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Biomedical subjects

J L Cantrell

Publications and source records attributed to J L Cantrell.

At least 19 recordsLinked to original sources
PubMed1999

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities.

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

Adjuvants, Immunologic↗
PubMed1999

Synthesis and biological evaluation of a new class of vaccine adjuvants: aminoalkyl glucosaminide 4-phosphates (AGPs).

A novel series of acylated omega-aminoalkyl 2-amino-2-deoxy-4-phosphono-beta-D-glucopyranosides (aminoalkyl glucosaminide 4-phosphates) was synthesized and screened for immunostimulant activity. Several of these compounds enhance the production of tetanus toxoid-specific antibodies in mice and augment vaccine-induced cytotoxic T cells against EG.7-ova target cells.

Adjuvants, Immunologic↗
PubMed1989

Adjuvant effects of trehalose dimycolate on the antibody response to type III pneumococcal polysaccharide.

Treatment with trehalose dimycolate (TDM) increases the magnitude of the immunoglobulin M (IgM) antibody response of mice to type III pneumococcal polysaccharide (SSS-III). Such enhancement is demonstrable over a wide range of immunizing doses and does not require thymus-derived (T) cells to be elicited. Although young adult mice immunized with SSS-III do not usually make anti-SSS-III antibodies of the IgG1 and IgG3 classes, antibodies of one or both isotypes were produced after immunization and treatment with TDM and/or monophosphoryl lipid A (MPL); the additive nature of the effect produced by both TDM and MPL suggests that the two immunomodulators act by different mechanisms. TDM and MPL have different effects on the induction and expression of low-dose immunological paralysis, a form of unresponsiveness known to be mediated by suppressor T cells. The relevance of these findings to the modes of action of TDM and MPL is discussed.

Adjuvants, Immunologic↗
PubMed1989

Immunomodulatory activity of monophosphoryl lipid A in C3H/HeJ and C3H/HeSnJ mice.

Treatment with nontoxic monophosphoryl lipid A (MPL) derived from a polysaccharide-deficient, heptoseless Re mutant of either Salmonella typhimurium or Salmonella minnesota R595 enhanced the immunoglobulin M (IgM) anti-type III pneumococcal polysaccharide (SSS-III) antibody response of C3H/HeSnJ mice. Such an adjuvant effect was not observed in lipopolysaccharide-nonresponder C3H/HeJ mice. Nevertheless, C3H/HeJ spleen cells produced a weak mitogenic response to both preparations of MPL in vitro, and C3H/HeJ mice showed a significant increase in serum IgM levels without an increase in numbers of splenic IgM-secreting plaque-forming cells after in vivo treatment with MPL. A significant increase in serum IgG3 levels was accompanied by a transient decrease in serum IgG1 levels in C3H/HeSnJ mice given MPL; such non-antigen-specific polyclonal effects were not observed in C3H/HeJ or in athymic nu/nu mice. Since the enhanced antibody response to SSS-III has been attributed to the inactivation of suppressor T cells by MPL and since suppressor-T-cell activity is demonstrable in both C3H/HeSnJ and C3H/HeJ mice, these findings imply that (i) the suppressor T cells of C3H/HeJ mice are refractory to inactivation by MPL and (ii) some of the polyclonal and mitogenic effects produced in C3H/HeJ mice are due to the direct action of MPL on B lymphocytes.

Adjuvants, Immunologic↗
PubMed1988

Ability of monophosphoryl lipid A to augment the antibody response of young mice.

Treatment with nontoxic monophosphoryl lipid A increased the magnitude of the immunoglobulin M (IgM) antibody response to type III pneumococcal polysaccharide in young (2- to 4-week-old) mice. This was accompanied by the appearance of significant numbers of IgG1- and IgG3- secreting antibody-forming cells in 4-week-old mice. These findings indicate that monophosphoryl lipid A can be used as an adjuvant to improve the immunogenicity of poorly immunogenic antigens in young, immunologically immature animals.

Adjuvants, Immunologic↗
PubMed1988

Inactivation of suppressor T-cell activity by nontoxic monophosphoryl lipid A.

Treatment with nontoxic monophosphoryl lipid A (MPL), which was derived from a polysaccharide-deficient, heptoseless Re mutant of Salmonella typhimurium, was found to inactivate suppressor T-cell activity, as evidenced by a decrease in the degree of low-dose immunological paralysis expressed and an increase in the magnitude of the antibody response to type III pneumococcal polysaccharide. The effects produced, which could not be attributed to the polyclonal activation of immune B cells by MPL, were dependent upon the dose of MPL used, as well as the time when MPL was given relative to low-dose priming or immunization with type III pneumococcal polysaccharide. Neither amplifier nor helper T-cell activity was decreased by treatment with the same, or larger, doses of MPL. The significance of these findings to the use of MPL as an immunological adjuvant or an immunomodulating agent is discussed.

Adjuvants, Immunologic↗
PubMed1985

Salmonella typhimurium mitogen induces proliferation of human B lymphocytes.

The maturation of human B lymphocytes can be described as a sequence of activation, proliferation, and differentiation into immunoglobulin-secreting cells. A variety of mitogens which are T cell dependent or independent have been employed to study this process. These moieties generally induce B-cell activation and proliferation followed by differentiation, making the study of initial events difficult. This study characterizes the mitogenic activity of Salmonella typhimurium mitogen (STM), a protein fraction of S. typhimurium. Glass-nonadherent peripheral blood lymphocytes were rosetted with affinity-purified rabbit anti-human F(ab')2-coupled ox erythrocytes and separated on a Ficoll-Hypaque gradient. This population of B lymphocytes, when cultured in dilutions of STM showed dose-dependent proliferation by [3H]thymidine incorporation. Maximal proliferation occurred on Day 7 using STM at 100 micrograms/ml (control, 5692 +/- 1704 cpm; STM, 58,541 +/- 5655 cpm). On Day 7 the percentage of blast cells by Giemsa stain was 14 +/- 4% in control cultures and 52.5 +/- 8.7% with STM. ELISA quantitation of IgG and IgM in culture supernatants revealed no secretion above unstimulated controls. When B lymphocytes were enriched by a negative selection technique, significant proliferation was not observed. STM is a novel B lymphocyte mitogen which induces proliferation but not activation or differentiation of human B lymphocytes into immunoglobulin-secreting cells.

B-Lymphocytes↗
PubMed1985

Synergistic effects of combination sequential immunotherapies in a murine ovarian cancer model.

The antitumor effects of Corynebacterium parvum in a murine ovarian teratocarcinoma model depend upon a sequential activation of neutrophils and macrophages within the peritoneal cavity. We studied the sequential administration of biological response modifiers that independently activate each phase of the response. Tumor-challenged mice treated by i.p. injection of a pyridine-extracted fraction of cell-free Propionibacterium acnes (PA-PE, 1400 micrograms) demonstrated prolonged survival in less than 20% of the cases. An i.p. injection of a detoxified Salmonella endotoxin (DSE) preparation (150 micrograms) had no effect on tumor outgrowth. However, i.p. treatment with PA-PE (1400 micrograms), followed by 150 micrograms of DSE 1 day later, resulted in long-term survival (greater than 100 days) in 40 to 60% of mice. This antitumor effect was only evident when PA-PE was administered first (before DSE) and optimal when DSE was administered 24 h after PA-PE. The synergistic antitumor effect could be duplicated when tumor-challenged mice were first treated i.p. with peritoneal polymorphonuclear leukocytes, elicited by injection of PA-PE, and then treated with DSE 18 h later. These data indicate that appropriately timed injection of biological response modifiers with complementary effects can result in a synergistic prevention of tumor growth.

Animals↗
PubMed1984

Influence of fine structure of lipid A on Limulus amebocyte lysate clotting and toxic activities.

We examined the relationship between the fine structure of lipid A and the toxicity of endotoxin or lipopolysaccharides as measured by the Limulus amebocyte lysate (LAL), rabbit pyrogenicity, chicken embryo lethal dose, and dermal Shwartzman reaction tests. Lipid A and lipid A-like compounds obtained from deep-rough mutants of Salmonella spp. and Escherichia coli had a wide range of structural variations. These compounds included native lipopolysaccharides, diphosphoryl and monophosphoryl lipid A's, and lipid X (a monosaccharide). The LAL test was positive for all lipids tested with lysates from Travenol Laboratories and from Associates of Cape Cod (2.9 X 10(3) to 2.6 X 10(7) endotoxin units per mg), except for O-deacylated and dephosphorylated lipid X, which were negative. The Mallinckrodt lysate gave negative tests for lipid X. In the rabbit pyrogenicity and chicken embryo lethal dose tests, only native lipopolysaccharide and diphosphoryl lipid A's were judged toxic. The Shwartzman reaction was positive for a specific purified diphosphoryl lipid A (thin-layer chromatography-3 fraction) but negative for the purified monophosphoryl lipid A (also a thin-layer chromatography-3 fraction). These results show that the LAL test is not a valid measure of all parameters of toxicity of a lipid A or lipid A-like compound and can yield false-positive results. However, these findings are not in conflict with the widespread use of the LAL assay for pyrogens in the pharmaceutical industry since a good correlation exists between LAL results and pyrogenicity when undegraded endotoxin is evaluated in parallel assays.

Animals↗
PubMed1984

Immunotherapy with biochemically dissociated fractions of Propionibacterium acnes in a murine ovarian cancer model.

The antitumor effect of two strains of Propionibacterium acnes (PAI and PAII) and chemically derived fractions from the whole bacterial cell were studied using a murine ovarian teratocarcinoma (MOT) model. When injected i.p. in high doses (700 to 1400 micrograms/mouse), both strains produce survival of a significant proportion of tumor-bearing mice (30 to 90%). On a weight to weight basis, however, PAI was significantly more effective than PAII. PAI and PAII were extracted using pyridine, which yielded four fractions, i.e., pyridine-extracted strains PAI and PAII (PA-PEI and PA-PEII, respectively) which are composed of the cell wall material extracted by pyridine, and the residues of PA-PEI and PA-PEII (PA-RI and PA-RII, respectively) which are composed of the residue material following the chemical extraction. The chemical composition of PA-PEI was different from that of PA-PEII (the latter had proportionately three times as many carbohydrates and one-third of the protein content of the former) and so were their antitumor properties in the MOT model. PA-PEI had markedly reduced antitumor effect when compared to the untreated cell on a per weight basis. Furthermore, curability was only seen when using a high dose (1400 micrograms/mouse). By contrast, the cell wall components extracted by pyridine from PAII (PA-PEII) had powerful antitumor effects, i.e., greater than 50% of mice given 1400-micrograms injections survived. The material contained in PA-PEII was further fractionated on the basis of its organic solubility in chloroform:methanol solvent. The water-soluble and solvent-insoluble fractions retained most of the antitumor effects of PA-PEII, while the water-insoluble and solvent-soluble fractions were only moderately effective, suggesting that the active moiety(ies) was associated with the nonlipid components of this fraction. Both residue fractions (PA-RI and PA-RII) were as effective on a per weight basis in controlling the growth of 10(5) tumor inoculum as were whole untreated cells. However, periodate oxidation of PA-RI resulted in complete loss of its antitumor effects. When surviving mice that had no evidence of tumor persistence following a tumor challenge (10(5) MOT cells) and i.p. treatment with PA were subsequently rechallenged with 10(4) tumor cells, survival was significantly prolonged, as compared to tumor-challenged (10(4) MOT) naive mice. In addition, 10 to 20% of these rechallenged mice had complete eradication of the tumor inoculum (no evidence of disease for greater than 120 days).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Structural requirements of endotoxic glycolipid for antitumor and toxic activity.

Endotoxic glycolipids extracted from the polysaccharide heptose-less Re mutant of Salmonella typhimurium were hydrolyzed with alkaline and acid reagents. Treatment with hydroxylamine caused the liberation of all O-ester linked fatty acids and resulted in abrogation of the toxicity (lethality to chick embryos) and ability to regress tumors (line-10 tumors in strain 2 guinea pigs). Treatment with dilute sodium hydroxide caused partial removal of O-ester linked fatty acids without loss of these activities. Toxicity and tumor-regressive potency were retained after removal of 2-keto-3-deoxyoctonate (KDO) by exposing the glycolipids to sodium acetate solution at pH 4.5. The majority of the glycolipids of the endotoxic extracts were rendered non-toxic but retained antitumor activity when hydrolyzed with boiling 0.1 N hydrochloric acid, which split KDO and glycosidic phosphate from the glycolipid molecules. Non-toxic glycolipid fractions possessing antitumor activity were separated from the acid hydrolysate by means of preparative thin layer chromatography. It was concluded that glycosidic bound phosphate and at least a portion of the fatty acids of the lipid A moiety are essential for toxicity, but that this phosphate is not an essential structural feature for tumor-regression activity.

Animals↗
PubMed1982

Biological and immunological properties of Coxiella burnetii vaccines in C57BL/10ScN endotoxin-nonresponder mice.

Vaccines prepared from Formalin-killed whole cells of Coxiella burnetii (Ohio strain) or from chloroform-methanol residue (CMR) and extract (CME) of such cells were examined for biological and immunological properties in male C57BL/10ScN endotoxin nonresponder mice. Vaccines containing killed whole cells induced a high incidence of gross pathology, as evidenced by liver necrosis, significant splenomegaly, and significant hepatomegaly in mice. The degree and onset of these pathological changes were directly and inversely proportional, respectively, to the dosage of killed organisms administered. Conversely, no splenomegaly, hepatomegaly, or liver necrosis were observed in mice inoculated with CMR or CME. Moreover, killed whole cells were lethal for mice at dosages of 150 to 1,200 micrograms, whereas no deaths were seen in animals given 1,200 micrograms of CMR. In addition, antibodies against phase I and phase II antigens of C. burnetii were detected in the sera of mice inoculated with either whole cells or CMR. Enhanced blastogenic response of splenic lymphocytes was observed when animals were vaccinated with killed whole cells and CMR but not with CME. Moreover, 80 to 90% of mice inoculated with 300 micrograms of the CMR were protected against a lethal challenge of viable rickettsiae, whereas only 50% of the animals given 300 micrograms of killed whole cells were protected. Treatments with CME were essentially without value, since no antibodies were detectable and no significant protection was elicited. Collectively, these results show that, although killed whole cells induced immunity in C57BL/10ScN mice, they induced deleterious tissue reactions, whereas CMR, which also induced immunity, was essentially nondeleterious, based on the parameters employed. These observations suggest that the chloroform-methanol-extractable component(s) is implicated in the deleterious tissue reactions and that the phase I and II antigens may not be involved in the induction of the pathology observed in C57BL/10ScN mice.

Animals↗