Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM-1) is a transmembrane protein found on leukocytes, endothelium, and epithelium. Its activation can attenuate colitis in murine models. Microarray analysis revealed that CEACAM-1 is increased in the small bowel during intestinal graft-versus-host-disease (GVHD). We studied the role of CEACAM-1 in mouse models for allogeneic bone marrow transplantation. We found that CEACAM-1-/- donor T cells caused significantly more GVHD (p<0.05), while CEACAM-1-Tg donor T cells caused significantly less GVHD (p<0.01). Administration of a CEACAM-1 agonistic antibody CC1 also significantly attenuated GVHD (p<0.01) Histopathological analysis revealed significantly increased GVHD of the large bowel in recipients of CEACAM-1-/- T cells (p<0.05), while recipients of CEACAM-1-Tg T cells had decreased GVHD in all organs (p<0.01). We performed an extensive analysis and found that alloactivated CEACAM-1-/- T cells (a) have increased CD25 and decreased CD62L expression (b) have increased expression of the gut- homing integrin ?4?7 (LPAM) and (c) preferentially infiltrate the intestines, while CEACAM-1-Tg T cells (d) have decreased infiltration of all organs. Therefore the major hypothesis of this application is: CEACAM-1 is an important negative regulator of donor T cells during GVHD. We will test the following specific hypotheses: (1) CEACAM-1 regulates tumor growth and the graft-versus-tumor activity;(2) CEACAM-1 regulates alloreactive T cell trafficking and integrin ?4?7 expression;(3) CEACAM-1 regulates DC-mediated imprinting of gut-specific homing of alloreactive T cells;(4) CEACAM-1 regulates T cell polarization toward the Th1, Th2, Th17, and regulatory T cells;and (5) the administration of the CEACAM-1 agonist CC1 can ameliorate GVHD.
Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for hematological malignancies, but graft-versus-host-disease (GVHD) is a serious complication. Our preliminary studies show that Carcinoembryonic Antigen Associated Cell Adhesion Molecule 1 (CEACAM-1) could negatively regulate GVHD. We therefore propose studies in clinically-relevant mouse allo-BMT models to analyze how CEACAM- 1 regulates GVHD. This could lead to the development of CEACAM-1 activation as a novel strategy for GVHD prevention or treatment.
