus before CTLA4Ig and rapamycin...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Immunosuppresseurs › Tacrolimus before CTLA4Ig and rapamycin...