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PubMed1987

Treatment of massive haematuria with aluminous salts.

Fifteen patients with massive vesical haematuria were treated with a 1% aluminium potassium sulphate solution in sterile distilled water, using continuous intravesical lavage with a double channel catheter. The haematuria was caused by vesical tumours in 13 patients, radiation cystitis in one and transurethral resection in one. Immediate side effects were few and none were noted in the long term, as judged by randomised biopsies from vesical mucosa. A complete response was noted in 66% of the patients, partial response in 15% and failure in 20%. This treatment is recommended for intractable bleeding from radiation cystitis and bladder tumours.

Aged↗
PubMed1993

Psychological testing on schoolchildren before and after pollution of drinking water in North Cornwall.

The tap water supply in Camelford, North Cornwall and environs was contaminated by aluminium and other metals in 1988. Richmond tests were routinely given before and after the pollution and here scores are compared between 39 children from schools in the contaminated area and 64 children from Cornish schools outside the polluted area. The study was retrospective and it was not possible to determine whether or how much polluted water individuals had consumed. No differences were found between groups either before or after the pollution accident nor was there any evidence for any sub-group of the polluted group which had been affected. The limits of conclusions which can be drawn from data available are discussed.

Alum Compounds↗
PubMed1995

Generation of rubella virus-neutralising antibodies by vaccination with synthetic peptides.

Four short peptides from rubella virus proteins E1 and E2, predicted to contain B cell epitopes, were used to vaccinate BALB/c mice. Sera from peptide-vaccinated animals reacted with viral antigens in ELISA and three of the four induced virus-neutralising antibody (nAb) responses. Peptide PY4, in contrast to the others, induced IgG2a responses upon vaccination and stimulated spleen cells in vitro produced IFN gamma in the absence of IL-5. It was reasoned that vaccination with PY4 caused Th1 subset activation, the appropriate type of response for anti-viral immunity and hence the efficient neutralising antibody response. Presentation of peptide for vaccination proved to be as important as the sequence. Similar profiles of IgG1 and IgG2a were detected in the sera of mice vaccinated with PY4 in Freund's complete adjuvant or alum; however nAb responses were not found when alum was used.

Alum Compounds↗
PubMed2001

CpG ODN can re-direct the Th bias of established Th2 immune responses in adult and young mice.

Induction of an appropriate immune response is essential for successful immunization. For example, Th1 type immune responses are necessary for the control of intracellular infections whereas Th2 type responses are more useful for the control of extracellular infections. Immunostimulatory CpG ODN (oligonucleotides containing unmethylated cytosine and guanine dinucleotides in specific base contexts) act as potent adjuvants and have been shown to induce Th1 type immune responses with a number of different antigens. This study investigates the effect of CpG ODN on the Th bias of immune responses generated against the hepatitis B major surface antigen (HBsAg) in adult (6-8 weeks old) and young (<1 week old) BALB/c mice. It also investigates the potential of CpG DNA to reverse a pre-established Th2 response generated as an adult or as a neonate, following re-exposure to HBsAg in adult life. Both adult and young mice immunized with HBsAg/CpG ODN had a Th1 biased immune response (strong cytotoxic T-lymphocyte (CTL) induction, IgG2a>>IgG1). In contrast, mice immunized with HBsAg/alum had a Th2 type immune response (poor CTL, IgG1>>IgG2a). More importantly, when animals were immunized with HBsAg/alum and boosted with HBsAg/CpG ODN, the CpG ODN were able to re-direct the Th2 response pre-established by alum, whereas the animals receiving the primary immunization with HBsAg/CpG ODN and later boosted with HBsAg/alum maintained their Th1 bias, even after the boost with alum. These data suggest that CpG ODN have the ability to augment both humoral and cell mediated immune responses and override the Th2 bias created by alum, even in very young animals, which are known to have a Th2 biased immune system.

Adjuvants, Immunologic↗
PubMed2001

Priming of immune responses to hepatitis B surface antigen in young mice immunized in the presence of maternally derived antibodies.

Early vaccination is necessary to protect infants from various infectious diseases. However, this is often unsuccessful largely due to the immaturity of the neonatal immune system. Furthermore, maternally derived antibodies can interfere with active immunization. We have previously shown in young mice that immune responses against several different antigens can be improved by the addition of oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN). In this study we have evaluated immunization of newborn (1-7-day-old) BALB/c mice against hepatitis B surface antigen (HBsAg), with alum and/or CpG ODN, in the presence of high levels of maternal antibody against HBsAg (anti-HBs). Seroconversion rates and anti-HBs titers were compared to those induced by a HBsAg-expressing plasmid, since other studies had suggested DNA vaccines to be superior to protein vaccines in young mice with maternal antibody. HBsAg/alum/CpG ODN was superior to DNA vaccine in inducing HBsAg-specific CTL responses in young mice in the presence of maternally transferred anti-HBs antibodies. However, B cell responses to both HBsAg/alum/CpG ODN and DNA vaccines remained weak in the presence of maternally transferred anti-HBs antibodies.

Adjuvants, Immunologic↗
PubMed2002

Parenteral and mucosal prime-boost immunization strategies in mice with hepatitis B surface antigen and CpG DNA.

Synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG ODN) are potent adjuvants to protein antigens administered by parenteral or mucosal routes to BALB/c mice. To date, there have been no studies using combined parenteral/mucosal approaches with CpG DNA as adjuvant. In this study we evaluated different parenteral prime-mucosal boost and mucosal prime-parenteral boost strategies using hepatitis B surface antigen (HBsAg) alone or with different adjuvants: aluminum hydroxide (alum), cholera toxin (CT), CpG ODN. In addition, since CpG ODN has previously been shown to act synergistically with other adjuvants after parenteral or mucosal delivery, we also evaluated adjuvant combinations: alum+CpG ODN and CT+CpG ODN. The effects of adjuvant and administration strategy on systemic and mucosal humoral responses were measured, as well as cell-mediated immune responses (cytotoxic T lymphocyte activity). These results were compared to parenteral only or mucosal only strategies. Our findings demonstrate that parenteral immunization can prime for mucosal responses even when different lymph nodes were being targeted. HBsAg-specific immune responses (IgG in plasma, cytotoxic T lymphocytes) induced by parenteral prime could all be significantly enhanced by mucosal boosting and despite the fact that intramuscular immunization alone could not induce mucosal IgA, it could prime for a subsequent mucosal boost. In addition, the presence of adjuvant at time of boosting could influence the nature of subsequent immune responses (Th1 vs. Th2). Mice primed intranasally could have their systemic immune responses boosted with a parenteral administration and it was also possible to enhance mucosal responses induced by intranasal prime with an intramuscular boost.

Adjuvants, Immunologic↗
PubMed2002

The partially degraded lipopolysaccharide of Burkholderia cepacia and ornithine-containing lipids derived from some Gram-negative bacteria are useful complex lipid adjuvants.

The partially degraded lipopolysaccharide of Burkholderia cepacia (LPSdegr) and the ornithine-containing lipids were purified from some bacteria. The substances were developed as complex lipid adjuvants, because they have weak toxicity and are able to activate the immune systems of the living body. After various toxoid antigens such as pertussis toxoid, diphtheria toxoid and tetanus toxoid were mixed with the complex lipid adjuvants, the mixtures were administered to mice subcutaneously. Antitoxoid IgG antibody titers in the serum were measured several times over 3 months. The efficacy of the LPSdegr as adjuvant was almost as high as that of the ornithine-containing lipids, and it was almost equal to that of the aluminum hydroxide adjuvant (Alum), which is generally used as a vaccine adjuvant.

Adjuvants, Immunologic↗
PubMed1992

Impaired stimulation of anti-bovine serum albumin IgG antibodies by vaccine adjuvants in murine acquired immunodeficiency syndrome.

The effect of three adjuvants - alum, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), and liposomes - on the IgG antibody isotype response to bovine serum albumin (BSA), was determined in normal and LP-BM5 retrovirus infected C57BL/6 mice. Alum and MDP induced comparable levels of IgG antibodies in normal mice (predominantly IgG1 (greater than 90%)), whereas liposomes induced IgG1 (60%), IgG2a/b (30%) and IgG3 (10%) antibodies. IgG antibody levels using liposomes as adjuvant were five-fold higher than those observed with alum or MDP. Immunization after LP-BM5 infection significantly reduced the effectiveness of alum and MDP, IgG antibody levels being reduced by 80 and 90% at 3 or 7 weeks respectively. The adjuvant activity of liposomes was reduced by 55 and 65% when immunization was started 3 or 7 weeks post LP-BM5 infection. Boosting of pre-immune mice with BSA and alum, MDP or liposomes 3 weeks after LP-BM5 infection showed that, while the magnitude of the antibody response and isotype distribution was not affected, the persistence of the response was severely diminished compared to control, non-infected mice. The reduced immunoadjuvant activity correlated with a reduction in the frequency of splenic Thy1.2+/CD4+ T cells. These results demonstrated that liposomes were more effective than alum or MDP in inducing IgG antibodies, and that immunoadjuvant activity for prophylactic or therapeutic immunization for all 3 adjuvants was significantly impaired by retroviral infections.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

The effect of immunization on the response to P. gingivalis infection in mice is adjuvant-dependent.

AIM: Studies on vaccines against the periodontal pathogen Porphyromonas gingivalis have produced conflicting results, but no consideration has been given to the role of different adjuvants in these vaccines. We have previously shown that an intra-chamber challenge with heat-killed P. gingivalis was modified by immunization with different adjuvants. This study tested the hypothesis that different adjuvants in P. gingivalis vaccines would differentially modify the host response to a live P. gingivalis infection. RESULTS: Using P. gingivalis-infected subcutaneous chambers in mice, we show that vaccination with P. gingivalis in alum attenuated the pro-inflammatory cytokine levels at the site of infection, while the vaccine containing incomplete Freund's adjuvant did the opposite. Although both vaccines induced a similar humoral IgG response, P. gingivalis-induced abscesses were significantly smaller in the alum-adjuvant group. CONCLUSIONS: The results suggest that the immune response and the resultant protection to a P. gingivalis infection, in P. gingivalis-vaccinated mice, are adjuvant-dependent.

Adjuvants, Immunologic↗
PubMed1994

Effects of aluminum (III) and fluoride on the demineralization of bovine enamel: a longitudinal microradiographic study.

Longitudinal microradiography has been used to determine inhibiting effects of aluminum (III), Al, and fluoride on mineral loss from slices of bovine enamel exposed to a demineralizing solution 4 h daily for 35 days. Inhibitor treatment was 5 min four times daily. For the remaining time, the samples were immersed in a neutral calcium phosphate solution which allowed neither remineralization nor demineralization. This study indicates that a 1-mM (27 ppm) solution of Al in a 0.1-M lactate solution, pH 5, has an inhibitory effect on the in vitro demineralization of bovine enamel. Application of this solution alternating with 20 mM (380 ppm) fluoride gave the same total inhibition as treatment with 20 mM fluoride alone.

Alum Compounds↗
PubMed1984

Bronchial anaphylaxis in actively sensitized Sprague Dawley rats: studies on mediators involved.

Previous experiments have shown that SD rats actively sensitized to ovalbumin (OA) undergo bronchial anaphylaxis at intravenous challenge with a specific antigen. The inhibitory effect of antiallergic drugs in this experimental system and the relation of the response to serum reaginic antibody levels, depend on sensitization conditions (Dahlbäck 1981; Dahlbäck et al. 1982). The present experiments indicate that the main primary mediators of the respiratory anaphylaxis are serotonin and product(s) of the cyclooxygenase pathway of arachidonic acid metabolism. This is the case whether the animals are sensitized with 10 or 100 micrograms OA together with 100 mg alum and whether they are examined 2-3 or 5-6 weeks after sensitization. However, the bronchoconstrictory efficacy of exogenously added 5-HT varies with the immunization conditions of the animals: those given 100 micrograms OA together with alum are more reactive to 5-HT at intravenous challenge than animals given 10 micrograms AO and alum. Moreover, compounds known to affect the lipoxygenase pathway of arachidonic acid metabolism influence the bronchial anaphylactic reaction in different ways depending on immunization and test conditions. These data suggest that 5-HT and some not yet identified product(s) of cyclooxygenase/thromboxane synthetase are main mediators of allergen-induced bronchial anaphylaxis in the rat and that products of the lipoxygenase pathway play a minor direct role but may modulate the response.

Acetylcholine↗
PubMed1993

A new hypothesis for the mechanism of amyloid toxicity, based on the calcium channel activity of amyloid beta protein (A beta P) in phospholipid bilayer membranes.

Amyloid beta protein (A beta P) is the 40-42 residue polypeptide implicated in the pathogenesis of Alzheimer's disease (AD). We have reconstituted this peptide into phosphatidylserine liposomes and then fused the liposomes with a planar lipid bilayer. When incorporated into this bilayer, the A beta P forms cation selective channels capable of transporting calcium and some monovalent cations including cesium, lithium, potassium, and sodium. The channels behave in an ohmic fashion and single channels can be shown to exhibit multiple subconductance states. Hitherto, A beta P has been presumed to be neurotoxic, although direct demonstration of toxicity has proved elusive. On the basis of the present data we suggest that the ion channel activity of the polypeptide may be the basis of its neurotoxic effects.

Alum Compounds↗
PubMed1996

Direct measurement of cytokines (IFN-gamma, IL-4, -5, and -6) from organs after antigenic challenge.

A mouse in vivo model has been developed in which cytokines produced within the regional lymph nodes and other organs after an antigenic challenge were measured directly without the need of an in vitro reculturing step. Mice were subcutaneously (s.c.) immunized with antigens such as keyhole limpet hemocyanin (KLH) in aluminium hydroxide (alum) at the base of the tail. After defined periods of time lymph nodes, spleen, liver, and lung were collected and frozen. The organs were then homogenized (or sonicated), centrifuged, and the cytokine levels, for example, IFN-gamma, IL-4, IL-5, and IL-6 were determined by ELISA. It was found that injection of alum alone caused measurable cytokine production in draining lymph nodes, but inoculation of an antigen-alum mixture, such as KLH and dust-mite antigen (DMA), significantly increased in vivo cytokine production over that of alum alone. In the dose range tested there appeared to be an inverse relationship between the dose of antigen and cytokine levels. Thus, 0.1-microgram KLH induced more IL-4 in vivo than 10-micrograms KLH. Kinetic studies showed that for IL-4 and IFN-gamma, peak production occurred around days 5 and 6, respectively. Route of immunization and the dose of antigen were found to be very critical, in that injection of 10-micrograms DMA intraperitoneally induced significant levels of cytokines in the lung, while the same dose of antigen given at the base of tail, s.c., did not induce appreciable levels of cytokines in any organ tested. Cyclosporin A inhibited in vivo production of IFN-gamma, IL-4, and IL-5 by approximately 80%, but not that of IL-6. Surprisingly, dexamethasone enhanced the production of IL-6 while inhibiting all the other cytokines. In conclusion, these results suggest that direct determination of cytokines in the organs may provide an easy readout to assess differential effects of immunoregulatory molecules on the production of Th1- and Th2-type cytokines in vivo.

Alum Compounds↗
PubMed1995

Particle size studies for subcutaneous delivery of poly(lactide-co-glycolide) microspheres containing ovalbumin as vaccine formulation.

The primary objectives of the present study were to produce poly(lactide-co-glycolide) (PLGA) microspheres with different diameters, to characterize these microspheres which were loaded with a model antigen, ovalbumin and to evaluate the effect of microsphere particle size on the serum antibody levels following administration to mice. Four kinds of ovalbumin-loaded PLGA microspheres with different diameters (1.2, 3.5, 7.0 and 14.3 microns as mean volume diameter) were manufactured by a w/o/w emulsion/solvent evaporation method. Low loading percent (0.08%-0.25% w/w) and efficiencies (8-25% w/w) were observed. Examination using scanning electron photomicrographs showed smooth spherical particles. The in-vitro release of ovalbumin from microspheres showed an expected burst release with all batches and the extent of the burst release increased with decreasing diameters of spheres; PLGA microspheres with the smallest diameter (1.2 microns) showed an 80% burst release within one day. Approximately 10-60% of ovalbumin remained unreleased 30 days later. The single subcutaneous administrations of ovalbumin-loaded PLGA microspheres with different diameters to mice induced good antibody responses above ovalbumin saline negative controls at 3, 6, 9, and 12 weeks after inoculation. Especially, 0.16% ovalbumin-loaded PLGA microspheres having mean volume diameter of 3.5 microns exhibited the best immune responses with values greater than those obtained after inoculation with adjuvants such as complete Freund's adjuvant or alum as positive control. The strong adjuvant activity of PLGA microspheres as vaccine formulation was suggested.

Alum Compounds↗
PubMed2004

Promotion of B cell immune responses via an alum-induced myeloid cell population.

Exposure of naïve B cells to the cytokine interleukin-4 (IL-4) and/or antigen leads to a state of "priming," in which subsequent aggregation of major histocompatibility complex class II molecules induces the mobilization of calcium ions and cell proliferation. However, it is not clear how critical this priming is for immune responses or how it is normally induced in vivo. Injection of mice with the commonly used adjuvant alum led to priming of splenic B cells and to the accumulation in the spleen of a previously unknown population of IL-4-producing, Gr1+ cells. These cells and IL-4 were both required for in vivo priming and expansion of antigen-specific B cells, as well as for optimal production of antibody. These studies reveal a key role for a previously unknown accessory myeloid cell population in the generation of humoral immune responses.

Adjuvants, Immunologic↗