Treatment of mice with heat-killed (HK)Mycobacterium

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Hosts infected with low doses of mycobacteria develop T helper cell type 1 (Th1) immunity, but at relatively higher doses, a switch to Th2 immunity occurs. Prostaglandin E2 (PGE2) is a proposed mediator of the Th1-to-Th2 shift of immune responses, and mycobacterial products induce PGE2-releasing macrophages (PGE2-MØ) in the mouse spleen in a dose-dependent manner. Splenic PGE2-M Ø from Balb/c mice, given 0.01 or 1 mg heat-killed (HK) Mycobacterium bovis bacillus Calmette-Guerin (BCG) intraperitoneally (i.p.), were characterized by the ex vivo release of PGE2 (>10 ng/10(6) cells), cytokine production, and expression of PGG/H synthase (PGHS)-1, PGHS-2, cytosolic PGE synthase (PGES), and microsomal PGES-1. At Day 14 after the treatment, mice treated with 1 mg, but not 0.01 mg, BCG had increased levels of PGHS-2+ PGE2-MØ, total serum immunoglobulin E (IgE), and serum IgG1 antibodies (Th2 responses) against heat shock protein 65 and purified protein derivative. Cultures of spleen cells isolated from these mice expressed interleukin (IL)-4 and IL-10 in recall responses. Treatment of mice receiving 1 mg BCG with NS-398 (a PGHS-2 inhibitor, 10 mg/kg i.p., daily) resulted in enhanced interferon-gamma (IFN-gamma) production with reduced IL-4 and IL-10 production in recall responses. This treatment also resulted in decreased total serum IgE levels. Treatment of C57Bl/6 mice with HK-BCG (0.5 mg dose) also induced a mixture of Th1 and Th2 responses, although IFN-gamma production was markedly increased, and IL-4 was decreased compared with Balb/c mice. Thus, our results indicate that by 14 days following treatment of mice with high doses of HK-BCG, splenic PGE2-MØ formation is associated with a PGHS-2-dependent shift from Th1-to-Th2 immune responses.

High viability, good dispersion and efficient binding to tumor cells by BCG bacilli in the Tokyo172 preparation seem to be the main reasons for the lower clinical dose of this preparation compared with the Connaught preparation (18 vs 81 mg dry weight).

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