Authors

Sydney X Lu, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Lucy W Kappel, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Immunology, Weill Cornell Graduate School of Medical Sciences
Anne-Marie Charbonneau-Allard, Goodman Cancer Center and Departments of Biochemistry, Medicine, and Oncology, McGill Cancer Center, Montreal, Quebec, Canada
Renée Atallah, Goodman Cancer Center and Departments of Biochemistry, Medicine, and Oncology, McGill Cancer Center, Montreal, Quebec, Canada
Amanda M Holland, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Immunology, Weill Cornell Graduate School of Medical Sciences
Claire Turbide, Goodman Cancer Center and Departments of Biochemistry, Medicine, and Oncology, McGill Cancer Center, Montreal, Quebec, Canada
Vanessa M Hubbard, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Pathology, Albert Einstein College of Medicine
Jimmy A Rotolo, Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center
Marsinay Smith, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
David Suh, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Christopher King, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Uttam K Rao, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Nury Yim, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Johanne L Bautista, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Robert R Jenq, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center
Olaf Penack, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Hematology and Oncology, Charite´ CBF - Universita¨tsmedizin Berlin, Berlin, Germany
Il-Kang Na, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Hematology and Oncology, Charite´ CBF - Universita¨tsmedizin Berlin, Berlin, Germany
Chen Liu, Department of Pathology, University of Florida College of Medicine
George Murphy, Department of Pathology, Brigham and Women’s Hospital
Onder Alpdogan, Department of Medical Oncology, Thomas Jefferson University; Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center; Department of Medicine, Yale University Medical SchoolFollow
Richard S Blumberg, Department of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
Fernando Macian, Department of Pathology, Albert Einstein College of Medicine
Kathryn V Holmes, Department of Microbiology, University of Colorado School of Medicine
Nicole Beauchemin, Goodman Cancer Center and Departments of Biochemistry, Medicine, and Oncology, McGill Cancer Center, Montreal, Quebec, Canada
Marcel R M van den Brink, Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center

Document Type

Article

Publication Date

7-6-2011

Comments

This article has been peer reviewed and is published in PLoS One 2011, 6(7). The published version is available at DOI: 10.1371/journal.pone.0021611. © Public Library of Science

Abstract

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 α(4)β(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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