title: Blocking CD27-CD70 costimulatory pathway suppresses experimental colitis.
abstract: The pathogenesis of human inflammatory bowel disease (IBD) and most experimental models of IBD is dependent on the activation and expansion of CD4(+) T cells via interaction with mucosal APCs. The costimulatory receptor CD70 is transiently expressed on the surface of conventional dendritic cells, but is constitutively expressed by a unique APC population in the intestinal lamina propria. We used two experimental IBD models to evaluate whether interfering the interaction between CD70 and its T cell ligand CD27 would affect the development of colitis. Adoptive transfer of naive CD27-deficient CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice resulted in significantly less disease than when wild-type CD45RB(high)CD4(+) T cells were used. Moreover, a monoclonal anti-CD70 Ab prevented the disease caused by the transfer of wild-type CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice and the same Ab also ameliorated an established disease. The colitis associated proinflammatory cytokines IL-6, TNF-alpha and IFN-gamma were significantly reduced after anti-CD70 Ab treatment, suggesting an overall reduction in inflammation due to blockade of pathogenic T cell expansion. Anti-CD70 Ab treatment also suppressed trinitrobenzene sulfonic acid-induced colitis in SJL/J mice. Because anti-CD70 Ab treatment suppressed multiple proinflammatory cytokines, this may be a more potent therapeutic approach for IBD than blockade of individual cytokines.
authors.affiliation: Department of Pediatrics, Immune Disease Institute and Harvard Medical School, Boston, MA 02131, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Manocha
authors.forename: Svend
authors.initials: S
authors.lastname: Rietdijk
authors.forename: Rietdijk
authors.initials: R
authors.lastname: Svend
authors.forename: Amale
authors.initials: A
authors.lastname: Laouar
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.forename: Atul
authors.initials: A
authors.lastname: Bhan
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
authors.forename: Jannine
authors.initials: J
authors.lastname: Borst
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: N
authors.initials: N
authors.lastname: Manjunath
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D053282:CD27 Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002465:Cell Movement / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D053282:CD27 Ligand; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014302:Trinitrobenzenesulfonic Acid