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Transplantation of Vascularized Composite Allografts in a Mismatched Setting Without the Need for Chronic Immunosuppression
David W. Mathes, MD1, Jeff Chang, MD1, Scott Graves, PhD2, Tiffany Butts-Miwongtum, BS2, Rainer Storb, MD2.
1University of Washington, Seattle, WA, USA, 2Fred Hutchinson Cancer Reasearch Center, Seattle, WA, USA.

Purpose:
The hand and face transplants that have been performed across the world demonstrate the clinical promise of vascularized composite allotransplantation (VCA). The survival of the transplant is dependent on the use of chronic immunosuppression which is costly and associated with toxicities such as opportunistic infections and malignancy. In order for the field of reconstructive transplantation to expand beyond its current experimental status, techniques need to be developed that lead to reduction or elimination of the need for chronic immunosuppression
In our previous study we demonstrated that the simultaneous transplantation of hematopoietic stem cells (HSC) and a VCA could lead to tolerance in our minor mismatch canine model. In this experiment we sought to extend our findings in a genetically mismatched setting.
Methods:
Eight transplants were performed across a single haplotype dog leukocyte antigen (DLA) mismatched barrier. All dogs received 450 cGy of radiation on the day of transplant and underwent a VCA transplant (Myocutaneous rectus flap). 4 dogs received donor mobilized peripheral blood stem cells (PBSC) and 4 dogs received donor bone marrow. All recipients received post-grafting immunosuppression (35 days of Cyclosporine and 28 days of Mycophenolate Mofetil). They were followed for donor cell chimerism in their peripheral blood. The allografts underwent routine biopsies and were followed clinically.
Results:
All dogs that received PBSC demonstrated tolerance to their VCA (days, >562, >200, >90, and >70). However, three of the dogs have demonstrated 100% engraftment of the donor PBSC and two developed graft-vs-host disease. Interestingly one of the dogs lost donor chimerism at week 15 post-transplant but maintained tolerance to the donor VCA (Figure 1). Only 1 of the dogs that received donor bone marrow demonstrated long-term tolerance to the VCA (>290 days). The other 3 dogs demonstrated prolongation but all ultimately rejected their marrow grafts (at 35 days) and their VCA (days, 50, 45, and 38)
Conclusion: This study demonstrates that in a mismatched setting using a non-myeloablative protocol, the simultaneous transplant of PBSC and a VCA can lead to tolerance. Whereas, the use of donor bone marrow as the source of HSC is insufficient to reliably induce tolerance across a mismatched barrier. Tolerance induction appears to be dependent on the administration of HSC but the maintenance of tolerance towards VCA may not require persistence of donor cell chimerism.


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