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PubMed2006

Trehalose 6,6'-dimycolate and lipid in the pathogenesis of caseating granulomas of tuberculosis in mice.

Trehalose 6,6'-dimycolate (TDM) is the most abundant, most granulomagenic, and most toxic lipid extractable from the surface of virulent Mycobacterium tuberculosis (MTB). We further examined its toxicity, which requires activation by oily surfaces. Injections of MTB and/or TDM into sensitized mice induced caseating granulomas that centered on oil droplets. If large doses of MTB were injected in saline, caseating granulomas developed in adipose tissue, but MTB with surface TDM removed induced only acute inflammation that did not persist. Variations in protocols produced several variants of caseating granulomas, each with characteristics of human tuberculosis. In each instance, MTB were localized in fat cells or oil drops during initiation of caseating granulomas suggesting that necrosis was caused by activation of the toxicity of TDM toxicity. Evidence extending these findings to the lung was derived from the observation that in sensitized mice, as in humans, tuberculosis development stimulates accumulation of lipid selectively in alveoli. MTB preferentially associated with lipid droplets in developing necrotic foci in late-stage murine tuberculosis. This supports the hypothesis that pulmonary tuberculosis sequesters MTB in a protected environment that accumulates lipid until it is able to activate the toxicity of TDM and initiate necrosis that results in caseating granulomas.

Adipose Tissue↗
PubMed1988

Pathogenesis of trehalose dimycolate-induced interstitial pneumonitis. IV. Evidence against roles for immunoglobulins and the complement system.

We showed previously that trehalose dimycolate (TDM) in oil administered intraperitoneally into susceptible mice produced interstitial and hemorrhagic pneumonitis by the seventh day after injection and that mature T cells are necessary for the production of these lesions. TDM has been reported to activate complement and to be chemotactic for macrophages in vitro. Accordingly, we looked for involvement of humoral mechanisms in the pathogenesis of TDM-induced pneumonitis. Genetically C5-deficient B10D2/oSn mice developed pulmonary lesions just as well as C5-sufficient mice. No activation of C3 occurred in the plasma of TDM-treated mice as determined by crossed immunoelectrophoresis. Some splitting of C3 occurred in bronchoalveolar lavage fluids, but this was similar in control and experimental mice. By immunofluorescence microscopy, there was no deposition of C3 or immunoglobulins (Ig) along the alveolar membranes. These findings and our published data provide additional evidence that TDM-induced interstitial inflammation in mice is exclusively a T-lymphocyte-dependent process.

Animals↗
PubMed1987

No evidence for an interaction of the bacterial immunomodulator trehalose dimycolate (TDM) with liver drug-metabolizing system in mice.

Trehalose dimycolate (TDM), an immunomodulatory glycolipid component of Mycobacteria, was tested from the point of view of possible effects on drug metabolism. TDM was given intraperitoneally as a single 0.1 mg dose to mice. Basic parameters of the liver mixed-function oxidase system were assayed 1 or 7 days later. No significant changes were found in contents of cytochromes P-450 and b5, as well as in specific activities of microsomal enzymes--aniline hydroxylase, ethylmorphine demethylase, and glucuronide transferase. Similarly, liver microsomal protein concentration and activities of serum aspartate and alanine transaminases remained unchanged. The susceptibility of microsomal membranes to lipid peroxidation was significantly decreased 7 days after TDM administration. TDM may thus be presumed not to influence range and magnitude of effects of concurrently administered drugs.

Animals↗
PubMed1989

[An immune adjuvant activity of mycolic acid-containing glycolipid, trehalose-2,3,6'-trimycolate, derived from Gordona aurantiaca].

A mycolic acid-containing glycolipid, trehalose-2,3,6'-trimycolate (GaGM), derived from Gordona aurantiaca, an acid-fast bacterium closely related taxonomically to Mycobacterium, was investigated for its immune adjuvant activity on cell-mediated responses in the mouse. I.V. injection of liposomes containing GaGM enhanced the generation of cytotoxic T-lymphocyte (CTL) against syngeneic and allogeneic tumor cells. In addition, the injection of GaGM augmented the natural killer (NK) activity and the antibody-dependent cellular cytotoxicity (ADCC). These results suggest that the injection of GaGM induces the production of interleukin-2 (IL-2), since such effector cells as CTL, NK and K cells have been shown to require IL-2 for their development.

Adjuvants, Immunologic↗
PubMed1989

[In vitro activation of immune cells by a mycolic acid-containing glycolipid, trehalose-2,3,6'-trimycolate, derived from Gordona aurantiaca].

A mycolic acid-containing glycolipid, trehalose-2,3,6'-trimycolate (GaGM), derived from Gordona aurantiaca, an acid-fast bacteria closely related taxonomically to Mycobacterium, was investigated for its immune adjuvant activity in vitro. The liposomes containing GaGM showed strong mitogenic effects on murine spleen cells at the doses used (25-100 micrograms/ml), but not on T-cell-depleted spleen cells or macrophage-depleted spleen cells. These results suggest that the mitogenic property of liposomes containing GaGM differs from that of such as lipopolysaccharide, a B-cell mitogen and that its mitogenic effects depend on the presence of macrophages. In addition, liposomes containing GaGM augmented the mixed lymphocyte reaction (MLR) and in vitro induction of cytotoxic T-lymphocytes (CTLs) against allogeneic tumor cells. These results suggest that liposomes containing GaGM have immune adjuvant properties in vitro and the adjuvant activity may be related to such cytokines as interleukin-1 and -2.

Adjuvants, Immunologic↗
PubMed1999

Serodiagnosis of Hansen's disease/leprosy by enzyme-linked immunosorbent assay using cord factor (trehalose 6,6'-dimycolate) as an antigen.

IgG and/or IgM antibodies against mycobacterial cord factor (trehalose 6,6'-dimycolate, TDM) in sera of 65 patients of Hansen's disease (21 cases with smear-positive and 44 cases with smear-negative) and 60 healthy individuals were tested by enzyme-linked immunosorbent assay (ELISA) with TDM purified from Mycobacterium tuberculosis H37Rv as an antigen. Of 65 patients with Hansen's disease, 58 cases (89.2%) had positive results (21 samples from 21 patients, 100% with acid-fast bacilli positive in the lesion, and 37 samples from 44 patients, 84.0% with acid-fast bacilli negative Hansen's disease diagnosed clinically). The sensitivity and specificity of anti-cord factor ELISA were higher than those of anti-phenolic glycolipid-I (PGL-I) agglutination test. Among the total, 34 patients were classified clinically into three types of the disease, lepromatous leprosy (LL), borderline lepromatous (BL) and borderline tuberculoid (BT). The antibody titer showed LL > BL > BT, indicating that the elevation of anti-cord factor antibody titers appeared to be parallel with the degree of humoral immune response against M. leprae. By using semisynthetic cord factor consisting of a single subclass of mycolic acid from M. tuberculosis, it was revealed that sera from patients with Hansen's disease were highly reactive against alpha-mycoloyl cord factor (alpha-TDM) and less reactive against methoxy mycoloyl TDM (methoxy TDM), differed from sera of tuberculosis patients, which were highly reactive against both methoxy and alpha-mycoloyl cord factor (alpha-TDM). Most of sera from patients with Hansen's disease were more reactive against TMM than TDM, differed from sera of tuberculosis patients which were highly reactive against TDM. ELISA using TDM as an antigen is simple, reproducible and useful for the rapid serodiagnosis of Hansen's disease, especially for smear-negative cases.

Aged↗
PubMed1979

Induction of delayed-type sensitivity to Leishmania parasite in a case of leishmaniasis cutanea diffusa with BCG and cord-factor (Trehalose-6-6' dimycolate).

The delayed hypersensitivity against the leishmania parasite was restored to a patient who had suffered from diffuse cutaneous leishmaniasis (DCL) for 26 years, by the application of an ointment containing heat-killed and lyophilized BCG and cord-factor (trehalose-6-6'-dimycolate) after stripping the affected and adjacent areas with scotch-tape.

BCG Vaccine↗
PubMed1999

Tumor necrosis factor is required for the priming of peritoneal macrophages by trehalose dimycolate.

Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. We have developed an original model of macrophage activation where TDM is injected in vivo to prime peritoneal macrophages. These primed macrophages do not express inducible NO synthase (NOS II), however, they can be fully activated, i.e. induced to express NOS II and to develop a NOS II-dependent antiproliferative activity, following in vitro exposure to low concentrations of LPS. In a previous paper, we have shown that TDM-priming of mouse peritoneal macrophages is mediated by the sequential production of IL-12 and IFN-gamma. In the present paper, we investigated the role of TNF in the priming of macrophages by TDM. By semi-quantitative RT-PCR, we have shown that TDM injection induced transcription of TNF-alpha in peritoneal cells. TNF-mRNA levels peaked 5 hours after TDM injection and remained elevated for at least 32 hours. TNF expression was absolutely necessary for macrophage priming, as injection of an anti-TNF monoclonal antibody, 4 h before and 20 hours after TDM injection, prevented LPS-dependent activation of macrophages in vitro. This result was confirmed by the inability of TDM to prime macrophages from LT-alpha/TNF-alpha knockout (LT/TNFKO) mice. In addition, analysis of LT/TNFKO mice treated with TDM revealed that induction of the IL-12 transcript in their peritoneal cells and expression of a functional NADPH oxidase in macrophages are TNF-independent events.

Adjuvants, Immunologic↗
PubMed2000

[cDNA cloning, sequence analysis of trehalose-6-phosphate synthase gene from Saccharomyces cerevisiae AS2.1416].

The trehalose-6-phosphate synthase gene tps1 was amplified from yeast S. cerevisiae AS2.1416 cDNA library by polymerase chain reaction. This 1.5 kb fragment was cloned into PstI and BamHI sites of pGEM-T easy vector and the sequence of the gene indicated the cloned tps1 gene contained 1485 nucleotides encoding for 495 amino acid and shared a sequence homology of 99.6% with that from S. cerevisiae S288C.

Cloning, Molecular↗
PubMed2000

[Cloning and expression of the gene encoding maltoologosyl trehalose synthase from Sulfolobus shibatae in E. coli].

2.2 kb DNA fragment encoding a novel enzyme, maltooligosyl trehalose synthase (MTSase) was amplified from Sulfolobus shibatae by using PCR technique. The amplified 2.2 kb DNA fragment was inserted into an expression vector, pBV220, to yield the recombinant plasmid pSBGT1. MTSase gene in pBSGT1 was expressed in E. coli. The molecular weight of expressed MTSase detected by SDS-PAGE was about 74 kD, which is conformed with that deduced from nucleotide sequence. The expressed MTSase protein accounted for about 4.4% of the total cell protein. The MTSase from transformants containing pBSGT1 is capable of decreasing DE value, forming non-reducing or less-reducing saccharides when allowed to act on reducing partial starch hydrolysates.

Cloning, Molecular↗
PubMed2001

[Cloning of trehalose-6-phosphate synthase gene from S. cerevisiae and its plant expression vector construction].

Total RNA, mRNA were isolated from baker's yeast S. cerevisiae, the cDNA was prepared with AMV Reverse Transcriptase from the total mRNA. The gene of trehalose-6-phosphate synthase was cloned from the cDNA with PCR amplification. The gene was sequenced and the results showed that the tpsl gene contains 1507 nucleotides and 99.6% identity with S. cerevisiae. The tps1 gene was constructed on the plant expression vector pBin438.

Base Sequence↗
PubMed1992

Synthetic trehalose dicorynomycolate and antimicrobials increase survival from sepsis in mice immunocompromised by radiation and trauma.

When mammalian antimicrobial defenses are compromised by radiation, death from sepsis may occur. Tissue trauma in irradiated hosts significantly increases mortality from bacterial infections and makes antimicrobial treatments more difficult than when individuals are subjected to trauma or radiation alone. We determined that postirradiation therapy with the immunomodulator synthetic trehalose dicorynomycolate (S-TDCM) and antimicrobials increases survival in mice after lethal irradiation and tissue trauma. Single agent therapy with systemic oxacillin, gentamicin, ofloxacin, and S-TDCM did not increase survival. Topical treatment of the injury with gentamicin cream in addition to systemic therapy with oxacillin or S-TDCM was necessary to enhance survival. Therapy with gentamicin and S-TDCM had a synergistic effect on survival. Therapies combining augmentation of non-specific host defense mechanisms with antimicrobials may be valuable in treating irradiated patients also sustaining tissue trauma.

Animals↗
PubMed1991

Growth inhibition of tumour cells by a liposome-encapsulated, mycolic acid-containing glycolipid, trehalose 2,3,6'-trimycolate.

In vivo growth of syngeneic tumour cells in the peritoneal cavity was strongly inhibited by intraperitoneal injection of a liposome-encapsulated, mycolic acid-containing glycolipid, trehalose 2,3,6'-trimycolate (TTM), derived from a non-pathogenic, acid-fast bacterium. Gordona aurantiaca. Peritoneal macrophages from mice after this treatment lysed tumour cells in vitro at a low effector/target ratio, and their culture supernatant inhibited tumour cell growth. The supernatant inhibited growth of not only tumour necrosis factor (TNF)-sensitive tumour cells, but also TNF-insensitive tumour cells. This inhibitory activity was enhanced by addition of lipopolysaccharide (LPS) to the culture medium of the macrophages. The macrophages released more superoxide (O2-), TNF and interleukin-1 (IL-1) on LPS triggering, and the releases of these compounds were further increased by addition of recombinant interferon-gamma (IFN-gamma) to the medium. Moreover, splenic T cells of TTM liposome-primed mice were found to produce eight times more IFN-gamma upon stimulation with LPS. These results indicated that priming with TTM liposomes resulted in strong activation of macrophages, which lysed tumour cells directly and also inhibited tumour cell growth by released factors.

Animals↗
PubMed1990

Trehalose dimycolate enhances survival of fission neutron-irradiated mice and Klebsiella pneumoniae-challenged irradiated mice.

The survival of B6D2F1 female mice exposed to lethal doses of fission neutron radiation is increased when trehalose dimycolate (TDM) preparations are given either 1 h after exposure or 1 day before exposure to radiation. TDM in an emulsion of squalene, Tween 80, and saline was the most effective formulation for increasing the 30-day survival of mice when given 1 day before (90%) or 1 h after (88%) exposure to radiation. An aqueous suspension of a synthetic analog of TDM was less effective at increasing 30-day survival (60%) when given 1 day prior to radiation exposure and not effective when given 1 h after radiation. Mice receiving a sublethal dose (3.5 Gy) of fission neutron radiation and either the TDM emulsion or synthetic TDM 1 h after irradiation were substantially more resistant to challenge with 10, 100, 1000, or 5000 times the LD50/30 dose of Klebsiella pneumoniae than untreated mice.

Animals↗
PubMed1988

Correlation between augmented resistance to influenza virus infection and histological changes in lung of mice treated with trehalose-6,6'-dimycolate.

Mice inoculated intravenously with trehalose-6,6'-dimycolate (TDM), a glycolipid component of the cell wall of Mycobacterium, in an oil-in-water emulsion (TDM emulsion) acquired a high resistance to intranasal infection by influenza virus. Athymic nude mice inoculated with TDM emulsion could not acquire such an augmented resistance to influenza virus infection. The augmented antiviral resistance of TDM emulsion-treated mice was diminished by prior intravenous inoculation of silica particles, which selectively impair macrophage functions. In vitro experiments showed that macrophage cultures treated with TDM emulsion released an activator(s) of T lymphocytes. Histological studies of the lung of TDM emulsion-inoculated mice revealed that a typical granuloma and severe perivascular lymphocyte infiltration appeared, though no such histological change was observed in the lung of control emulsion-inoculated mice. The lungs from TDM emulsion-treated athymic nude mice and the lungs from silica particle- and TDM emulsion-treated mice showed fewer and smaller granulomata and milder perivascular lymphocyte infiltration than a typical granuloma and lymphocyte infiltration in the lungs of TDM emulsion-treated mice. These and earlier results suggest that an acquired antiviral resistance of TDM emulsion-treated mice was caused by elicitation of macrophages with TDM, then activation of T lymphocytes, leading to granuloma formation and an amplified earlier interferon production in response to influenza virus infection.

Animals↗
PubMed1989

[The pathogenesis of trehalose dimycolate-induced hemorrhagic pneumonia induced in mice as animal model of human alveolar hemorrhagic syndrome].

Trehalose dimycolate (TDM) is a glycolipid contained in the cell walls of Mycobacteria, Nocardia and Corynebacteria. An intraperitoneal injection of TDM into mice has been known to produce hemorrhagic pneumonia without affecting any other organs. Thus, it provides a unique experimental model for studies of the mechanisms of alveolar hemorrhagic syndrome, including idiopathic pulmonary hemosiderosis. It has been reported that T lymphocytes are essential for the production of TDM-induced hemorrhagic pneumonia, however, the overall cellular mechanism is not yet clear. The purpose of this study is to re-examine and clarify the role of T lymphocytes in the pathogenesis of TDM-induced hemorrhagic pneumonia. To achieve it we considered 1) the dynamics of infiltrating lymphocytes to find out if there is a certain T lymphocyte subpopulation infiltrating predominantly into the lung, 2) the effect of in vivo depletion of T lymphocyte subpopulation by monoclonal antibodies, and 3) the effect of transfer of T lymphocytes into nude mice. The analysis of the dynamic change of the number of lymphocytes showed that the number of L3T4+ cells as well as Lyt2+ cells decreased on day 2 or 3 after TDM injection, thereafter increased, however, neither subpopulation infiltrated predominantly into the lung. Alveolar hemorrhages occurred in L3T4+ cell-depleted and/or Lyt2+ cell-depleted mice, and hemorrhages were enhanced in Lyt2+ cell-deplete mice. Alveolar hemorrhages occurred even in nude mice, and the intensity of hemorrhages or the cell numbers in the lung did not differ from those in T lymphocyte-reconstituted nude mice, however, hemorrhages were enhanced in L3T4+ cell-reconstituted nude mice. These results suggested that T lymphocytes are not primarily involved in the cellular mechanisms of the pathogenesis of TDM-induced hemorrhagic pneumonia, however, L3T4+ cells modify the process of the production of hemorrhagic pneumonia secondarily and enhance it.

Animals↗
PubMed1984

[In vivo and in vitro effect of trehalose dimycolate on tumoricidal activity of peritoneal macrophages from rats].

Trehalose dimycolate (TDM), a well-defined component of Mycobacterium tuberculosis cell wall has been tested in vivo and in vitro for its effect on the tumoricidal activity of Rat peritoneal macrophages. Macrophages could be rendered cytolytic against syngeneic tumor cells by an intraperitoneal injection of an aqueous suspension of TDM. However, as we failed to render them tumoricidal in vitro, we consider that the activation process is not due to a direct effect on macrophages.

Animals↗