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

• 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.

Nyckelord

Animals

Antibodies

Blocking

adverse effects

therapeutic use

Antibodies

Monoclonal

adverse effects

therapeutic use

Colitis

immunology

pathology

Colon

drug effects

immunology

Disease Models

Animal

Female

GTP-Binding Protein alpha Subunit

Gi2

GTP-Binding Protein alpha Subunits

Gi-Go

deficiency

genetics

Immunoglobulin A

blood

Immunoglobulin G

blood

Inflammatory Bowel Diseases

genetics

immunology

therapy

Integrin alpha4

immunology

Lymphoid Tissue

drug effects

immunology

Male

Mice

Mice

Inbred C57BL

Mice

Knockout

Proto-Oncogene Proteins

deficiency

genetics

Spleen

drug effects

immunology

T-Lymphocytes

drug effects

immunology

Time Factors

Animals

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