Received for publication February 21, 2006.
Revised April 16, 2006.
Accepted for publication April 17, 2006.

Immunomodulatory Therapeutic Effect of Glatiramer Acetate on Several Murine Models of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is characterized by detrimental immune reactivity in the gut and imbalance between pro-inflammatory and anti-inflammatory reactivity. In an attempt to down regulate colitis we investigated the effect of the immunomodulator glatiramer acetate (GA, Copaxone, Copolymer 1), on two murine models of IBD - chemically induced and spontaneous. Acute experimental colitis of different levels of severity was induced in C57BL/6 mice by dextran sulfate sodium (DSS) administered orally at different concentrations and frequencies. It was manifested in weight loss, intestinal bleeding and diarrhea, as well as by macroscopic and microscopic colon damage. GA treatment led to amelioration of all these pathological manifestations resulting in improved long-term survival. Moreover, even when colitis was induced by three cycles of DSS in this highly susceptible mouse strain, as well as in BALB/c mice which exhibit a chronic disease pattern, a substantial reduction in disease activity and mortality was obtained. GA treatment induced a beneficial effect also in a spontaneous model of colitis developed in the C3H/HeJBir IL-10 deficient mice. The detrimental pro-inflammatory response manifested by proliferation, TNF- and IFN- expression was modulated by GA, while the regulatory anti-inflammatory TGF- and IL-10 cytokines response was elevated. This was demonstrated on the level of protein secretion in splenocytes and local mesenteric lymphocytes, in the response to syngeneic colon extract and in the overall response to anti-CD3, as well as on the level of mRNA expression in the colon.

Key words: Glatiramer Acetate, Inflammatory bowel disease, Spontaneous colitis model, anti-inflammatory cytokines, dextran sulfate sodium induced colitis, immunomodulation