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      Ceacam1 Separates Graft-versus-Host-Disease from Graft-versus-Tumor Activity after Experimental Allogeneic Bone Marrow Transplantation


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          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.


          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 4β 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.


          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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          Most cited references44

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          The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.

          Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)
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            Redefined nomenclature for members of the carcinoembryonic antigen family.

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              In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets.

              Graft-versus-host disease (GVHD) is a major obstacle in allogeneic hematopoietic cell transplantation. Given the dynamic changes in immune cell subsets and tissue organization, which occur in GVHD, localization and timing of critical immunological events in vivo may reveal basic pathogenic mechanisms. To this end, we transplanted luciferase-labeled allogeneic splenocytes and monitored tissue distribution by in vivo bioluminescence imaging. High-resolution analyses showed initial proliferation of donor CD4+ T cells followed by CD8+ T cells in secondary lymphoid organs with subsequent homing to the intestines, liver, and skin. Transplantation of purified naive T cells caused GVHD that was initiated in secondary lymphoid organs followed by target organ manifestation in gut, liver, and skin. In contrast, transplanted CD4+ effector memory T (T(EM)) cells did not proliferate in secondary lymphoid organs in vivo and despite their in vitro alloreactivity in mixed leukocyte reaction (MLR) assays did not cause acute GVHD. These findings underline the potential of T-cell subsets with defined trafficking patterns for immune reconstitution without the risk of GVHD.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 July 2011
                08 July 2011
                : 6
                : 7
                : e21611
                [1 ]Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
                [2 ]Department of Immunology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America
                [3 ]Goodman Cancer Center and Departments of Biochemistry, Medicine, and Oncology, McGill Cancer Center, Montreal, Quebec, Canada
                [4 ]Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America
                [5 ]Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
                [6 ]Department of Hematology and Oncology, Charité CBF - Universitätsmedizin Berlin, Berlin, Germany
                [7 ]Department of Pathology, University of Florida College of Medicine, Gainesville, Florida, United States of America
                [8 ]Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [9 ]Department of Medicine, Yale University Medical School, New Haven, Connecticut, United States of America
                [10 ]Department of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [11 ]Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
                Universidade de Sao Paulo, Brazil
                Author notes

                Conceived and designed the experiments: SXL LWK A-MC-A RA AMH CT VMH JAR CL GM OA MRMvdB. Performed the experiments: SXL LWK A-MC-A RA AMH CT VMH JAR CL GM MS DS CK UKR NY JLB RRJ OP I-KN. Analyzed the data: SXL JAR CL GM OA MRMvdB. Contributed reagents/materials/analysis tools: RSB FM KVH NB. Wrote the paper: SXL OA MRMvdB.

                ¶ These authors also contributed equally to this work.

                Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 9 March 2011
                : 2 June 2011
                Page count
                Pages: 11
                Research Article
                Immune Cells
                T Cells
                Immunologic Subspecialties
                Tumor Immunology
                Immune Response
                Bone Marrow and Stem Cell Transplantation



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