Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease.
Recent evidence suggests that dendritic cells (DCs) can regulate and amplify immune responses. Flt3 ligand (FL)-derived DC function was tested as a stimulator of allogeneic lymphocytes in vitro and in vivo. Treatment of mice with FL dramatically expanded DC number, but DCs isolated from FL-treated mice (FL DCs) were poor stimulators of allogeneic T-cell responses in vitro. Further activation of FL DCs did not restore their stimulatory ability, and FL DCs did not suppress the stimulation of the allogeneic T cells by normal DCs. FL treatment significantly increased the CD8 alpha(+) DC subset, which appeared to be the reason for their poor stimulatory capacity. These observations were confirmed in vivo using a mouse model of acute graft-versus-host disease (GVHD) wherein host DCs play a critical role. FL treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P <.01). These data represent a novel strategy that alters host DCs and reduces acute GVHD.
Teshima
Takanori
T
Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, 48109-0942, USA.
Reddy
Pavan
P
Lowler
Kathleen P
KP
KuKuruga
Mark A
MA
Liu
Chen
C
Cooke
Kenneth R
KR
Ferrara
James L M
JL
D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D016827:CD8 Antigens / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology / Q000379:methods
D000276:Adjuvants, Immunologic; D016827:CD8 Antigens; C431698:CD8alpha antigen; D008565:Membrane Proteins; C084881:flt3 ligand protein