FLT3 ligand promotes engraftment of allogeneic hematopoietic stem cells without significant graft-versus-host disease.
BACKGROUND
Graft-versus-host (GVH) reactions contribute to stable engraftment of allogeneic hematopoietic stem cell transplants. It was hypothesized that the in vivo expansion of recipient dendritic cells (DC) with the administration of ligand for Flt3 (FL) could promote allogeneic engraftment after reduced-intensity conditioning by enhancing the GVH effect.


METHODS
FL was first administered to three nonirradiated healthy dogs for 13 days at a dosage of 100 microg/kg/day. Next, nine dogs received 4.5 Gy total-body irradiation (TBI) and unmodified marrow grafts from dog leukocyte antigen (DLA)-identical littermates without posttransplant immunosuppression. FL was administered to the recipients at a dosage of 100 microg/kg/day from day -7 until day +5.


RESULTS
In normal dogs, FL produced significant increases in monocytes (CD14+) and neutrophils in the peripheral blood, a marked increase in CD1c+ cells with DC-type morphology in lymph nodes, and increased alloreactivity of third-party responders to peripheral blood mononuclear cells in mixed lymphocyte reactions (P<0.001). Sustained engraftment was observed in eight of nine (89%) FL-treated dogs compared with 14 of 37 (38%) controls (P=0.02, logistic regression). All engrafted FL-treated dogs became stable complete (n=2) or mixed (n=6) hematopoietic chimeras without significant graft-versus-host disease (GVHD). Recipient chimeric dogs (n=4) were tolerant to skin transplants from their marrow donors but rejected skin grafts from unrelated dogs within 7 to 9 days (median, 8 days).


CONCLUSIONS
In this study, the authors showed that FL administered to recipients promotes stable engraftment of allogeneic marrow from DLA-identical littermates after 4.5 Gy TBI without significant GVHD.
Yunusov
Murad Y
MY
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Georges
George E
GE
Storb
Rainer
R
Moore
Peter
P
Hagglund
Hans
H
Affolter
Verena
V
Lesnikova
Marina
M
Gass
M John
MJ
Little
Marie-Térèse
MT
Loken
Michael
M
McKenna
Hilary
H
Storer
Barry
B
Nash
Richard A
RA
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D018949:Antigens, CD1; D001853:Bone Marrow / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology; D004285:Dogs; D006023:Glycoproteins; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006680:HLA Antigens / Q000032:analysis; D018380:Hematopoietic Stem Cell Transplantation; D007958:Leukocyte Count; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000627:therapeutic use*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000166:cytology; D012016:Reference Values; D016038:Skin Transplantation; D014019:Tissue Donors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000276:Adjuvants, Immunologic; D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D006680:HLA Antigens; D008565:Membrane Proteins; C084881:flt3 ligand protein