Delayed donor bone marrow infusion induces liver transplant tolerance

Yan Xie, Yang Wu, Kang Xin, Jiao Jing Wang, Hong Xu, Suzanne T. Ildstad, Joseph Leventhal, Guang Yu Yang, Zheng Zhang*, Josh Levitsky

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background. Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. Methods. Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-TCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 106 T cell-depleted bone marrow cells) followed by TAC withdrawal. Results. All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerismand blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory Tcells, and low DSA titers, similar to syngeneic grafts.While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. Conclusions. These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.

Original languageEnglish (US)
Pages (from-to)1056-1066
Number of pages11
JournalTransplantation
Volume101
Issue number5
DOIs
StatePublished - Jan 1 2017

Fingerprint

Liver Transplantation
Tacrolimus
Bone Marrow
Transplants
Liver
Antibodies
Transplantation Tolerance
T-Lymphocytes
Chimerism
Whole-Body Irradiation
Homologous Transplantation
Graft vs Host Disease
Regulatory T-Lymphocytes
Bone Marrow Cells
Histology
Spleen

ASJC Scopus subject areas

  • Transplantation

Cite this

Xie, Yan ; Wu, Yang ; Xin, Kang ; Wang, Jiao Jing ; Xu, Hong ; Ildstad, Suzanne T. ; Leventhal, Joseph ; Yang, Guang Yu ; Zhang, Zheng ; Levitsky, Josh. / Delayed donor bone marrow infusion induces liver transplant tolerance. In: Transplantation. 2017 ; Vol. 101, No. 5. pp. 1056-1066.
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abstract = "Background. Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. Methods. Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-TCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 106 T cell-depleted bone marrow cells) followed by TAC withdrawal. Results. All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerismand blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory Tcells, and low DSA titers, similar to syngeneic grafts.While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. Conclusions. These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.",
author = "Yan Xie and Yang Wu and Kang Xin and Wang, {Jiao Jing} and Hong Xu and Ildstad, {Suzanne T.} and Joseph Leventhal and Yang, {Guang Yu} and Zheng Zhang and Josh Levitsky",
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Delayed donor bone marrow infusion induces liver transplant tolerance. / Xie, Yan; Wu, Yang; Xin, Kang; Wang, Jiao Jing; Xu, Hong; Ildstad, Suzanne T.; Leventhal, Joseph; Yang, Guang Yu; Zhang, Zheng; Levitsky, Josh.

In: Transplantation, Vol. 101, No. 5, 01.01.2017, p. 1056-1066.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Delayed donor bone marrow infusion induces liver transplant tolerance

AU - Xie, Yan

AU - Wu, Yang

AU - Xin, Kang

AU - Wang, Jiao Jing

AU - Xu, Hong

AU - Ildstad, Suzanne T.

AU - Leventhal, Joseph

AU - Yang, Guang Yu

AU - Zhang, Zheng

AU - Levitsky, Josh

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N2 - Background. Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. Methods. Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-TCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 106 T cell-depleted bone marrow cells) followed by TAC withdrawal. Results. All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerismand blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory Tcells, and low DSA titers, similar to syngeneic grafts.While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. Conclusions. These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.

AB - Background. Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. Methods. Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-TCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 106 T cell-depleted bone marrow cells) followed by TAC withdrawal. Results. All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerismand blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory Tcells, and low DSA titers, similar to syngeneic grafts.While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. Conclusions. These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.

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Xie Y, Wu Y, Xin K, Wang JJ, Xu H, Ildstad ST et al. Delayed donor bone marrow infusion induces liver transplant tolerance. Transplantation. 2017 Jan 1;101(5):1056-1066. https://doi.org/10.1097/TP.0000000000001684