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Abstracts

2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model

Howard D. WangJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USACorrespondence[email protected]

, MD,

Edward W. SwansonJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Hsu-Tang ChengJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Jeffrey WalchJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD, PhD,

Jose C. Alonso-EscalanteJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Keli KolegraffJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD, PhD,

Joseph LopezJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD, MBA,

Georg FurtmullerJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Byoung Chol OhJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, DVM, PhD,

Amy QuanJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MPH,

Joshua BudihardjoJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

Sara AlFadilJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Sara MullaJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Samuel FidderJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Paul AkreJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MS,

Justin M. SacksJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Steven C. BonawitzJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Giorgio RaimondiJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, PhD,

Jaimie T. ShoresJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD,

Damon S. CooneyJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD, PhD,

W. P. Andrew LeeJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD &

Gerald BrandacherJohns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA

, MD show all

Background

Vascularized composite allografts (VCA) can enhance the quality of life for patients with severe facial or extremity injuries, and induction of tolerance would avoid the risk of immunosuppression and increase application of VCA The purpose of this study is to investigate strategies for tolerance induction in a large animal model

Methods

Heterotopic osteomyocutaneous hind limb transplantation was performed in 19 MGH miniature swine across full swine leukocyte antigen mismatch All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction Group I was treated with high-dose tacrolimus (15–20 ng/ml) maintenance therapy Group II was treated with low-dose tacrolimus (4–6 ng/ml) Group III received low-dose tacrolimus and 20 mg/kg of CTLA4-Ig administered on POD2, 7, 14, 30, 60, 90, and 120 Group IV received transient high-dose tacrolimus until POD60 Group V received transient high-dose tacrolimus until POD60 and was switched to CTLA4-Ig administered on POD60, 85, 100, 120 and 150 Graft rejection was monitored by clinical assessment and protocol skin biopsies Alloreactivity against donor antigens was assessed using an optimized CFSE-based mixed lymphocyte reaction (MLR)

Results

Prolonged high-dose tacrolimus led to maintenance of VCA in 3/3 animals but was associated with major infectious complications 2/3 animals in group II rejected their grafts by POD46 and 217 In group III, 2/5 animals demonstrated rejection prior to POD150, while 3/5 animals achieved long-term survival of their VCA beyond POD300 3/3 animals in group IV and 4/5 animals in group V achieved indefinite graft survival beyond POD300 despite weaning of all immunosuppression The one animal in group V that rejected its graft began to show evidence of rejection on POD277 Donor specific unresponsiveness was confirmed in all long-term survivors in vitro by CFSE-MLR

Conclusions

Tolerance of VCA containing vascularized bone marrow can be achieved with a regimen of peritransplant high-dose tacrolimus without myeloablative conditioning. These findings describe a potential induction regimen to eliminate the need for long-term immunosuppression after reconstructive transplantation.

2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model

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2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model

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