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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3456-3464
TRANSPLANTATION
Durable engraftment of major histocompatibility
complex-incompatible cells after nonmyeloablative conditioning with
fludarabine, low-dose total body irradiation, and posttransplantation
cyclophosphamide
Leo Luznik,
Sanju Jalla,
Laura W. Engstrom,
Robert Iannone, and
Ephraim J. Fuchs
From the Divisions of Hematopoiesis/Immunology,
Hematologic Malignancies, and Pediatric Oncology, Johns Hopkins
Oncology Center, Baltimore, MD.
Treatment of leukemia by myeloablative conditioning and
transplantation of major histocompatibility complex (MHC)-mismatched stem cells is generally avoided because of the high risk of graft rejection or lethal graft-versus-host disease (GVHD). This study shows
that MHC-incompatible cells can engraft stably after nonmyeloablative conditioning with immunosuppressive chemotherapy and low-dose total
body irradiation (TBI). Long-term mixed hematopoietic chimerism, clonal
deletion of donor-reactive T cells, and bidirectional cytotoxic T-cell
tolerance were achieved by transplanting MHC-mismatched marrow cells
into recipients conditioned with pretransplantation fludarabine or
cyclophosphamide (Cy), 50 to 200 cGy TBI on day  1, and Cy 200 mg/kg
intraperitoneally on day 3. In this model, long-term donor chimerism
was proportional to the dose of TBI or donor marrow cells.
Pretransplantation fludarabine and posttransplantation Cy were both
required for alloengraftment, but the drugs had additional effects. For
example, fludarabine sensitized host stem cells to the toxicity of TBI,
because animals conditioned with both agents had higher chimerism than
animals conditioned with TBI alone (P < .05). Also,
posttransplantation Cy attenuated lethal and nonlethal GVH reactions,
because F1 recipients of host-reactive, parental spleen
cells survived longer (P < .05) and had lower donor cell chimerism (P < .01) if they received posttransplantation
Cy than if they did not. Finally, delayed infusions of donor
lymphocytes into mixed chimeras prolonged survival after leukemia
challenge (P < .0001) without causing lethal GVHD. These
results indicate that stable engraftment of MHC-incompatible cells can
be induced after fludarabine-based, nonmyeloablative conditioning and
that it serves as a platform for adoptive immunotherapy with donor lymphocyte infusions.
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