A Clinically Relevant Protocol Induces Tolerance to a Vascularized Composite Allograft Across Major Histocompatibility Barrier In A Large Animal Model
David Mathes, MD1, Bruce Swearingen, MD1, Rainer Storb, MD2.
1University of Colorado, Aurora, CO, USA, 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
PURPOSE: We developed a clinically relevant protocol for Vascularized Composite Allograft (VCA) transplantation. One barrier has been the need for pre-conditioning limiting the protocols to living transplants. We have developed a protocol using a rapid stem cell mobilizer (AMD3100) for day 0 application . METHODS: 7 DLA-haploidentical, recipients [Group I] received conditioning with 350cGy total body irradiation (TBI), AMD3100 mobilized stem cells, bone marrow aspirate, and VCA transplantation and a limited course of post-grafting immunosuppression. 3 DLA-mismatched recipients [Group 2] received conditioning with 450cGy TBI, AMD3100 mobilized stem cells, BM aspirate, and VCA transplantation with post-grafting immunosuppression. We added 28 days Rapamycin to increase the T regulatory cell population. Donor cell chimerism was evaluated by PCR and allograft survival was followed clinically and histologicallyRESULTS: Initial stem cell engraftment and donor chimerism were seen in all animals. Group 1 demonstrated tolerance to the transplants and engraftment off immunosuppression (POD 426, 265, 176, 131, 95). Two animals had pulmonary issues and were sacrificed (POD 59, 45). One dog lost donor cell chimerism at POD 70 and had a single rejection episode of the skin (POD 79) that resolved and is currently tolerant (POD 176). Group 2 demonstrated donor cell engraftment and tolerance to the VCA (H910 POD 93, H912 POD 73). The third dog is on-going with good initial engraftment. CONCLUSION: This is the first clinically relevant protocol to induce tolerance in a large animal model across genetic mismatches. This protocol can be done without preconditioning and is applicable for cadaveric transplantation.
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