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Mismatched VCA Transplantation Without the Need for Donor Cell Chimerism: A Model to Achieve Tolerance While Eliminating Chronic Immunosuppression and the Risks of GVHD
Bruce Swearingen, MD1, Jeff Chang, MD1, Scott Graves, Phd2, Tiffany Migwongtum-Butts, MS2, Rainer Storb, MD2, David W. Mathes, MD1.
1University of Washington, Seattle, WA, USA, 2Fred Hutchison Cancer Research Center, Seattle, WA, USA.

Purpose: The clinical application of Vascularized Composite Allograft (VCA) transplantation is limited by the need for chronic immunosuppression. Tolerance induction protocols using donor stem cell transplantation can eliminate this requirement but the engraftment of these donor cells can lead to Graft-Versus-Host-Disease (GVHD). A protocol to prevent the long-term engraftment of these cells but still allow for the establishment of donor-specific tolerance would solve these problems. In this current study, we have modified our protocol to allow for transient donor engraftment after VCA transplantation and with selective rejection of donor stem cells.
Materials and Methods: 5 Haploidentical canine recipients received a non-myeloablative conditioning regimen of 350 cGy TBI, mobilized donor stem cells (PBMC) and VCA transplantation followed by a short course of immunosuppression (MMF for 56 days and Cyclosporine for 70 days). Peripheral blood chimerism was evaluated by PCR techniques weekly. Peripheral blood cytokine expression was evaluated by flow cytometry. VCA rejection was followed clinically and confirmed histologically after routine biopsies.
Results: All 5 animals tolerated the conditioning regimen. Three dogs rejected their donor stem cells after cessation of immunosuppression without rejection of their donor VCAs. One of these dogs was euthanized for persistent fevers at pod 147 with no sign of rejection. One dog is still on immunosuppression. One dog rejected the PBMC at 5 weeks post transplantation and went on to reject the VCA transplant following the cessation of immunosuppression. No dog developed GVHD. Early cytokine analysis in tolerant versus non-tolerant animals reveals a significantly elevated IL-4 and IL-10 compared to baseline, suggesting a Th2 profile during induction of tolerance.
Conclusions: In this study we demonstrate that our non-myeloablative protocol allows for selective rejection of donor stem cells and elimination of GVHD risks without rejection of the donor VCA transplant. It appears that a certain length of transient donor cell chimerism or engraftment is required to induce tolerance, but after induction, maintenance of tolerance is not dependent on chimerism. Early after conditioning the establishment of aTh2 profile appears to contributing to the anti-inflammatory environment and may allow tolerance induction in the absence of persistent donor cell chimerism.


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