Biol. Pharm. Bull. 28(1) 78—82 (2005)

helper T lymphocytes (Th) were subdivided into two distinct populations, Th1 and Th2 cells. Th1 cells producing interferon-g (IFN-g) play a critical role in cellular immunity, while Th2 cells producing interleukin (IL)-4 and IL-5 are essential for the regulation of humoral immunity. The balance between Th1and Th2-dominant immunity (Th1/Th2 balance) was thought to be important for the development and maintenance of various diseases. For example, the predominance of Th2 and increased serum IgE level were reported in patients with atopic dermatitis; in cancer patients, imbalance of Th1 and Th2 was found in the peripheral lymphocytes. Thus, immunomodulators which can skew the Th1/Th2 balance into Th1 dominance may be useful drugs for treating atopic dermatitis and cancer. Regarding the laboratory investigations on the effect of Th1/Th2 balance modulators such as IFN-g and IL-12 (an inducer of IFN-g) in atopic dermatitis and intradermal cancer models, there are several studies using NC/Nga (NC) mice and intradermal transplantation of B16F10 melanoma. NC mice, an inbred strain established from fancy Japanese mice, develop atopic dermatitis-like skin lesions under conventional care, or upon treatment with repeated challenge with picryl chloride, and have thus been considered a useful model for human atopic dermatitis. The elevation of plasma IgE level has been reported to correlate with the appearance of skin lesions in NC mice; Th2-specific chemokines and their receptors have been also reported to be highly expressed in the lesions of the NC mice. Although these findings suggest the possible involvement of Th2 development in the pathogenesis of NC mice, the reported effects of Th1/Th2 modulators are not necessarily coincident: one report demonstrated that IFN-g or IL-12 could reduce skin lesions as well as decrease the elevation of plasma IgE level, but another report demonstrated that neither IFN-g or IL-12 was able to reduce them, or worsened them. Thus, the involvement of Th2 development in the pathogenesis of NC mice remains unclear. On the other hand, B16F10 melanoma-bearing mice are a frequently used animal model for the evaluation of anti-cancer agents. IFN-g production of splenocytes from B16F10bearing mice was smaller than that of normal mice, indicating Th2 dominance in Th1/Th2 balance. In fact, repeated injections of IFN-g or IL-12 could suppress the tumor growth in B16F10-bearing mice. Thus, treatment with these Th1 cytokines alone is effective in this model. However, down-regulation of Th2 may act negatively on the host defense against cancer, because several reports have shown that not only Th1 but also Th2 are important for anti-cancer immunity. We had been searching for orally-active synthetic compounds which could down-regulate Th2 response, and found a unique immunomodulator, M50367 (ethyl 3-hydroxy-3-[2(2-phenylethyl)benzoimidazol-4-yl]propanoate, Fig. 1). This compound directly acted on naïve Th cells to suppress their differentiation into Th2 cells in vitro; because the development of Th1/Th2 is reciprocally regulated, this compound resulted in the enhancement of Th1 cell differentiation. 78 Biol. Pharm. Bull. 28(1) 78—82 (2005) Vol. 28, No. 1