STREPTOCOCCAL PREPARATION OK-432 IS A POTENT INDUCER OF IL-12 AND A T-HELPER CELL-1 DOMINANT STATE

Streptococcal preparation OK-432 is a bacterial immunopotentiator exte nsively used in Japan for adjuvant cancer therapy, Using a C57BL/6 mou se model, OK-432 was found to induce multiple cytokines including the Th1 polarizing cytokine IL-12, Expression of IL-12 protein by murine s plenocytes was restricted to macrophages and B cells and led to high l evels of IFN-gamma production from both CD4(+) and CD8(+) T cells. Of the Th2 cytokines IL-4 and IL-10, only IL-10 protein was detected and originated primarily from the adherent cell population, Its expression was delayed relative to IL-12 A similar pattern of cytokine induction was observed from human PBMCs, OK-432-driven IFN-gamma production was inhibited by anti-IL-12 Ab, anti-IL-2 Ab, anti-TNF-alpha Ab, and anti -IL-2R alpha Ab, suggesting that IFN-gamma production from Th1 cells i s induced by the cooperation action of these cytokines through the IL- 2R alpha pathway, When compared with another widely used immunopotenti ator bacillus Calmette-Guerin (BCG), OK-432 was a stronger IL-12 and I FN-gamma inducer, Furthermore, the mechanism of lFN-gamma induction by OK-432 differed from BCG in that coincident granulocyte-macrophage CS F and IL-l expression played little to no role, These results suggest that OK-432 is a potent multicytokine inducer, specifically a strong i nducer of IL-12, and that OK-432 may exert its antitumor effect by pro moting a Th1-dominant state.