Transplantation of the bone marrow microenvironment leads to hematopoietic chimerism without cytoreductive conditioning.
BACKGROUND
It has been hypothesized that regimens to induce transplantation tolerance and long-term hematopoietic chimerism require recipient conditioning with whole body irradiation or a cytoablative regimen to create space within the marrow microenvironment to permit pluripotent stem cell engraftment. The purpose of this study was to determine if transplantation of an intact bone marrow microenvironment in the form of a bone graft would permit stable hematopoietic stem cell engraftment, shape the repertoire of developing T cells, and induce donor-specific unresponsiveness in the absence of a conditioning regimen.


METHODS
Fragments of femur were transplanted under the kidney capsule of recipient mice. At defined time points after bone graft transplantation recipients were assayed for chimerism, bone graft viability, and responses to donor and third party alloantigens in vitro and in vivo.


RESULTS
In the absence of an immunological barrier, bone graft transplantation resulted in long-term multi-lineage hematopoietic chimerism in the peripheral blood. Nude bone graft transplantation into SCID recipients resulted in development of donor- derived T cells that underwent negative selection on bone graft derived I-E+ cells within the thymus. Across a fully allogeneic barrier in immunocompetent recipients treated with combined blockade of the CD40 and CD28 pathways bone graft transplantation resulted in long-term donor-specific hyporesponsiveness in vitro and acceptance of donor specific skin grafts.


CONCLUSIONS
Transplantation of bone marrow in the form of a bone graft may facilitate the production of hematopoietic chimerism and lead to long-term donor-specific hyporesponsiveness in the absence of a cytoreductive conditioning regimen.
The Carlos and Marguerite Mason Transplantation Biology Research Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
A W
AW
Bingaman
S Y
SY
Waitze
D Z
DZ
Alexander
H R
HR
Cho
A
A
Lin
C
C
Tucker-Burden
S R
SR
Cowan
T C
TC
Pearson
C P
CP
Larsen
D000818:Animals; D016026:Bone Marrow Transplantation; D016025:Bone Transplantation; D002678:Chimera; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D019172:Transplantation Conditioning