Tolerance induction through megadose bone marrow transplantation with two-signal blockade.
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.
Lee
Eun-Na
EN
Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Lee
Jienny
J
Kim
Eun-Young
EY
Park
Hae-Jung
HJ
Chang
Chi-Young
CY
Jung
Da-Yeon
DY
Choi
Su-Young
SY
Lee
Suk-Koo
SK
Kwon
Choon-Hyuck
CH
Joh
Jae-Won
JW
Kim
Sung-Joo
SJ
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
D000911:Antibodies, Monoclonal; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens