Administration of mAb against α(E)β₇ prevents and ameliorates immunization-induced colitis in IL-2(-/-) mice

We previously demonstrated that 2,4,6-trinitrophenol (TNP)-OVA immunization leads to a transmural colitis in the IL-2(-/-) mouse that is caused by IL-12-driven CD4⁺ Th1 T cells and resembles human Crohn's disease. The integrin α(E)β₇ is highly expressed on colonic intraepithelial lymphocytes and has been suggested to function as a homing or retention molecule for intraepithelial lymphocytes. To evaluate the role of α(E)β₇ in colitis, we administered a mAb against α(E)β₇ to IL-2(-/-) mice that were immunized at the same time with TNP-OVA in CFA. To our surprise, this treatment resulted in a significantly reduced colitis severity score, 0-2 vs 3-4, that was associated with a significant reduction in CD4⁺ lamina propria lymphocyte subpopulation (p < 0.01). In contrast, the total number of splenic CD4⁺ T cells of treated animals was significantly elevated compared with that of untreated animals (3.2 ± 0.6 x 10⁷ VS 1.2 ± 0.2 x 10⁷; p < 0.05). Similarly, functional studies revealed that IFN-γ production by lamina propria lymphocytes isolated from IL-2(-/-) TNP-OVA-immunized mice treated with anti-α(E)β₇ was significantly lower than in untreated IL-2(-/-) TNP- OVA-immunized mice. In contrast, IFN-γ production by splenic cells isolated from treated IL-2(-/-) TNP-OVA-immunized mice was significantly higher than in untreated mice. Finally, TNP-OVA-immunized IL-2(-/-) mice that were treated after the colitis had been established also showed a significant decrease in mucosal inflammation after α(E)β₇ mAb administration. Thus, the above findings demonstrate that the onset and maintenance of inflammatory bowel disease depends on the colonic localization of lamina propria CD4⁺ lymphocytes expressing α(E)β₇.