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Lymphoid reconstitution after transplantation of congenic hematopoietic
cells in busulfan-treated mice
AM Yeager, C Shinn and DM Pardoll
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD
21205.
The effects of pretransplant conditioning with high-dose busulfan, a
myeloablative but nonimmunosuppressive alkylating agent, on reconstitution
of lymphoid tissues by donor cells after bone marrow transplantation (BMT)
has not been extensively examined. We used flow cytometric analyses to
study the kinetics and extent of lymphocyte repopulation in C57BL/6 mice
(immunophenotype Ly-5.2) given graded doses of busulfan (10 to 100 mg/kg)
or total body irradiation (TBI; 900 rad) and hematopoietic cell
transplantation (HCT; transplantation of bone marrow and spleen cells) from
congenic Ly-5.1 donors. Mice transplanted after 10 mg/kg of busulfan had
slow and incomplete lymphoid engraftment; only 6% to 11% of lymphocytes in
the peripheral blood, lymph nodes, and spleen were positive for Ly-5.1 at
30 days after transplant, slightly increased to 13% to 20% at 60 days, and
stabilized at 40% to 46% by 180 days after HCT. Higher doses of busulfan
(20 to 100 mg/kg) provided dose-dependent congenic lymphoid reconstitution.
Thirty days after HCT, the range of Ly-5.1 cells in blood, lymph nodes, and
spleen of Ly-5.2 recipient mice was 43% to 54% after 20 mg/kg of busulfan,
66% to 71% after 50 to 80 mg/kg, and 77% to 85% after 100 mg/kg. Sixty days
after transplant, lymphoid chimerism increased to 57% to 68% in 20 mg/kg
recipients, 72% to 79% after 35 mg/kg, and 75% to 90% in animals given 50
mg/kg or greater, as seen in radiation chimeras. Despite slower early
reconstitution after lower doses of busulfan, donor lymphocytes exceeded
90% to 95% by 90 to 120 days after HCT in all mice given at least 20 mg/kg.
Even though busulfan lacks directly immunosuppressive properties, virtually
complete sustained lymphoid reconstitution by transplanted congenic donor
stem cells occurs after its administration. These observations suggest that
pretreatment with busulfan may be effective in gene therapy strategies that
involve infusion of autologous marrow cells into which functional genes
have been inserted.
Volume 78,
Issue 12,
pp. 3312-3316,
12/15/1991
Copyright © 1991 by The American Society of Hematology
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