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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0166.
Submitted January 18, 2002
Accepted December 31, 1969
High Level Allogeneic Chimerism Achieved by Prenatal Tolerance Induction and Postnatal Non-Myeloablative Bone Marrow Transplantation
Aimen F Shaaban, William H Peranteau, Satoshi Hayashi, Michael Hsieh, and Alan W Flake*
The Children's Institute for Sugical Science, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
* Corresponding author; email: flake{at}email.chop.edu.
Clinical application of allogeneic bone marrow transplantation (BMT) has been limited by toxicity related to cytoreductive conditioning and immune response. In utero hematopoietic stem cell transplantation (IUHSCTx) is a non-ablative approach that achieves mixed chimerism and donor specific tolerance, but has been limited by minimal engraftment. We hypothesized that mixed chimerism achieved by IUHSCTx could be enhanced after birth by non-myeloablative total body irradiation (TBI) followed by same donor BMT. To test this hypothesis, mixed chimerism was created by IUHSCTx in an MHC mismatched strain combination. After birth, chimeric animals received non-myeloablative TBI followed by transplantation of donor congenic BM cells. Our results show that: (1) low level chimerism after IUHSCTx can be enhanced to high level chimerism by this strategy; (2) enhancement of chimerism is TBI dose dependent; (3) the mechanism of TBI enhancement is via a transient competitive advantage for non-irradiated HSC; (4) engraftment observed in the tolerant, fully allogeneic IUHSCTx recipient is equivalent to a congenic recipient; and (5) host reactive donor lymphocytes are deleted with no evidence of GVHD. This study supports the concept of prenatal tolerance induction to facilitate non-myeloablative postnatal strategies for cellular therapy. If clinically applicable, such an approach could dramatically expand the application of IUHSCTx.
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