TY - JOUR
T1 - The intragraft vascularized bone marrow component plays a critical role in tolerance induction after reconstructive transplantation
AU - Lin, Cheng Hung
AU - Anggelia, Madonna R.
AU - Cheng, Hui Yun
AU - Wang, Aline Yen Ling
AU - Chuang, Wen Yu
AU - Lin, Chih Hung
AU - Lee, W. P.Andrew
AU - Wei, Fu Chan
AU - Brandacher, Gerald
N1 - Funding Information:
This work was supported by grants from the Ministry of Science and Technology of Taiwan, China (MOST 106-2314-B-182A-048-MY3) and Chang Gung Medical Foundation (CMRPG3B0261, CMRPG6F0601-3, and CMRPG3C121-3). We are thankful for the technical assistance provided by Nian-Yi Hsu, Hsien-Tang Lin, and Shu-Ping Yeh.
Publisher Copyright:
© 2019, CSI and USTC.
PY - 2021/2
Y1 - 2021/2
N2 - The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 108 or 3 × 107 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4+ and CD8+ T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.
AB - The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 108 or 3 × 107 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4+ and CD8+ T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.
KW - Chimerism
KW - Costimulation blockade
KW - Donor-specific tolerance
KW - Vascularized bone marrow transplantation
KW - Vascularized composite allotransplantation
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U2 - 10.1038/s41423-019-0325-y
DO - 10.1038/s41423-019-0325-y
M3 - Article
C2 - 31754236
AN - SCOPUS:85085136492
SN - 1672-7681
VL - 18
SP - 363
EP - 373
JO - Cellular and Molecular Immunology
JF - Cellular and Molecular Immunology
IS - 2
ER -