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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0166.
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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2225-2234
TRANSPLANTATION
High-level allogeneic chimerism achieved by prenatal tolerance
induction and postnatal nonmyeloablative bone marrow
transplantation
William H. Peranteau,
Satoshi Hayashi,
Michael Hsieh,
Aimen F. Shaaban, and
Alan W. Flake
From the Children's Institute for Surgical Science,
The Children's Hospital of Philadelphia, PA.
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 (IUHSCT) is a nonablative approach that
achieves mixed chimerism and donor-specific tolerance but has been
limited by minimal engraftment. We hypothesized that mixed
chimerism achieved by IUHSCT could be enhanced after birth by
nonmyeloablative total body irradiation (TBI) followed by same-donor
BMT. To test this hypothesis, mixed chimerism was created by IUHSCT in
a major histocompatibility complex-mismatched strain combination. After
birth, chimeric animals received nonmyeloablative TBI followed by
transplantation of donor congenic bone marrow cells. Our results show
that: (1) low-level chimerism after IUHSCT can be enhanced to
high-level chimerism by this strategy; (2) enhancement of chimerism is
dependent on dose of TBI; (3) the mechanism of TBI enhancement is via a
transient competitive advantage for nonirradiated hematopoietic stem
cells; (4) engraftment observed in the tolerant, fully allogeneic IUHSC transplant recipient is equivalent to a congenic recipient; and (5)
host-reactive donor lymphocytes are deleted with no evidence of
graft-versus-host disease. This study supports the concept of prenatal
tolerance induction to facilitate nonmyeloablative postnatal strategies
for cellular therapy. If clinically applicable, such an approach could
dramatically expand the application of IUHSCT.
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