Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acid-induced experimental colitis.
Inflammatory bowel diseases are characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and antiinflammatory reactivity. In an attempt to downregulate inflammatory bowel disease, we tested whether the immunomodulator glatiramer acetate (GA; Copaxone, copolymer 1), an approved drug for the treatment of multiple sclerosis, can ameliorate trinitrobenzene sulfonic acid (TNBS)-induced colitis, a murine model that resembles human Crohn's disease. Experimental colitis was induced by rectal instillation of TNBS in 3 mice strains: BALB/c, SJL/J, and (SJL/JXBALB/c)F1, and its severity was evaluated by gross colon injury, histologic damage, body weight, and survival rate. We studied the effect of GA on all these parameters as well as on lymphocyte reactivity manifested by proliferation and secretion of tumor necrosis factor-alpha, and transforming growth factor-beta. GA treatment significantly suppressed the various manifestations of TNBS-induced colitis as demonstrated by substantial reduction in the macroscopic colonic damage, preservation of the microscopic colonic structure, reduced weight loss, and improved long-term survival, in GA treated mice compared with untreated mice. The parenteral route was more effective than the oral route. GA suppressed the proliferation of local mesenteric lymphocytes to syngeneic colon extract and the detrimental tumor necrosis factor-alpha secretion. In addition, it induced a beneficial secretion of transforming growth factor-beta. The ability of GA to effectively modulate the clinical manifestations and the detrimental immune response involved in experimental colitis warrants further studies to determine the clinical efficacy of GA in the treatment of human inflammatory bowel diseases.
Aharoni
Rina
R
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Kayhan
Basak
B
Arnon
Ruth
R
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000662:veterinary; D003424:Crohn Disease / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009103:Multiple Sclerosis; D010455:Peptides / Q000494:pharmacology*; D011108:Polymers; D012720:Severity of Illness Index; D016019:Survival Analysis; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage
D007166:Immunosuppressive Agents; D010455:Peptides; D011108:Polymers; D000068717:Glatiramer Acetate; D014302:Trinitrobenzenesulfonic Acid