Absence of P-selectin in recipients of allogeneic bone marrow transplantation ameliorates experimental graft-versus-host disease.
Alloreactive T cells are crucial for graft-versus-host disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report in this paper that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs, such as the intestines and skin. Compared with wild-type (WT) recipients of allogeneic bone marrow transplantation, P-selectin(-/-) recipients exhibit decreased GVHD mortality and decreased GVHD of the skin, liver, and small bowels. This was associated with diminished infiltration of alloactivated T cells into the Peyer's patches and small bowels, coupled with increased numbers of donor T cells in the spleen and secondary lymphoid organs (SLOs). Surprisingly, however, donor T cells deficient for P-selectin glycoprotein ligand 1, the most well described P-selectin ligand, mediated GVHD similar to WT T cells and accumulated in SLO and target organs in similar numbers as WT T cells. This suggests that P-selectin may be required for trafficking into inflamed tissues but not SLO and that donor T cells may use multiple P-selectin ligands apart from P-selectin glycoprotein ligand 1 to interact with P-selectin and traffic into inflamed tissues during GVHD. We conclude that targeting P-selectin may be a viable strategy for GVHD prophylaxis or treatment.
Lu
Sydney X
SX
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Holland
Amanda M
AM
Na
Il-Kang
IK
Terwey
Theis H
TH
Alpdogan
Onder
O
Bautista
Jhoanne L
JL
Smith
Odette M
OM
Suh
David
D
King
Christopher
C
Kochman
Adam
A
Hubbard
Vanessa M
VM
Rao
Uttam K
UK
Yim
Nury
N
Liu
Chen
C
Laga
Alvaro C
AC
Murphy
George
G
Jenq
Robert R
RR
Zakrzewski
Johannes L
JL
Penack
Olaf
O
Dykstra
Lindsay
L
Bampoe
Kevin
K
Perez
Lia
L
Furie
Bruce
B
Furie
Barbara
B
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D014184:Transplantation, Homologous
D018836:Inflammation Mediators; D008024:Ligands; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein