Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment.
OBJECTIVE
In the absence of immunodeficiency, only microchimerism (<0.1%) has been achieved in human fetal recipients or nonhuman primates following in utero hematopoietic cell transplantation (IUHCT). We hypothesized that enhanced long-term engraftment might be more reliably achieved in microchimeric systems if higher levels of chimerism existed during development of adaptive immunity. To evaluate this hypothesis, we stimulated the donor cells with vascular endothelial growth factor (VEGF) and stem cell factor (SCF) prior to IUHCT in a chimerism-resistant murine strain combination.


METHODS
Donor Balb/c marrow was cultured in media with or without VEGF and SCF supplementation for 12 hours prior to IUHCT into B6 fetuses at 14 days postcoitum (dpc). Donor cell phenotype, homing, and chimerism were assessed at short and long-term time points and transplanted animals received skin allografts at 8 weeks.


RESULTS
In pretreated allogeneic recipients, early chimerism rates were more than double that of controls (71% vs 33%, p = 0.01). These differences were associated with higher numbers of pretransplant donor cell colony-forming cells without change in donor cell homing. Despite prolonged skin allograft survival for pretreated recipients compared with controls (mean survival = 20.8 vs 8.2 days, p < 0.001), long-term engraftment was unchanged.


CONCLUSIONS
These findings demonstrate that higher levels of early chimerism in recipients of cytokine-stimulated marrow result in improved short-term chimerism and tolerance. Future studies are needed to confirm the existence of a "threshold" level of chimerism necessary to sustain long-term engraftment.
Shaaban
Aimen F
AF
Laboratory for Fetal Cellular Therapy, Department of Surgery, University of Wisconsin Medical School, Madison, WI 53792-7375, USA. shaaban@surgery.wisc.edu
Kim
Heung Bae
HB
Gaur
Lasya
L
Liechty
Kenneth W
KW
Flake
Alan W
AW
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005315:Fetal Diseases / Q000628:therapy*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D016038:Skin Transplantation / Q000379:methods; D019089:Stem Cell Factor / Q000494:pharmacology*; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology; D014181:Transplantation Immunology / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A