Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potential.

Byoung Chol Oh,Stefan Schneeberger,Johanna Krapf,Gerald Brandacher,W.P Andrew Lee,Damon S Cooney,Franka Messner,Yinan Guo,Georg J Furtmüller,Madeline L Fryer,Giorgio Raimondi

doi:10.1172/jci.insight.128560

Abstract

Vascularized composite allotransplantation (VCA) has become a valid therapeutic option to restore form and function after devastating tissue loss. However, the need for high-dose multidrug immunosuppression to maintain allograft survival is still hampering more widespread application of VCA. In this study, we investigated the immunoregulatory potential of costimulation blockade (CoB; CTLA4-Ig and anti-CD154 mAb) combined with nonmyeoablative total body irradiation (TBI) to promote allograft survival of VCA in a fully MHC-mismatched mouse model of orthotopic hind limb transplantation. Compared with untreated controls (median survival time [MST] 8 days) and CTLA4-Ig treatment alone (MST 17 days), CoB treatment increased graft survival (MST 82 days), and the addition of nonmyeloablative TBI led to indefinite graft survival (MST > 210 days). Our analysis suggests that VCA-derived BM induced mixed chimerism in animals treated with CoB and TBI + CoB, promoting gradual deletion of alloreactive T cells as the underlying mechanism of long-term allograft survival. Acceptance of donor-matched secondary skin grafts, decreased ex vivo T cell responsiveness, and increased graft-infiltrating Tregs further indicated donor-specific tolerance induced by TBI + CoB. In summary, our data suggest that vascularized BM-containing VCAs are immunologically favorable grafts promoting chimerism induction and long-term allograft survival in the context of CoB.

Highlights

Vascularized composite allotransplantation (VCA) has become a clinical reality, with more than 130 hand/ forearm/arm transplants and 40 face transplants performed worldwide with highly encouraging immunological and functional outcomes [1]
Current research in VCA focuses on determining significant differences in immunologic features between solid organ transplants and vascularized composite allografts
We aimed to investigate a potentially novel strategy to prevent VCA rejection by using costimulation blockade (CoB) by means of CTLA4-Ig and MR-1 combined with nonmyeloablative induction therapy (Figure 1, B and C)

Summary

Introduction

Vascularized composite allotransplantation (VCA) has become a clinical reality, with more than 130 hand/ forearm/arm transplants and 40 face transplants performed worldwide with highly encouraging immunological and functional outcomes [1]. Despite these successes, wider utilization of VCA is hindered by the need for long-term, high-dose immunosuppression. As shown in various small and large animal models of solid organ and skin transplantation, the addition of antiCD154 mAb or donor-specific transfusion (DST) to CTLA4-Ig treatment prevented acute and chronic rejection and led to long-term allograft survival and tolerance [7, 9,10,11,12].

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