A murine model of antimetabolite-based, submyeloablative conditioning for bone marrow transplantation: Biologic insights and potential applications

W. Goebel, Nancy K. Pech, Justin L. Meyers, Edward Srour, Mervin Yoder, Mary C. Dinauer

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Nonmyeloablative conditioning regimens for marrow transplantation are desirable in many settings. Because repeated doses of the antimetabolite 5-fluorouracil (5-FU) decreases marrow long-term repopulating ability (LTRA) upon transplantation into lethally irradiated hosts, we hypothesized that mice given sequential doses of 5-FU (termed paired dose 5-FU) may permit substantial syngeneic marrow engraftment. C57Bl/6 or X-linked chronic granulomatous disease (X-CGD) mice were administered 5-FU (150 mg/kg) on days -5 and -1. Assessment of host marrow phenotype and repopulating ability occurred on day 0. Transplantation of syngeneic donor marrow occurred on day 0 or day +15. We confirmed that the number of Sca-1 +lin - cells and the LTRA of marrow from paired dose 5-FU-treated animals were diminished. C57Bl/6 hosts conditioned with paired doses of 5-FU followed by transplantation of 20 × 10 6 fresh B6.SJL marrow cells on day 0 displayed 44.9% ± 7.1% donor chimerism 2 months posttransplant, and 34.4% ± 8.6% donor chimerism 6 months posttransplant. In contrast, paired dose 5-FU-conditioned hosts transplanted with similar numbers of donor cells on day +15 exhibited only 3.4% ± 1.2% donor chimerism at 2 months. Paired dose 5-FU-conditioned X-CGD hosts transplanted with MSCV-m91Neo-transduced X-CGD marrow averaged 6.6% ± 2.3% (range, 4%-10%) NADPH oxidase-reconstituted neutrophils 12-16 months after transplant. These findings support the concept that impairment of host stem cell competitiveness may be an important mechanism for permitting engraftment of donor cells, and suggest that only a brief period of modest host stem cell impairment may be necessary to achieve substantial donor cell engraftment.

Original languageEnglish
Pages (from-to)1255-1264
Number of pages10
JournalExperimental Hematology
Volume32
Issue number12
DOIs
StatePublished - Dec 2004

Fingerprint

Antimetabolites
Bone Marrow Transplantation
Fluorouracil
Bone Marrow
Chronic Granulomatous Disease
Chimerism
Transplantation
Stem Cells
Isogeneic Transplantation
NADPH Oxidase
Neutrophils
Cell Count
Transplants
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

A murine model of antimetabolite-based, submyeloablative conditioning for bone marrow transplantation : Biologic insights and potential applications. / Goebel, W.; Pech, Nancy K.; Meyers, Justin L.; Srour, Edward; Yoder, Mervin; Dinauer, Mary C.

In: Experimental Hematology, Vol. 32, No. 12, 12.2004, p. 1255-1264.

Research output: Contribution to journalArticle

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abstract = "Nonmyeloablative conditioning regimens for marrow transplantation are desirable in many settings. Because repeated doses of the antimetabolite 5-fluorouracil (5-FU) decreases marrow long-term repopulating ability (LTRA) upon transplantation into lethally irradiated hosts, we hypothesized that mice given sequential doses of 5-FU (termed paired dose 5-FU) may permit substantial syngeneic marrow engraftment. C57Bl/6 or X-linked chronic granulomatous disease (X-CGD) mice were administered 5-FU (150 mg/kg) on days -5 and -1. Assessment of host marrow phenotype and repopulating ability occurred on day 0. Transplantation of syngeneic donor marrow occurred on day 0 or day +15. We confirmed that the number of Sca-1 +lin - cells and the LTRA of marrow from paired dose 5-FU-treated animals were diminished. C57Bl/6 hosts conditioned with paired doses of 5-FU followed by transplantation of 20 × 10 6 fresh B6.SJL marrow cells on day 0 displayed 44.9{\%} ± 7.1{\%} donor chimerism 2 months posttransplant, and 34.4{\%} ± 8.6{\%} donor chimerism 6 months posttransplant. In contrast, paired dose 5-FU-conditioned hosts transplanted with similar numbers of donor cells on day +15 exhibited only 3.4{\%} ± 1.2{\%} donor chimerism at 2 months. Paired dose 5-FU-conditioned X-CGD hosts transplanted with MSCV-m91Neo-transduced X-CGD marrow averaged 6.6{\%} ± 2.3{\%} (range, 4{\%}-10{\%}) NADPH oxidase-reconstituted neutrophils 12-16 months after transplant. These findings support the concept that impairment of host stem cell competitiveness may be an important mechanism for permitting engraftment of donor cells, and suggest that only a brief period of modest host stem cell impairment may be necessary to achieve substantial donor cell engraftment.",
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