Johns Hopkins RTR Consortium: A Collaborative Approach to Advance Translational Science and Standardize Clinical Monitoring of Restorative Transplantation - Immunomodulation and Tolerance Induction after VCA using Biologic Agent (cTLA4-Ig) and Donor Bone Marrow Cells.

摘要

For many devastating combat and civilian injuries where conventional reconstruction is not achievable, 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 regimens for immunomodulation and tolerance induction after VCA using a translational large animal model. During the current reporting period the group set out to establish a belatacept-based protocol to enable calcineurin inhibitor minimization after heterotopic swine hind-limb allotransplantation across a full SLA mismatch (Aim 1). All animals were induced with 100 cGy whole body irradiation and 700 cGy thymic irradiation. Group I animals received highdose tacrolimus postoperatively (10-20 ng/dl), Group II animals received low dose tacrolimus postperatively (4-6 ng/dl), and Group III animals will receive low dose tacrolimus with intermittent belatacept (CTLA4-Ig). All Group I animals (n=3) have undergone transplantation and have shown no signs of rejection. However, 2 of 3 animals died prematurely (POD 70 and 96) due to infectious complications related to high dose tacrolimus. One animal from Group II has been completed and underwent rejection within 20 days of lowering the tacrolimus dose into the target range of 4-6 ng/dl. Remaining Group II and all of Group III transplantations have been delayed due to unexpected irradiation issues. A total of four animals died prematurely (all within 15 days postoperatively) due to pancytopenia related to dosing complications resulting from technical problems with preoperative irradiation.