title: Absence of P-selectin in recipients of allogeneic bone marrow transplantation ameliorates experimental graft-versus-host disease.
abstract: 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.
authors.affiliation: Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sydney X
authors.initials: SX
authors.lastname: Lu
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Holland
authors.forename: Il-Kang
authors.initials: IK
authors.lastname: Na
authors.forename: Theis H
authors.initials: TH
authors.lastname: Terwey
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Jhoanne L
authors.initials: JL
authors.lastname: Bautista
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: David
authors.initials: D
authors.lastname: Suh
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Adam
authors.initials: A
authors.lastname: Kochman
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Rao
authors.forename: Nury
authors.initials: N
authors.lastname: Yim
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Alvaro C
authors.initials: AC
authors.lastname: Laga
authors.forename: George
authors.initials: G
authors.lastname: Murphy
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
authors.forename: Lindsay
authors.initials: L
authors.lastname: Dykstra
authors.forename: Kevin
authors.initials: K
authors.lastname: Bampoe
authors.forename: Lia
authors.initials: L
authors.lastname: Perez
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
authors.forename: Barbara
authors.initials: B
authors.lastname: Furie
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: 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
chemical_list: D018836:Inflammation Mediators; D008024:Ligands; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein