In utero engraftment of fully H-2-incompatible versus congenic adult bone marrow transferred into nonanemic or anemic murine fetal recipients.
We have established a murine in utero bone marrow transplantation model system and have investigated the effects of donor strain differences, cell dose, and the number of injections on murine fetal survival and engraftment rates. In a series of experiments, 1221 nonanemic C57BL/6 fetuses were injected transplacentally on day 11 of gestation with 10(6) non-T-depleted adult bone marrow cells (BMC) from C57BL/6-CAST (congenic), BALB/c and DBA/1 (allogeneic) strains without recipient conditioning. Overall fetal survival was 45%, with a 4% engraftment rate in 475 evaluable day 5 newborns. Engrafted newborns initially had up to 75-100% donor peripheral blood cell engraftment, particularly with DBA/1 BMC. Surprisingly, a significantly (P < 0.05) higher incidence of engraftment was observed using allogeneic (5.2%) as compared with congenic donors (0.7%). However, engraftment in all groups was transient since engrafted recipients studied > or = 6 weeks post-natally had nondetectable levels of donor cells. In contrast, engraftment of congeneic marrow into anemic, stem cell-defective Wv/Wv recipients lead to a higher incidence (40%) of engraftment that persisted for > or = 6 weeks, increasing in the level of engraftment over time. Additional studies were performed in an attempt to further increase the incidence and permanence of engraftment. Neither doubling the cell dose nor doubling the number of injections improved engraftment rates in recipients of allogeneic bone marrow. Similarly, pretreatment of congeneic donors with 5-fluorouracil 4 days prior to harvesting marrow was not effective in increasing engraftment. Despite the inability to detect donor cells > or = 6 weeks postallografting, 2 of 10 evaluable recipients engrafted with DBA/1 BMC had specific and permanent (> 6 months observation time) tolerance to the donor skin graft with an intact capacity to reject third-party grafts. Thus short-term engraftment of allogeneic adult marrow stem cells can be successfully accomplished in a proportion of nonanemic fetal recipients. Engraftment of allogeneic donor cells can also lead to induction of a degree of tolerance in a proportion of recipients at maturity. These data form the basis of future studies directed toward understanding the mechanisms involved in in utero and postnatal marrow graft resistance, which will ultimately lead to designing strategies that will further enhance the permanence of engraftment with the use of adult marrow cells.
Howson-Jan
K
K
Department of Medicine, University of Minnesota Hospital and Clinic, Minneapolis.
Matloub
Y H
YH
Vallera
D A
DA
Blazar
B R
BR
D000740:Anemia / Q000601:surgery*; D000818:Animals; D016026:Bone Marrow Transplantation; D017690:Cell Transplantation; D005260:Female; D005333:Fetus / Q000276:immunology / Q000601:surgery*; D006085:Graft Survival; D016031:Liver Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011247:Pregnancy; D016038:Skin Transplantation