Critical role of DNAX accessory molecule-1 (DNAM-1) in the development of acute graft-versus-host disease in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 43; pp. 18593 - 18598
• Main Authors: Nabekura, Tsukasa, Shibuya, Kazuko, Takenaka, Eri, Kai, Hirayasu, Shibata, Kai, Yamashita, Yumi, Harada, Kyoichi, Tahara-Hanaoka, Satoko, Honda, Shin-ichiro, Shibuya, Akira, Yokoyama, Wayne M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.10.2010; National Acad Sciences
• Subjects: Acute Disease; Allografts; Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Antigens; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; Biological Sciences; Blood; Bone marrow; bone marrow transplant; Bone Marrow Transplantation - adverse effects; Bone Marrow Transplantation - immunology; Bone Marrow Transplantation - pathology; CD226 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Proliferation; coculture; Female; gamma -Interferon; Graft vs host disease; Graft vs Host Disease - etiology; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Graft vs Host Disease - therapy; Graft-versus-host reaction; Immunoglobulins; Immunotherapy; interferon-gamma; Interferon-gamma - biosynthesis; Intestine; intestines; Irradiation; Ligands; Liver; Lymphocytes T; Major histocompatibility complex; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Molecular structure; Mortality; Receptors; Rodents; Splenocytes; T lymphocytes; Transplantation; Transplantation, Homologous; Transplants & implants
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1005582107

Acute graft-versus-host disease (GVHD) is a life-threatening complication following bone marrow transplantation; however, no effective molecular-targeting therapy has been determined. Here, we show that mice that received allogeneic splenocytes deficient in DNAX accessory molecule-1 (DNAM-1) had significantly milder GVHD and lower mortality than those that received allogeneic WT splenocytes. Donor CD8⁺ T cells deficient in DNAM-1 showed significantly less proliferation and infiltration of the liver and intestines of recipient mice and produced less IFN-γ after coculture with allogeneic splenocytes than WT CD8⁺ T cells. Mice prophylactically treated with an anti–DNAM-1 antibody showed milder GVHD and lower mortality than those treated with a control antibody. Moreover, treatment with a single administration of the antibody after the overt onset of GVHD ameliorated GVHD and prolonged survival. Finally, we show that the anti–DNAM-1 antibody therapy also ameliorated the overt GVHD in lethally irradiated mice after MHC-matched, minor antigen-mismatched bone marrow transplantation. These results indicate that DNAM-1 plays an important role in the development of GVHD and is an ideal molecular target for therapeutic approaches to GVHD.