Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice.

Bjursten, Malin,1976Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk immunologi,Institute of Laboratory Medicine, Dept of Clinical Immunology (författare)

Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 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 alpha4 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.

Bland, Paul William,1949Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk immunologi,Institute of Laboratory Medicine, Dept of Clinical Immunology(Swepub:gu)xblapa (författare)
Willén, Roger,1939Uppsala universitet,Institutionen för genetik och patologi (författare)
Hultgren-Hörnquist, Elisabeth,1965Gothenburg University,Göteborgs universitet,Institutionen för laboratoriemedicin, Avdelningen för klinisk immunologi,Institute of Laboratory Medicine, Dept of Clinical Immunology(Swepub:gu)xhorel (författare)
Göteborgs universitetInstitutionen för laboratoriemedicin, Avdelningen för klinisk immunologi (creator_code:org_t)

Av författaren/redakt...: Bjursten, Malin, ...; Bland, Paul Will ...; Willén, Roger, 1 ...; Hultgren-Hörnqui ...

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