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


METHODS
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.


RESULTS
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 x 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.


CONCLUSIONS
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.
Goebel
W Scott
WS
Herman B Wells Center for Pediatric Research and Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Ind., USA.
Pech
Nancy K
NK
Meyers
Justin L
JL
Srour
Edward F
EF
Yoder
Mervin C
MC
Dinauer
Mary C
MC
D000818:Animals; D000950:Antigens, Ly / Q000097:blood; D000963:Antimetabolites / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005472:Fluorouracil / Q000008:administration & dosage*; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D006105:Granulomatous Disease, Chronic; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D011828:Radiation Chimera / Q000097:blood; D019172:Transplantation Conditioning / Q000379:methods; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
D000950:Antigens, Ly; D000963:Antimetabolites; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D005472:Fluorouracil