The Johns Hopkins RTR Consortium: A Collaborative Approach to Advance Translational Science and Standardize Clinical Monitoring of Restorative Transplantation
Technical Report,15 Sep 2015,14 Sep 2016
Johns Hopkins University Baltimore United States
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For many devastating combat and civilian injuries where conventional reconstruction is inadequate, vascularized composite allotransplantation VCA has become a viable alternative. However, the toxicities and adverse effects of high dose immunosuppressive drugs have curtailed wider application. Thus the purpose of this project is to develop novel clinically relevant immunosuppression sparing regimens allowing for immunomodulation and tolerance induction after VCA using a translational large animal model. A total of 24 MGH miniature swine underwent heterotopic osteomyocutaneous hind limb transplantation across full swine leukocyte antigen mismatch. All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction. Aim1 Group I was treated with high-dose tacrolimus 15-20ngml maintenance therapy. Group II was treated with low-dose tacrolimus 4-6ngml. Group III received low-dose tacrolimus and 20 mgkg of CTLA4-Ig administered on POD2, 7, 14, 30, 60, 90, and 120. Aim2 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. Aim3 Group VI received the non-myeloablative conditioning plus bone marrow infusion BMI and intermediate dose tacrolimus 10-15 ngml for 30 days only. Group VIII received the induction regimen, BMI and CTLA4-Ig and a short-term dose of tacrolimus 30 days. In all groups, 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. All group I animals died prematurely due to infectious complications related to high dose tacrolimus treatment. 23 animals that received sub-therapeutic tacrolimus group II have rejected their grafts.
- Anatomy and Physiology
- Medicine and Medical Research