Journal
PLOS ONE
Volume 6, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0021611
Keywords
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Categories
Funding
- National Institutes of Health [RO1-HL069929, RO1-CA107096, RO1-AI080455, PO1-CA33049, R01-HL095075, P20-CA103694]
- US Department of Defense [W81XWH-09-1-0294]
- Radiation Effects Research Foundation (RERF-NIAID)
- Ryan Gibson Foundation (Dallas, TX)
- Elsa U. Pardee Foundation (Midland, MI)
- Byrne Foundation (Etna, NH)
- Emerald Foundation (New York, NY)
- Mr. William H. Goodwin and Mrs. Alice Goodwin, Alex's Lemonade Stand
- Commonwealth Foundation for Cancer Research (Richmond, VA)
- Bobby Zucker Memorial Fund (Phoenixville, PA)
- Lymphoma Foundation (New York, NY)
- Canadian Institutes of Health Reseach
- National Marrow Donor Program (NMDP)
- Marrow Foundation
- Deutsche Krebshilfe, Mildred-Scheel-Stiftung
- Deutsche Forschungsgemeinschaft
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Background: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. Methods: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin alpha(4)beta(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. Conclusions: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.
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