title: Combined treatment with regulatory T cells and vascularized bone marrow transplantation creates mixed chimerism and induces donor-specific tolerance to vascularized composite allografts without cytoreductive conditioning.
abstract: BACKGROUND
  Cotreatment with regulatory T cells (T(reg)) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T(reg) treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats.
  
  
  METHODS
  Recipient Lewis rats treated (day 0) with or without naturally sorted T(reg) (3 × 10(6)) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus-host disease were assessed clinically and histologically.
  
  
  RESULTS
  The combination of T(reg) and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18%) and long-term donor-specific tolerance to VCAs (89% acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without T(reg) treatment. Graft-versus-host disease did not occur in the VBMT recipients.
  
  
  CONCLUSIONS
  Cotreatment with T(reg) and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive T(reg)-VBMT protocol has potential for clinical application in VCAs.
authors: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors: Jeng-Yee
authors: JY
authors: Lin
authors: Feng-Chou
authors: FC
authors: Tsai
authors: Christopher Glenn
authors: CG
authors: Wallace
authors: Wei-Chao
authors: WC
authors: Huang
authors: Fu-Chan
authors: FC
authors: Wei
authors: Shuen-Kuei
authors: SK
authors: Liao
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D060908:CTLA-4 Antigen / Q000502:physiology; D007108:Immune Tolerance; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D060908:CTLA-4 Antigen