TY - JOUR
T1 - Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potential
AU - Oh, Byoung Chol
AU - Furtmüller, Georg J.
AU - Fryer, Madeline L.
AU - Guo, Yinan
AU - Messner, Franka
AU - Krapf, Johanna
AU - Schneeberger, Stefan
AU - Cooney, Damon S.
AU - Andrew Lee, W. P.
AU - Raimondi, Giorgio
AU - Brandacher, Gerald
N1 - Funding Information:
The authors thank Richa Kalsi (Department of Surgery, University of Maryland, Baltimore, Maryland, USA) for her help with the graphic abstract for this manuscript. We would like to acknowledge internal support from the Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI.INSIGHT.128560
DO - 10.1172/JCI.INSIGHT.128560
M3 - Article
C2 - 32271163
AN - SCOPUS:85085384596
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 7
M1 - e128560
ER -