Blocking CD27-CD70 costimulatory pathway suppresses experimental colitis

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^highCD4⁺ 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.