A Clinically Relevant Protocol for Vascularized Composite Allotransplantation Using A Single Dose of AMD3100 for Stem Cell Mobilization
Bruce J. Swearingen, MD1, Scott S. Graves, PhD2, Rainer Storb, MD2, David W. Mathes, MD1.
1University of Colorado School of Medicine, Aurora, CO, USA, 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
PURPOSE:Vascularized Composite Allograft (VCA) transplantation is a clinical reality but its application is limited by the toxicities of chronic immunosuppression and rejection. Current clinical tolerance protocols require recipient conditioning that limits use to living donor transplants. We sought to design a clinically relevant protocol applicable to cadaveric organs. We modified our existing non-myeloablative stem cell canine VCA transplant model to use AMD3100 (Plerixafor) for stem cell mobilization.
4 DLA-haploidentical, related canine recipients [Group I] received conditioning with 350cGy TBI, AMD3100-mobilized donor stem cells and VCA transplantation with a short course of immunosuppression (MMF:56 days/CSP 70 days +/- taper). 5 DLA-haploidentical, related canine recipients [Group II] underwent identical conditioning plus an infusion of Bone Marrow (BM) harvested on the day of transplant. Aspirate in addition to AMD3100. CD34+ hematopoietic progenitor cells were quantified via flow cytometry. Peripheral blood chimerism was evaluated by PCR techniques weekly. VCA graft survival was followed clinically and histologically.
All dogs in the first group exhibited prolonged thrombocytopenia and one dog was euthanized secondary to this complication (POD 32). All 4 demonstrated initial engraftment of the stem cells. One dog had very poor initial engraftment and went on to reject the VCA on POD 146. The remaining 2 dogs remained tolerant to their VCA transplant (POD 79 and 101). The addition of marrow eliminated the problems with prolonged thrombocytopenia. In Group II, Two of the dogs were euthanized secondary to pneumonia (POD 12 and 95) and one for liver dysfunction (POD 45). Currently two dogs are doing well with no evidence of GVHD or loss of the VCA transplant (POD 186 and POD 67).
CONCLUSION:This study demonstrates that a clinically relevant protocol using a single dose of AMD3100 and addition of a bone marrow aspirate combined with our non-myeloabative protocol can lead to tolerance the VCA across a significant genetic barrier.
|DOG||POD||MOBILIZED STEM CELLS/kg||CD34+||BM ASPIRATE/kg||CD34+||VCA RECJECTION|
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