Hideharu Ishida

Induction of tumoricidal macrophages and production of cytokines by synthetic muramyl dipeptide analogues

The ability of various synthetic muramyl dipeptide (MDP) derivatives to induce the production of interleukin-1 (IL-1) and colony stimulating factor (CSF) in vitro and in vivo and to induce cytotoxic macrophages was studied. 6-O-L18-MDP(Me) and MDP-Lys(L18), which were potent inducers of IL-1 and CSF production and of cytotoxic macrophages, had protective activity against Sendai virus infection in mice. In contrast, 1-O-L18-(6-O-P)-MDP(Me) and 2-N-L18-MDP exhibited weak or no ability to induce IL-1 and CSF production and no induction of tumoricidal macrophages, and did not protect against infection of Sendai virus. MDP derivatives, except 2-N-L18-MDP, efficiently rendered macrophages cytotoxic against target cells in the presence of murine recombinant interferon-gamma in vitro. The derivatives that induced cytokines and cytotoxic macrophages appeared to produce anti-viral activity.

Syntheses of Trehalose Monomycolate and Related Compounds, and Their Lethal Toxicity and Adjuvant Activity

Abstract Five monoesters, 6-O-mycoloyl-α, α-treha lose (TMM), 6-O-mycoloyl-D-glucose (GlcM), 6-O-mycoloyl-N-acetyl-D-glucosamine (GlcNAcM), 5-O-mycoloyl-D-arabinose (AraM) and 6-O-mycoloyl-D-galactose (GalM), were synthesized by use of mycolic acid isolated from Mycobacterium tuberculosis strain Aoyama B. Their toxicity and macrophage activating ability were examined in mice. A single intravenous administration of 400 μg of TMM in 9% oil-in-water emulsion killed 8 of 8 treated mice. The other analogs showed less lethal toxicity to mice at the same dose. Tumoricidal activity of mouse peritoneal macrophages was induced by intraperitoneal injection of TMM, GlcM, and GlcNAcM, respectively.

Chemical synthesis and biological activities of 6,6′-di-O-mycoloyl-β,β- and -α,β-trehalose

Abstract 6,6′-Di- O -mycoloyl-β,β-trehalose (β,β-TDM) and 6,6′-di- O -mycoloyl-α,β-trehalose (α,β-TDM) were synthesized and their toxicity and ability to activate peritoneal macrophages in situ were examined in mice, in comparison with 6,6′-di- O -mycoloyl-α,α-trehalose (TDM). Both β,β-TDM and α,β-TDM caused a decrease in body weight two days after injection, however the weights reverted to a normal level. No deaths were caused by either analog. On the other hand, TDM showed potent toxicity, causing decrease in body weight and death of all animals injected. β,β-TDM and α,β-TDM were effective in the in situ activation of mouse peritoneal macrophages.

Chemical Combination of Biologically Active Derivatives ofN-Acetylmuramoyl Dipeptide and Lipid-A, and Their Biological Activities

Abstract Chemical coupling of biologically active derivatives of N-acetyl-muramoyl dipeptide with a derivative related to the nonreducing sub-unit of lipid A was carried out using acyl groups as a spacer. The products exhibited efficient antitumor activity, as well as strong, immunoadjuvant activity.