Busulfan-conditioned bone marrow transplantation results in high-level allogeneic chimerism in mice made tolerant by in utero hematopoietic cell transplantation.
OBJECTIVE
In utero hematopoietic cell transplantation (IUHCT) is a non-ablative approach that achieves mixed allogeneic chimerism and donor-specific tolerance. However, clinical application of IUHCT has been limited by minimal engraftment. We have previously demonstrated in the murine model that low-level allogeneic chimerism achieved by IUHCT can be enhanced to near-complete donor chimerism by postnatal minimally myeloablative total body irradiation (TBI) followed by same-donor bone marrow transplantation. Because of concerns of toxicity related to even low-dose TBI in early life, we wondered if a potentially less toxic strategy utilizing a single myelosuppressive agent, Busulfan (BU), would provide similar enhancement of engraftment.


METHODS
In this study, mixed chimerism was created by IUHCT in a fully allogeneic strain combination. After birth, chimeric mice were conditioned with BU followed by transplantation of bone marrow cells congenic to the prenatal donor.


RESULTS
We demonstrate that: 1) low-level chimerism after IUHCT can be converted to high-level chimerism by this protocol; 2) enhancement of chimerism is BU dose-dependent; and 3) BU reduces the proliferative potential of hematopoietic progenitor cells thus conferring a competitive advantage to the non-BU-treated postnatal donor cells.


CONCLUSIONS
This study confirms the potential of IUHCT for facilitation of minimally toxic postnatal regimens to achieve therapeutic levels of allogeneic engraftment.
Ashizuka
Shuichi
S
The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
Peranteau
William H
WH
Hayashi
Satoshi
S
Flake
Alan W
AW
D000818:Animals; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000494:pharmacology*; D002678:Chimera; D005260:Female; D007108:Immune Tolerance; D018811:Maternal Exposure; D051379:Mice; D011247:Pregnancy; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
D002066:Busulfan