Blocking CD27-CD70 costimulatory pathway suppresses experimental colitis
The Journal of immunology, 2009•journals.aai.org
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 …
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 …
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-α and IFN-γ 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.
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