Journal
JOURNAL OF IMMUNOLOGY
Volume 185, Issue 3, Pages 1912-1919Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903148
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Funding
- National Institutes of Health [R01-HL069929, R01-CA107096, R01-AI080455, P01-CA33049, R01-HL095075, P20-CA103694]
- U.S. Department of Defense, U.S. Army Medical Research Acquisition Activity Award [W81XWH-09-1-0294]
- Ryan Gibson Foundation
- William H. Goodwin and Alice Goodwin
- Commonwealth Foundation for Cancer Research
- Bobby Zucker Memorial Fund
- Lymphoma Foundation
- National Marrow Donor Program
- Marrow Foundation
- Lymphoma Research Foundation
- Deutsche Krebshilfe
- Mildred-Scheel-Stiftung
- Deutsche Forschungsgemeinschaft
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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. The Journal of Immunology, 2010, 185: 1912-1919.
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