A clinically applicable tolerance protocol to induce tolerance to vascularized composite allografts without the need for persistent donor cell chimerism

Publication Type:

Journal Article

Source:

Journal of the American College of Surgeons, Volume 217, Number 3, p.S92-S92 (2013)

ISBN:

1072-7515

Keywords:

2013, Clinical Research Division, December 2013, Surgery

Abstract:

Introduction: Vascularized composite allograft (VCA) transplantation is limited by the need for immunosuppression. Tolerance induction using stem cell transplantation can eliminate this requirement but can lead to graft-versus-host-disease (GVHD). In this study, we have modified our protocol to allow for transient donor engraftment after VCA transplantation with selective rejection of donor stem cells.  Methods: 5 Haploidentical canine recipients received a conditioning regimen of 350 cGy TBI, mobilized donor stem cells (PBMC) and VCA transplantation followed by limited immunosuppression (MMF for 56 days and Cyclosporine for 70 days). Peripheral blood chimerism was evaluated and cytokine expression was evaluated by flow cytometry. VCA status was confirmed histologically.  Results: One rejected the PBMC at 4 weeks post transplant and went on to reject the VCA following the end of immunosuppression. One dog fully engrafted and remains tolerant to the VCA (POD 250). 3 dogs demonstrated initial engraftment of the PBMC (6 – 14 weeks) rejected the donor cells after cessation of immunosuppression without acute rejection of their donor VCAs. One of these dogs was euthanized for persistent fevers at pod 147 with no sign of rejection. No dog developed GVHD. Early cytokine analysis in tolerant versus non-tolerant animals reveals a significantly elevated IL-4 and IL-10, suggesting a Th2 profile.  Conclusions: In this study we demonstrate that our non-myeloablative protocol can allow for selective rejection of donor stem cells without acute rejection of the VCA transplant. Transient donor cell chimerism is required to induce tolerance, but after induction, maintenance of tolerance may not be dependent on chimerism.

Notes:

PT: J; CT: 99th Annual Clinical Congress of the American-College-of-Surgeons / 68th Annual Sessions of the Owen H Wangensteen Surgical Forum on Fundamental Surgical Problems; CY: OCT 06-10, 2013; CL: Washington, DC; SP: Amer Coll Surg; NR: 0; TC: 0; J9: J AM COLL SURGEONS; SU: S; PG: 1; GA: 233OG