| 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 (CD25hi, CD62Llo). Additionally, Ceacam1-/- CD8 T cells had greater expression of the gut-trafficking integrin α4β7, 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. © 2011 Lu et al. |
| Keywords: |
controlled study; protein expression; transplantation, homologous; unclassified drug; mortality; nonhuman; cd8+ t lymphocyte; cell proliferation; cd8-positive t-lymphocytes; protein analysis; animal cell; mouse; animal; cytology; metabolism; animals; mice; mus; carcinoembryonic antigen related cell adhesion molecule 1; dendritic cell; carcinoembryonic antigen; animal experiment; animal model; allogenic bone marrow transplantation; in vivo study; cytotoxicity; enzyme activation; in vitro study; pathology; radiation injury; radiation exposure; animalia; immunology; lymphocyte activation; dendritic cells; cd4+ t lymphocyte; lymphoma; organ specificity; graft versus host reaction; ionizing radiation; radiation, ionizing; radiosensitivity; cell polarity; antibody specificity; cytotoxicity, immunologic; cell regeneration; bone marrow transplantation; graft vs host disease; lymphoid tissue; small intestine; intestine, small; graft versus leukemia effect; graft vs tumor effect; integrin; t lymphocyte activation; lymphocyte count; allotransplantation; integrins; interleukin 2 receptor alpha; radiation injuries, experimental; l selectin; crypt cell; integrin alpha4beta7; alpha4beta7 integrin; ceacam1 protein, mouse
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