title: Delayed Donor Bone Marrow Infusion Induces Liver Transplant Tolerance.
abstract: 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.
  
  
  
  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-αβTCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 × 10 T cell-depleted bone marrow cells) followed by TAC withdrawal.
  
  
  
  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 chimerism and blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory T cells, and low DSA titers, similar to syngeneic grafts. While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not.
  
  
  
  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.
authors.affiliation: 1 Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL. 2 Department of Surgery, Tianjin Nankai Hospital, Tianjin, China. 3 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China. 4 University of Louisville School of Medicine, Institute for Cellular Therapeutics, Louisville, KY. 5 Division of Organ Transplantation, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL. 6 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL. 7 Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Xin
authors.forename: Jiao-Jing
authors.initials: JJ
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
authors.forename: Joseph
authors.initials: J
authors.lastname: Leventhal
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Josh
authors.initials: J
authors.lastname: Levitsky
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016031:Liver Transplantation; D008297:Male; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D023001:Transplantation Tolerance; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus