title: Tolerance induction through megadose bone marrow transplantation with two-signal blockade.
abstract: BACKGROUND
  Induction of mixed chimerism is currently the most promising concept for clinical tolerance induction; however, the toxicity of the required host conditioning for allogeneic bone marrow transplantation (BMT) should be overcome. Therefore, we explored tolerogenic effectiveness of megadose BMT with anti-CD45RB and anti-CD154 mAb (two-signal blockade) in murine recipients without conditioning.
  
  
  METHODS
  Recipient B6 mice of BALB/c skin allograft received conditioning and an optimal dose (2x10(7) cells) of BMT. For a megadose BMT model, the conditioning was not performed; instead, megadose (2x10(8) cells) of BM was transplanted. The recipients were then treated with anti-CD45RB mAb and anti-CD154 mAb alone or their combination. Flow cytometry was performed to analyze the degree and distribution of donor-derived cells, peripheral deletion of Vbeta5 or Vbeta11 T cells and intrathymic presence of donor MHC class II+ cells. Induction of chimerism-based tolerance to skin allograft was further determined.
  
  
  RESULTS
  High levels ( approximately 23.7%) of mixed and multi-lineage chimerism-based tolerance to skin allograft were induced in the recipients (91%) treated with the optimal-dose BMT and the two-signal blockade. The megadose BMT could replace the recipient conditioning and establish low (approximately 10%) and stable multilineage chimerism. Donor-specific tolerance to skin allograft was induced in these chimeras through clonal deletion of donor-reactive cells.
  
  
  CONCLUSIONS
  The megadose BMT with the two-signal blockade could effectively establish mixed and multi-lineage chimerism and induce donor-specific tolerance, suggesting its potential for clinical application.
authors.affiliation: Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Eun-Na
authors.initials: EN
authors.lastname: Lee
authors.forename: Jienny
authors.initials: J
authors.lastname: Lee
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Hae-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Chi-Young
authors.initials: CY
authors.lastname: Chang
authors.forename: Da-Yeon
authors.initials: DY
authors.lastname: Jung
authors.forename: Su-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Suk-Koo
authors.initials: SK
authors.lastname: Lee
authors.forename: Choon-Hyuck
authors.initials: CH
authors.lastname: Kwon
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Joh
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens