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THE USE OF MOBILIZED STEM CELLS MORE RELIABLY INDUCES TOLERANCE TO VASCULARIZED COMPOSITE ALLOGRAFTS IN MISMATCHED DOGS COMPARED TO BONE MARROW
Presenter: Jeff Chang
Co-Authors: Swearingen B; Hwang B; Miwongtum-Butts T; Graves S; Storb R; Mathes DW
University of Washington Medical Center

Introduction: The induction of tolerance to Vascularized Composite Allograft (VCA) in large animal models has been difficult to achieve. One promising technique has been the infusion of hematopoietic cells to establish a state of mixed chimerism. In this study we sought to compare the transplantation of bone marrow to mobilized hematopoietic stem cells (PBSC) to induce tolerance to VCA as part of our non-myeloablative protocol.

Methods: 8 transplants were performed across haploidentical DLA mismatched barrier. Dogs received 450 cGy of radiation on the day of transplant and underwent a VCA transplant. 4 dogs received PBSC and 4 dogs receiving donor bone marrow. All recipients received post-grafting immunosuppression (35 days of CSP and 28 days of MMF). They were followed for donor cell chimerism and underwent routine biopsies. Second donor skin grafts were placed on the long-term tolerant dogs. All dogs were also followed for T regulatory cells in the tissue and blood.

Results: Dogs that received PBSC demonstrated tolerance to their VCA (>562 days, >200 days, >90 days, and >70 days). 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 continued to be tolerant to the donor VCA. Only 1 of the dogs that received donor bone marrow demonstrated long-term tolerance to the VCA (>290 days). The other dogs demonstrated prolongation but all ultimately rejected their marrow grafts (at 35 days) and their VCA (38 - 50 days). All three long-term tolerant dogs accepted their donor skin graft and rejected the third-party skin graft. The dogs that received PBSC had higher expression of FoxP3 and more T regulatory cells in the peripheral blood and tissues.

Conclusion: This study demonstrates that in a mismatched setting using a non-myeloablative protocol, the simultaneous transplant of PBSC can more reliably induce tolerance with more T regs present. However, there is also a higher incidence of GVHD with the use of PBSC.


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