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Departments of
*
Surgery,
Pediatrics, and
Medicine, The Carlos and Marguerite Mason Transplantation Biology Research Center, Emory University School of Medicine, Atlanta, GA 30322
Mixed hemopoietic chimerism has the potential to correct genetic
hemological diseases (sickle cell anemia, thalassemia) and eliminate
chronic immunosuppressive therapy following organ transplantation. To
date, most strategies require either recipient conditioning
(
-irradiation, depletion of the peripheral immune system) or
administration of "mega" doses of bone marrow to facilitate
reliable engraftment. Although encouraging, many issues remain that may
restrict or prevent clinical application of such strategies. We
describe an alternative, nonirradiation based strategy using a single
dose of busulfan, costimulation blockade, and T cell-depleted donor
bone marrow, which promotes titratable macrochimerism and a reshaping
of the T cell repertoire. Chimeras exhibit robust donor-specific
tolerance, evidenced by acceptance of fully allogeneic skin grafts and
failure to generate donor-specific proliferative responses in an in
vivo graft-versus-host disease model of alloreactivity. In this model,
donor cell infusion and costimulation blockade without busulfan were
insufficient for tolerance induction as donor-specific
IFN--producing T cells re-emerged and skin grafts were rejected at
100 days. When applied to a murine 
-thalassemia model, this
approach allows for the normalization of hemologic parameters and
replacement of the diseased red cell compartment. Such a protocol may
allow for clinical application of mixed chimerism strategies in
patients with end-stage organ disease or
hemoglobinopathies.
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