Local administration of Mitomycin‐C‐Treated peripheral blood mononuclear cells (<scp>PBMC</scp><scp>s</scp>) prolongs allograft survival in vascularized composite allotransplantation

Radu, Christian Andreas; Kiefer, Jurij; Gebhard, Martha Maria; Bigdeli, Amir K.; Germann, Guenter; Lehnhardt, Marcus; Terness, Peter; Kneser, Ulrich; Kremer, Thomas

doi:10.1002/micr.30003

Cited by 5 publications

(5 citation statements)

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“…The lethal side effect of immunosuppressants raises the threshold of hand, face, and skin transplantations, which do not involve life‐threatening conditions. Combined immunosuppressive agents or BMMSCs, ADMSCs, and other cell therapies have been reported to have immunomodulatory effects in various transplantation models and to even promote functional recovery in rodent animals (Adamson et al, ; Fitzpatrick, Dehart, Brown, & Salgar, ; Plock et al, ; Radu et al, ; Siemionow & Nasir, ; Song, Muramatsu, Kurokawa, & Taguchi, ). Recent studies have also reported that rat iMSCs and human iMSCs have the potential of anti‐inflammatory effects in animal models (Ko et al, ; Lian et al, ; Wang et al, ; Yang et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Scale bars: 50 μm. ADMSCs, adipose-derived MSCs; BMMSCs, bone marrow-derived MSCs; hAD, human ADMSCs; hBM, human BMMSCs; hiM, human iMSCs; MSCs, mesenchymal stem cells; iMSCs, iPSCsderived mesenchymal stem cells; iPSCs, induced pluripotent stem cells; rAD, rat ADMSCs; rBM, rat BMMSCs have immunomodulatory effects in various transplantation models and to even promote functional recovery in rodent animals (Adamson et al, 2007;Fitzpatrick, Dehart, Brown, & Salgar, 2017;Plock et al, 2015;Radu et al, 2016;Siemionow & Nasir, 2007;Song, Muramatsu, Kurokawa, & Taguchi, 2005). Recent studies have also reported that rat iMSCs and human iMSCs have the potential of anti-inflammatory effects in animal models (Ko et al, 2018;Lian et al, 2010;Wang et al, 2018;Yang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Induced pluripotent stem cell‐derived mesenchymal stem cells prolong hind limb survival in a rat vascularized composite allotransplantation model

et al. 2019

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Background The reduction of systemic immunosuppressive agents is essential for the expansion of vascularized composite allotransplantation (VCA) in a clinical setting. The purpose of this study is to compare human‐induced pluripotent stem cell‐derived mesenchymal stem cells (iMSCs) with four other types of mesenchymal stem cells (human bone marrow‐derived MSCs [BMMSCs], human adipose‐derived MSCs [ADMSCs], rat BMMSCs, and rat ADMSCs) in vitro, and to investigate the in vivo immunomodulatory effect of iMSCs in a rat VCA model. Materials and methods One Brown Norway (BN) rat, 2 Lewis (LEW) rats, and 1 Wistar rat were used in the mixed lymphocyte reaction (MLR), and 9 BN rats and 3 LEW rats (for donors), and 24 LEW rats (for recipients) were used in the VCA model. The abovementioned five types of MSCs were imaged to examine their morphology and were also tested for suppressor function using a MLR. The 24 recipient LEW rats were divided randomly into four groups, and subjected to orthotopic hind limb transplantation. The three control groups were the Iso group, in which transplantation was performed on from three to six LEW rats without immunosuppressive treatment (n = 6); the FK group, in which transplantation was performed from BN rats to LEW rats and recipient rats were treated with tacrolimus alone (FK 506, 0.2 mg/kg, days 0–6 postoperatively, intraperitoneally) (n = 6); and the UT group, in which transplantation was performed from BN rats to LEW rats without any immunosuppressive treatment (n = 6). The experimental group was the iMSC group, in which transplantation was performed from BN rats to LEW rats and recipient rats were treated with tacrolimus (FK 506, 0.2 mg/kg, days 0–6 postoperatively, intraperitoneally) and injected with iMSCs (2 × 106 cells, day 7, intravenously) (n = 6). Hind limb survival was assessed by daily inspection of gross appearance until 50 days postoperatively. Histology of the skin and muscle biopsy were investigated on day 14 postoperatively. A time series of the plasma cytokine level (before transplantation, and at 10, 14, and 17 days after transplantation) was also analyzed. Results The size of adherent and trypsinized iMSCs was 67.5 ± 8.7 and 9.5 ± 1.1 μm, respectively, which was the smallest among the five types of MSCs (p < .01). The absorbance in MLR was significantly smaller with rat ADMSCs (p = .0001), human iMSCs (p = .0006), rat BMMSCs (p = .0014), human ADMSCs (p = .0039), and human BMMSCs (p = .1191) compared to without MSCs. In vivo, iMSC treatment prolonged hind limb survival up to 12.7 days in macroscopic appearance, which is significantly longer than that of the FK group (p < .01). Histology of the skin and muscle biopsy revealed that mononuclear cell infiltration was significantly reduced by iMSC injection (p < .01). iMSC treatment also affected proinflammatory cytokines (interferon‐gamma (IFNγ) and tumor necrosis factor α (TNFα)) and the anti‐inflammatory cytokine (interleukin‐10 (IL‐10)) of the recipient plasma. The IFNγ levels at Δ14 and the TNFα levels at Δ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Induced pluripotent stem cell‐derived mesenchymal stem cells prolong hind limb survival in a rat vascularized composite allotransplantation model

et al. 2019

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“…It was mainly intended to provide an overview of surgical simulation and techniques, and, as such, it was not focused on long-term postoperative function monitoring and failed to incorporate long-term immunosuppressive strategies to increase survival of the flaps. The effect of immunosuppressants in composite tissue transplantation is well documented in the literature [ 15 – 17 ]. A limitation to using a canine model is the lack of immune markers; there are a limited number of tools suitable for immunologic research—such as tolerance study—in a canine model compared with rodent models, such as mice or rats [ 13 , 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Experimental Forelimb Allotransplantation in Canine Model

Hong

Eun

2016

BioMed Research International

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As reconstructive transplantation is gaining popularity as a viable alternative for upper limb amputees, it is becoming increasingly important for plastic surgeons to renew surgical skills and knowledge of this area. Forelimb allotransplantation research has been performed previously in rodent and swine models. However, preclinical canine forelimb allotransplantation studies are lacking in the literature. The purpose of this paper is to provide an overview of the surgical skills necessary to successfully perform forelimb transplantation in canines as a means to prepare for clinical application. A total of 18 transplantation operations on canines were performed. The recipient limb was shortened at the one-third proximal forearm level. The operation was performed in the following order: bones (two reconstructive plates), muscles and tendons (separately sutured), nerves (median, ulnar, and radial nerve), arteries (two), and veins (two). The total mean time of transplantation was 5 hours ± 30 minutes. All of the animals that received transplantation were treated with FK-506 (tacrolimus, 2 mg/kg) for 7 days after surgery. Most allografts survived with perfect viability without vascular problems during the early postoperative period. The canine forelimb allotransplantation model is well qualified to be a suitable training model for standard transplantation and future research work.

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“…Im Rahmen der erstmaligen Applikation von MICs in einem experimentellen VCA-Modell konnten wir eine signifikante immunsuppressive Wirkung durch die systemische Applikation von MICs am Transplantationstag im Rattenmodell zeigen [14]. In Folgestudien führte sowohl die lokale, intramuskuläre Applikation von MICs als auch die Kombination aus systemischer MIC-Therapie und temporärer Immunsuppression im komplexen VCA-Modell zu einer signifikant späteren Abstoßungsreaktion und damit Potenzierung der immunsuppressiven Wirkung [15,16]. Nachdem die präoperative Applikation von MICs bei Herztransplantationen im Rattenmodell Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen.…”

Section: Introductionunclassified

“…Bei Versuchstieren der Kontrollgruppe F (n = 10, BN→BN) wurden syngene Hinterlauftransplantationen ohne immunsuppressive Therapie durchgeführt. Die experimentellen Ergebnisse der Kontrollgruppen B, D und E wurden von unserer Arbeitsgruppe in Teilen bereits publiziert[14][15][16]22]. Die Empfängertiere wurden postoperativ bzgl.…”

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Immunsuppressive Wirkung von Mitomycin-C-behandelten mononukleären Zellen des peripheren Blutes (MICs) in der Vaskularisierten Composite Allotransplantation

Kiefer

Diehm

Germann³

et al. 2021

Handchir Mikrochir Plast Chir.

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Zusammenfassung Hintergrund Vaskularisierte Composite Allotransplantationen (VCA) ermöglichen die Wiederherstellung komplexer Gewebedefekte. Die ersten erfolgreichen allogenen Hand- und Gesichtstransplantationen haben die Forschung zur Verbesserung der immunsuppressiven Therapien stetig vorangetrieben. Die Inkubation mononukleärer Zellen des peripheren Blutes (PBMCs) mit Mitomycin C (MMC) generiert immunmodulatorisch wirksame Zellen (MICs). In vorherigen Studien konnten wir eine signifikante immunsuppressive Wirkung durch die Applikation von Donor-MICs am Tag der Transplantation zeigen. Ziel dieser Studie ist es, den optimalen Zeitpunkt der Behandlung mit MICs in der VCA zu eruieren. Material und Methoden 60 allogene Hinterlauftransplantationen wurden in 6 experimentellen Gruppen durchgeführt. Lewis-Ratten (LEW) dienten als Spender-, Brown-Norway-Ratten (BN) als Empfängertiere. Tieren der Gruppe A wurden einmalig Spender-MICs 7 Tage präoperativ systemisch verabreicht. Gruppe B-F dienten als Kontrollgruppen. Tiere der Gruppe B erhielten keine immunsuppressive Therapie. In Gruppe C wurden unbehandelte Spender-PBMCs 7 Tage präoperativ verabreicht. Tiere der Gruppe D erhielten nur das Zellkulturmedium. Tieren der Gruppe E wurde eine Standardimmunsuppression mit Tacrolimus und Prednisolon verabreicht. In Gruppe F wurden syngene Hinterlauftransplantationen (BN→BN) durchgeführt. Der Abstoßungszeitpunkt wurde sowohl anhand klinischer Beobachtungen als auch aufgrund histologischer Parameter bestimmt. Ergebnisse In Versuchsgruppe A zeigte sich im Vergleich zu den Kontrollgruppen B, C und D (5,5 ± 0,7, 5,3 ± 0,7 und 5,7 ± 0,5) eine signifikant früher eintretende Abstoßungsreaktion der Hinterläufe nach 3,5 ± 0,2 Tagen (p < 0,01). In den Kontrollgruppen E und F zeigte sich keine Abstoßungsreaktion. Schlussfolgerung Die Ergebnisse der vorliegenden Studie zeigen, dass die immunmodulatorische Wirkung von MICs unmittelbar vom Applikationszeitpunkt abhängt. Nachdem in vorherigen Experimenten die Applikation von MICs am Transplantationstag eine signifikante immunsuppressive Wirkung aufwies, konnte im Rahmen dieser Studie gezeigt werden, dass die präoperative Gabe von MICs zu einer beschleunigten Abstoßung führt und damit das Überleben des Transplantates signifikant verkürzt wird. Folgestudien sind notwendig, um sowohl die Modifikation des Applikationszeitpunktes als auch die Dosis-Effekt-Beziehungen und Zellcharakteristika dieser potentiell immunsuppressiven Zellen weiter zu untersuchen.

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Local administration of Mitomycin‐C‐Treated peripheral blood mononuclear cells (PBMCs) prolongs allograft survival in vascularized composite allotransplantation

Cited by 5 publications

References 35 publications

Induced pluripotent stem cell‐derived mesenchymal stem cells prolong hind limb survival in a rat vascularized composite allotransplantation model

Induced pluripotent stem cell‐derived mesenchymal stem cells prolong hind limb survival in a rat vascularized composite allotransplantation model

Experimental Forelimb Allotransplantation in Canine Model

Immunsuppressive Wirkung von Mitomycin-C-behandelten mononukleären Zellen des peripheren Blutes (MICs) in der Vaskularisierten Composite Allotransplantation

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