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Biomedical subjects

E Ribi

Publications and source records attributed to E Ribi.

At least 37 records · Page 2Linked to original sources
PubMed1982

Induction of resistance to tuberculosis in mice with defined components of mycobacteria and with some unrelated materials.

Factors contributing to protection against experimental tuberculosis have been studied with refined and well characterized fractions from mycobacteria and with certain unrelated antigens. Mice were vaccinated intravenously with various combinations of materials presented on minute oil droplets in saline emulsions and were later challenged by aerosol. The minimal composition of an effective vaccine was P3 (a trehalose mycolate similar to cord factor) plus an antigen, which could be tuberculoprotein, or a low-molecular-weight tuberculin-active peptide, or unrelated antigen such as bovine serum albumin or bacterial endotoxin. Development of a hypersensitivity granuloma in the lungs appeared to be essential to protection in this laboratory model.

Animals↗
PubMed1981

Inhibition of pulmonary granuloma formation in mice by treatment with Mycobacterial protoplasm and immuno-suppressants and its relation to protection against aerosol infection with virulent Mycobacterium tuberculosis.

Because the pulmonary granuloma formation by mycobacterial cell walls (CW) is likely mediated by cellular immunity, the effect of specific antigens and various immunosuppressants on pulmonary granuloma formation and protection against virulent m. tuberculosis, strain H37Rv was investigated in mice immunized with oil-treated CW from BCG or M. Tuberculosis, strain Aoyama B. Results of desensitization experiments with specific antigens showed that multiple intravenous injections of BCG protoplasm inhibited the footpad delayed hypersensitivity, macrophage migration inhibitory activity of lung cells and pulmonary granuloma formation as well as the enhancement of resistance against aerosol challenge with M, tuberculosis, strain H37Rv. However, treatment with nonspecific immunosuppressants like con A, silica or carrageenan induced only abrogation of footpad delayed hypersensitivity but not prevention of pulmonary granuloma formation or resistance against aerosol challenge. These results suggest a close relationship between pulmonary granuloma formation and protection against H37Rv in mice immunized with oil-treated mycobacterial CW.

Aerosols↗
PubMed1981

Isolation of a nontoxic lipid A fraction containing tumor regression activity.

Galanos-type endotoxin obtained from the heptose-less mutant of Salmonella typhimurium was converted to Lipid A by two cycles of treatment with sodium acetate, pH 4.5, at 100 degrees and separated on a DEAE-cellulose column into several fractions (Fractions III to VII). Tumor regression studies with strain 2 guinea pigs and syngeneic line 10 hepatocellular carcinoma showed that all fractions were effective when combined with trehalose dimycolates and an additional tumor regression factor (previously designated ACP) and incorporated into oil droplets (78 to 100% cures). A low polar fraction (Fraction IV) was relatively nontoxic [the medium lethal dose for 11-day-old chick embryos inoculated i.v. (CELD50) was more than 10 micrograms] and nonpyrogenic [the dose estimated to give a fever index (area under fever curve) of 40 sq cm in rabbits when 1 hr and 1 degrees are plotted as 1 (FI40) was 5 micrograms] as compared to the unfractionated Lipid A (CELD50 of 0.0546 micrograms; FI40 of 0.046 micrograms). All other fractions were toxic and pyrogenic and caused severe endotoxic shocks when combined with N-acetylmuramyl-L-seryl-D-isoglutamine and injected i.v. into guinea pigs. Fraction IV plus N-acetylmuramyl-L-seryl-D-isoglutamine did not cause endotoxic shock. The phosphate content of Fraction IV was about one-half of that detected in the toxic fractions.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

A shortened synthesis of adjuvant dipeptide (MDP).

N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP), has been shown to be the minimal structure necessary for adjuvant activity. This compound can replace whole mycobacteria in Freund's complete adjuvant. In our continuing investigation of bacterial cell wall fragments of biological and immunotherapeutic interest, the necessity of obtaining MDP analogs of varying structure has proven to be of primary importance. We have found that the published routes to MDP could be effectively shortened to four steps starting from commercially available starting materials. As an example of this scheme, synthesis of the seryl analog will be detailed. gamma-benzyl glutamic acid could be elaborated in one step to the N-tertiary butoxycarbonyl seryl-gamma-benzyl isoglutamine. Deprotection of the Boc group followed by condensation with 1-O-benzyl-4, 6-O-benzylidine N-acetyl muramic acid provided the protected MDP. Deprotection of this product by hydrogenolysis gave the final product. Physical chemical and biological data as proof of structure is presented. Utility of these compounds in the line-10 tumor system is demonstrated.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1979

Intralesional immunotherapy of malignant melanoma with mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate (P3).

The clinical efficacy of intralesional immunotherapy utilizing Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate attached to oil droplets was investigated in 15 patients with advanced malignant melanoma. Patients received 300 microgram to 1050 microgram of the CWS combined with one-half that amount of trehalose dimycolate every 1 to 2 weeks for a total of 8 treatments. Therapy was continued if regression of injected lesions only occurred. Therapy was discontinued if regression of noninjected disease also occurred. Six of the 15 patients had regression of at least one injected lesion. Four of these 6 patients also had regression of noninjected disease lasting 4+, 6, 16 and 18+ months. Response was highly related to immune status. Six (83%) of 7 patients who reacted to one of a battery of skin tests responded. All 8 patients who did not react to skin tests failed to respond to therapy. There was no correlation of response with sex, prior therapy, disease-free interval or presence of visceral disease. Mycobacterial CWS and trehalose dimycolate is an effective immunotherapeutic agent. Additional studies of purified immunoadjuvants are warranted.

Cell Wall↗
PubMed1979

[Immunotherapy with BCG and mycobacterial fractions and its use in bronchogenic carcinoma (author's transl)].

Animal experiments at the Nat. Cancer Inst. have established that only intra-tumorous application of BCG vaccine has a lasting immunotherapeutic effect on transplantable tumours. However, clinical observations have proved that BCG immunotherapy by the intra-tumorous route increases the incidence of complications, such as allergic reactions and generalized spread of BCG, to an unacceptable level. Ribi has produced a vaccine from mycobacterial fractions which is low in protein and which, as proved in clinical pilot studies in cases of melanoma and cancer of the breast, is so well tolerated that it can be injected into the tumour. Since bronchogenic carcinoma is in the majority of cases inoperable, but, on the other hand, can be reached directly via the bronchoscope or the perthoracic route a pilot study with the Ribi vaccine was started in patients with lung cancer. The preliminary results are reported.

BCG Vaccine↗
PubMed1978

Glucan: attempts to demonstrate therapeutic activity against five syngeneic tumors in guinea pigs and mice.

Animals with established syngeneic tumor transplants were treated with glucan to study the therapeutic potential of this agent under well-defined experimental conditions. The tumors used were a guinea pig hepatoma, 2 murine fibrosarcomas, a murine melanoma, and a murine adenocarcinoma. All tumors were syngeneic to the host. Living BCG, administered directly into guinea pig tumors, cured all animals, whereas glucan, administered under the same conditions, had no significant antitumor activity. Neither BCG nor glucan, when administered iv, was active against the guinea pig hepatoma. An emulsion prepared with endotoxin, a fraction of mycobacteria related to cord factor, and mineral oil when administered intratumorally was also effective in treatment of line 10 tumor. A similar emulsion, in which glucan was substituted for endotoxin, was inactive, intralesional, ip, or iv administration of glucan was ineffective against the murine tumors. Previous reports of glucan-induced activity against a B16 murine melanoma were not confirmed. BCG was tested against the 2 murine fibrosarcomas and, when given either intratumorally or iv, was found to be effective against one of them.

Animals↗
PubMed1978

Intratumor chemoimmunotherapy with mitomycin C and components from mycobacteria in regression of line 10 tumors in guinea pigs.

Intratumor chemotherapy with the use of mitomycin C and/or immunotherapy caused regression of line 10 carcinomas in strain 2 guinea pigs and resulted in development of tumor-specific immunity. The immunotherapeutic preparation consisted of oil-in-water emulsions containing Mycobacterium cell walls or residues of cell walls termed cell wall skeletons. The latter preparations were combined with trehalose dimycolate, which was isolated by microparticulate chromatography from whole cells of mycobacteria. Reducing mitomycin C to a single intratumor injection of 50 microgram produced little necrotizing effect and a mean tumor regression rate of 17%. Intratumor immunotherapy 1 day after treatment with 50 microgram of mitomycin C resulted in regression of 90% of the treated tumors as compared to mean regression rates of 30 to 50% for immunotherapy alone. In addition, chemoimmunotherapy was more effective than either chemotherapy or immunotherapy alone in producing regression of relatively large, as well as smaller, tumors.

Animals↗
PubMed1977

Immunotherapy of a guinea pig hepatoma with living BCG: a frozen liquid and a lyophilized preparation are equally active.

A freeze dried preparation of BCG with a low ratio of living to dead organisms (LV) was compared to a frozen liquid preparation with high viability (HV) for its ability to eradicate established dermal tumors and microscopic lymph node metastases in guinea pigs. The cure rate achieved by the intralesional injection of LV-BCG did not differ significantly from that of HV-bcg when similar numbers of viable organisms were injected.

Animals↗
PubMed1976

Immunotherapy with nonviable microbial components.

Structural components of microorganisms have been studied for immunopotentiating effect with the aid of transplantable (line 10) tumors in syngeneic guinea pigs. Microbial components were associated with oil droplets, suspended in Tween-saline, and injected intralesionally. BCG cell walls, given in this way, produced regression and cure of 50-60% of established tumors, as did viable BCG. Lipid extraction markedly reduced the tumor-regressing potency of cell walls, but P3, a trehalose mycolate present in the extract, restored full activity to the cell wall residue. P3 alone was nonsensitizing and had no antitumor activity, but it enhanced the latter property of various other microbial products. For example, the cure rates produced by cell walls of M. tuberculosis, M. bovis, M. phlei, or M. smegmatis were enhanced from 20-60% to as much as 90% by addition of P3. P3 also conferred antitumor activity on products from unrelated microbes, such as cell walls of E. coli, and in combination with endotoxins from rough Re mutant salmonellae, it produced cure rates of up to 93%. These results suggest that P3 is essential to the immunopotentiating activity of mycobacteria and that it may be broadly applicable in immunotherapy of cancer with microbial agents.

Animals↗
PubMed1976

Cutaneous granulomatous response to BCG cell walls with reference to cancer immunotherapy.

A chronic inflammatory response produced by cell walls of Mycobacterium bovis strain BCG associated with microscopic oil droplets (BCG CW-O) was studied with reference to the tumor-regressing ability of this preparation. When BCG CW-O was injected intradermally in the footpads of guinea pigs, intense inflammation developed at the site of injection and in the draining popliteal lymph node. This was characterized histologically as granulomatous inflammation. The intensity of the response was related to the dose of BCG CW-O. Cell walls without oil produced the same type of inflammation but much less in degree. Data are presented that demonstrate the immunological nature of this response and classify it as a cell-mediated immune reaction. Ramifications of this chronic inflammatory reaction occurring at the site of a tumor are discussed.

Animals↗