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PubMed1984

Protective effect of muramyl dipeptide analogs in combination with trehalose dimycolate against aerogenic influenza virus and Mycobacterium tuberculosis infections in mice.

The effects of two aminobutyryl and four seryl analogs of the synthetic muramyl dipeptide (MDP) against aerosol infections with influenza virus and Mycobacterium tuberculosis were studied. Regardless of the MDP analog employed, there was no evidence that the resistance against viral and bacterial aerosol infections was enhanced in the treated mice. In parallel studies, significant protection against influenza virus and M. tuberculosis infections was induced by the combination of MDP or analogs with the mycobacterial glycolipid trehalose dimycolate (TDM). Resistance conferred by the MDP + TDM combination against influenza virus was present 1 week after pretreatment and could be abrogated by macrophage inhibitory agents silica, dextran sulfate, and carrageenan. Splenic cells from MDP + TDM-pretreated animals generated markedly enhanced levels of luminol-dependent chemiluminescence in response to influenza A and B viruses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Phase I study of intravenous mycobacterial cell wall skeleton and trehalose dimycolate attached to oil droplets.

The toxic, clinical, and immunological effects of suspensions of mycobacterial cell wall skeleton (CWS) and trehalose dimycolate (TDM) attached to oil droplets and given intravenously in doses of 100-2,000 micrograms/m2 (CWS) every 1 or 2 weeks was investigated in this Phase I study. The major limiting side effects were fever and chills at a dose of 2 mg/m2 body surface area. There was no significant hematopoietic, renal, hepatic, or pulmonary toxicity. Evaluation of changes in the white cell count and lymphocyte and monocyte populations and function showed an increase in the white blood count, an increase in the number of T cells, and a decrease in blood monocytes. Measurements of lymphocyte blastogenesis, monocyte suppressor activity, and monocyte cytostasis showed no consistent changes. Intravenous therapy with oil/CWS/TDM was associated with complete regression of a bronchial squamous cell carcinoma in one of three patients receiving 2 mg/m2 weekly. Subsequent Phase II studies can be conducted at a weekly dose of 1-2 mg/m2.

Adjuvants, Immunologic↗
PubMed1982

Interstitial and hemorrhagic pneumonitis induced by mycobacterial trehalose dimycolate.

Intraperitoneal injections of cord factor (trehalose dimycolate, TDM) provides a model for interstitial and hemorrhagic lung disease that is produced by a chemically defined substance. A single injection of 10 micrograms of TDM, in light mineral oil or hexadecane, into C57BL/6 mice produces interstitial and hemorrhagic pneumonitis. Following injection of TDM the pulmonary lesions increase gradually and become maximal by the seventh to ninth day, at which time 70% of the mice show both gross hemorrhages and dense mononuclear infiltrates; an additional 20% of the mice show only microscopic lesions. From day 14 onward the incidence and severity of the lesions decrease, and by day 28 the lungs are normal by both gross and light-microscopy examination. Only 5% of the mice succumb. Except for peritonitis other organs are not affected. Doses of 3.3 and 10 micrograms of TDM are equally effective in producing the lesions, but a dose of 1.0 microgram of TDM causes only mild interstitial inflammation and lesser doses do not induce lesions. A single subcutaneous injection of 10 micrograms of TDM causes lesions in only 20% of mice. Vehicle-injected mice do not develop lesions. Electron microscopy revealed that the majority of the infiltrating cells are monocytes and macrophages and that extensive interstitial damage is produced. The mechanism of the effects of TDM are unknown and is currently under study. Our preliminary data suggests that the phenomenon is dependent upon T-lymphocytes.

Animals↗
PubMed1983

Phase I study of iv mycobacterial cell wall skeleton and cell wall skeleton combined with trehalose dimycolate.

A phase I study to determine the toxicity and immunologic effects of iv administered aqueous suspensions of mycobacterial cell wall skeleton (CWS) and CWS combined with trehalose dimycolate (TDM) was performed. A total of 26 patients received suspensions of either CWS or CWS/TDM given iv every 1 or 2 weeks in set doses of either 100, 250, 500, or 1000 micrograms/m2. The major dose-limiting side effects for both preparations were fever and chills at a dose of 1 mg/m2. This was more severe with the combined CWS/TDM. There was no renal or pulmonary toxicity. There was evidence of hepatic toxicity, with increases in the alkaline phosphatase and gamma glutamyl transferase, especially with high doses of CWS/TDM. Both the CWS and CWS/TDM groups had an increase in their wbc count. In the patients receiving CWS alone, there was a decrease in the peripheral blood monocytes. In the CWS/TDM group, there was an increase in the serum lysozyme, suggesting macrophage activation. No antitumor effect was seen in this phase I study. Aqueous suspensions of CWS and CWS/TDM can be administered safely iv over a period of time, with evidence of an effect on hematologic parameters.

Animals↗
PubMed1997

[Serodiagnosis with trehalose-6,6'-dimycolate of pulmonary tuberculosis].

Enzyme-linked immunosorbent assay (ELISA) was used to examine serum antibody levels of mycobacterial antigen in 92 patients with active tuberculosis, 36 with cured tuberculosis, 45 with nontuberculous mycobacteriosis, and as 31 with other diseases. Glycolipid fraction containing mainly cord factor (trehalose-6,6'-mycolate) from Mycobacterium tuberculosis H37Rv were used as ELISA antigen. Overall positive rates of the ELISA tests in the patients with active pulmonary tuberculosis, those with nontuberculous mycobacteriosis, and those with other diseases were 67.4%, 75.6%, and 6.5%, respectively. Patients with tuberculosis and those with nontuberculous mycobacteriosis differed from the control group (p < 0.0001). Higher positive rates were correlated with bacterial loads (smear-positive vs smear-negative, p < 0.01) and with chest roenrgenographic findings (far advanced or other cavitary vs noncavitary, p < 0.01). Because 18 of 36 smear-negative patients (50%) had positive results, we believe that the ELISA test with this antigen can be useful for diagnosis of M. tuberculosis, especially in patients with smear-negative.

Antibodies, Bacterial↗
PubMed1975

Immunotherapy and vaccination against cancer with non-living BCG and cord factor (trehalose-6,6'-dimycolate).

A vaccine containing non-living BCG and living tumour cells prevented the growth of 106 tumour cells introduced distally into the skin of guinea-pigs at the time of vaccination. A similar effect was achieved when living tumour cells of the vaccine were replaced by tumour cells pretreated with mitomycin C. The efficacy of the vaccine was significantly increased when cord factor was added to the vaccination mixture. The percentage of cures was about 88% (17 cases) in experiments in which the vaccine contained living tumour cells, 100% (10 cases) when mitomycin C-treated cells were used. The significance and implications of the above findings are discussed.

Animals↗