Abstract
BackgroundAllogeneic 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.MethodsWe 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.ConclusionsWe 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.
Highlights
Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a member of a large family of carcinoembryonic antigen proteins [2]
We first transplanted irradiated BALB/c mice with B6 TCDBM with WT or Ceacam12/2 T cells, and observed that recipients of Ceacam12/2 T cells had significantly increased mortality compared to recipients of WT T cells (Figure 1A, left)
We asked whether T cells overexpressing Ceacam1 would cause less disease, and transplanted BALB/c recipients with 0.56106 or 16106 donor WT or Ceacam 1-Tg T cells
Summary
Ceacam is a member of a large family of carcinoembryonic antigen proteins [2]. It is primarily a type I transmembrane protein with multiple splice variants [9], though soluble forms exist. Ceacam is widely expressed on a variety of tissues including endothelium [10], epithelium [11], hematopoietic cells [12] and both hematologic and solid tumors, and interacts in a homophilic and heterophilic fashion with physiological and pathogenassociated ligands, including carcinoembryonic antigen and the Neisseria spp. proteins [13]. 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 Ceacam negatively regulates inflammation in inflammatory bowel disease models
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