The therapeutic effect of glatiramer acetate in a murine model of inflammatory bowel disease is mediated by anti-inflammatory T-cells.
Inflammatory bowel diseases (IBDs) are complex multifactorial immunological disorders characterized by dysregulated immune reactivity in the gut and imbalance between pro-inflammatory and anti-inflammatory reactivity. The therapeutic effect of the immunomodulatory drug glatiramer acetate (GA, Copaxone, copolymer 1) has been established in several IBD models, including trinitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS)-induced colitis, as well as in a spontaneous colitis model. In the present study we investigated the mechanism of action of GA and cells specifically induced by it. Immunization of naive mice by GA, generated a lymphocyte population of the Th2/3 subtype, that drastically reduced disease manifestations upon their adoptive transfer to mice with DSS colitis. This was demonstrated by the substantial decrease in weight loss, intestinal bleeding and diarrhea, as well as by the prevention of macroscopic and microscopic colonic damage. In contrast, adoptive transfer of control lysozyme-specific cells did not induce any beneficial effect on the disease. Moreover, GA-specific short-term T-cell lines, either exogenously labeled or genetically marked, adoptively transferred by the intraperitoneal route to colitis-induced mice, localized in the inner layers of the colon and secreted in situ the regulatory cytokine TGF-beta. These results demonstrate the accumulation of GA-specific Th2/3 cells secreting regulatory cytokines in the injured colon, and thus draw a direct linkage between the therapeutic effect of GA in IBD and an immunomodulatory effect at the site in which the pathological process occurs.
Aharoni
Rina
R
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Sonego
Hagar
H
Brenner
Ori
O
Eilam
Raya
R
Arnon
Ruth
R
D019264:Adoptive Transfer; D000818:Animals; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D000068717:Glatiramer Acetate; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
D007155:Immunologic Factors; D010455:Peptides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000068717:Glatiramer Acetate; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate