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

Abstract

Targeted deletion of the heterotrimeric G protein, Gai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on a4 integrins. In previous studies, short-term administration of anti-a4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-a4 integrin antibodies on colitis in Gai2 -/-mice. Long-term blockade of a4 integrin significantly increased the severity of colitis in Gai2 -/-mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1b, TNF-a and IFN-c. Blockade of a4 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 a4 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.See accompanying commentary: http://dx

A Case for Regulatory B Cells

“…The MLN Breg subset characterized by CD19 high expression is involved in intestinal immunoregulation by recruiting novel Treg subsets, CD8 ϩ T cells, and NKT cells (30), both of which have recently been shown to inhibit intestinal inflammation (86 -88). The presence of such a regulatory mechanism is supported by a recent finding that both impairment of B cell activation and decrease in CD8 ϩ T cells is associated with the exacerbation of chronic intestinal inflammation observed in G␣i2 KO mice (89). Furthermore, B cells have been shown to induce such Tregs in a ␤ 2 -microglobulin-dependent fashion at the ocular immune privilege site (90).…”

Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis

“…In experimental colitis, short-term administration of anti-α 4 integrin monoclonal antibody attenuates intestinal inflammation, but long-term blockade increases disease severity and the risk of cancer in situ [111]. It is still rather early to appreciate the potential consequences of sustained morphological changes induced by fingolimod in lymphoid organs and the spleen [112].…”

Deoxycholate-Induced Colitis is Markedly Attenuated in Nos2 Knockout Mice in Association with Modulation of Gene Expression Profiles

“…Inhibition of leukocyte trafficking via integrin-α4 antibody blockage has been shown to attenuate intestinal inflammation in ulcerative colitis and Crohn's disease over the short term [28,34]. However, long-term treatment with integrin-α4 antibody increases the severity of colitis [35]. Our finding of an association of colitis with reduction of integrin-α4 in the DOC-fed Nos2( + / + ) mice, over an extended period, is consistent with the long-term deleterious effect of antibody blockage of integrin-α4.…”