The therapeutic effect of TV-5010 in a murine model of inflammatory bowel disease -- Dextran induced colitis.
TV-5010 is a higher molecular weight version of glatiramer acetate (GA), the active ingredient of Copaxone - an approved drug for the treatment of multiple sclerosis (MS). GA has been shown to ameliorate colitis in several experimental models when administered by daily injection. The present study aimed to explore the effect of TV-5010 in a murine model of inflammatory bowel disease (IBD) and the possibility for its administration in tapered frequency. As demonstrated here, TV-5010 ameliorated the various pathological manifestations of Dextran (DSS)-induced colitis, i.e. weight loss, intestinal bleeding and diarrhea, resulting in substantial reduction of disease activity, colonic damage and mortality. In contrast to GA, which was more effective when administered daily by injection of 2.0 mg/mouse, TV-5010 was most effective when administered once a week, at dose of 0.2-1.0 mg/mouse. TV-5010 treatment abrogated the characteristic inflammation in the diseased organ as demonstrated by reduction in the colonic mRNA expression of TNF-alpha, IFN-gamma and the Th1 transcription factor T-bet, as well as by augmentation of the regulatory cytokine TGF-beta. Injection of naive mice with TV-5010 generated lymphocyte population of the Th2/3 subtype that effectively reduced disease manifestations upon adoptive transfer to mice with DSS-colitis. Moreover, TV-5010-specific T-cells, either exogenously labeled or genetically marked, adoptively transferred to colitis-induced mice, localized in the inner layers of the injured colon and expressed TGF-beta in situ. Thus, TV-5010 is effective in the suppression of experimental colitis similarly to GA, with the advantage of less frequent administration, possibly via immunomodulation at the site of pathological damage.
Aharoni
Rina
R
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Brenner
Ori
O
Cohen
Adva
A
Arnon
Ruth
R
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003911:Dextrans / Q000494:pharmacology; D000068717:Glatiramer Acetate; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D003911:Dextrans; D010455:Peptides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000068717:Glatiramer Acetate; D007371:Interferon-gamma