TAK-603 SELECTIVELY SUPPRESSES TH1-TYPE CYTOKINE PRODUCTION AND INHIBITS THE PROGRESSION OF ADJUVANT ARTHRITIS

We have shown that TAK-603, a new anti-rheumatic drug, is more effecti ve in animal models in which cellular immunity plays a central role. H ere, we studied the effect of the drug on Th1 cytokines, which are dom inantly produced in this type of immune reaction, in an in vitro syste m and an in vivo model. We established Th1- and Th2-dominant T-cell Li nes, and studied the effect of TAK-603 on their cytokine production. T h1 cell lines were BALB/c mouse allo-reactive T cells and C57BL mouse mite antigen-reactive T cells, and the Th2 cell line was BALB/c mouse ovalbumin-reactive T cells. TAK-603 suppressed the production of Th1 c ytokines [interferon-gamma (IFN-gamma) and interleukin-2 (IL-2)] and n ot that of Th2 cytokines (IL-4, IL-5) in these cell lines. Furthermore , selective suppression of Th1 cytokine production was also observed i n the T-cell clones obtained from the ovalbumin-reactive T-cell line. To investigate the effect on cytokine production in animal models of a rthritis, we analysed the expression of cytokine messenger RNA using r everse transcription-polymerase chain reaction. In adjuvant arthritis rats, Th1-dominant cytokine production was observed both in the arthri tic joint and the spleen, and the time-course paralleled the progressi on of arthritis. On the other hand, in type-II collagen-induced arthri tis, in which TAK-603 has little effect, Th1-dominant cytokine product ion was not observed and Th2 cytokines were shown to be more important . The adjuvant arthritis rats treated with TAK-603 (6.25 mg/kg/day, pe r os) showed significantly lower cytokine mRNA expression both locally and systemically. These data suggest that TAK-603 selectively suppres ses Th1 cytokine production, which is consistent with its effect on ce llular immunity in animal models.