Long-term treatment with anti-α4 integrin antibodies aggravates colitis in Gαi2-deficient mice

Targeted deletion of the heterotrimeric G protein, G alpha i2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha 4 integrins. In previous studies, short-term administration of anti-alpha 4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha 4 integrin antibodies on colitis in G alpha i2(-/-) mice. Long-term blockade of alpha 4 integrin significantly increased the severity of colitis in G alpha i2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1 beta, TNF-alpha and IFN-gamma. Blockade of alpha 4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha 4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.