title: Blockade of B7-H1 suppresses the development of chronic intestinal inflammation.
abstract: A newly identified costimulatory molecule, programmed death-1 (PD-1), provides a negative signal that is essential for immune homeostasis. However, it has been suggested that its ligands, B7-H1 (PD-L1) and B7-dendritic cells (B7-DC; PD-L2), could also costimulate T cell proliferation and cytokine secretion. Here we demonstrate the involvement of PD-1/B7-H1 and B7-DC interaction in the development of colitis. We first examined the expression profiles of PD-1 and its ligands in both human inflammatory bowel disease and a murine chronic colitis model induced by adoptive transfer of CD4(+)CD45RB(high) T cells to SCID mice. Second, we assessed the therapeutic potential of neutralizing anti-B7-H1 and/or B7-DC mAbs using this colitis model. We found significantly increased expression of PD-1 on T cells and of B7-H1 on T, B, and macrophage/DCs in inflamed colon from both inflammatory bowel disease patients and colitic mice. Unexpectedly, the administration of anti-B7-H1, but not anti-B7-DC, mAb after transfer of CD4(+)CD45RB(high) T cells suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced the production of IFN-gamma, IL-2, and TNF-alpha, but not IL-4 or IL-10, by lamina propria CD4(+) T cells. These data suggest that the interaction of PD-1/B7-H1, but not PD-1/B7-DC, might be involved in intestinal mucosal inflammation and also show a possible role of interaction between B7-H1 and an as yet unidentified receptor for B7-H1 in inducing T cell activation.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. taka.gast@tmd.ac.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Teruji
authors.initials: T
authors.lastname: Totsuka
authors.forename: Koji
authors.initials: K
authors.lastname: Uraushihara
authors.forename: Shin
authors.initials: S
authors.lastname: Makita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koganei
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Fukushima
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Utako
authors.initials: U
authors.lastname: Machida
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwai
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D015703:Antigens, CD; D000954:Antigens, Surface / Q000096:biosynthesis / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D060890:B7-H1 Antigen; D001798:Blood Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D006801:Humans; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D043183:Irritable Bowel Syndrome / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor