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Biomedical subjects

A W Wheeler

Publications and source records attributed to A W Wheeler.

At least 37 records · Page 2Linked to original sources
PubMed1988

Immunological properties of chemically produced fragments of rye grass pollen extract.

Two fragment pools, one of MW greater than 10,000 and the other of MW between 1,000 and 10,000, were prepared by the sequential treatment of rye grass pollen extract with cyanogen bromide (cleavage at Met-X) and 2-nitro-5-thiocyanobenzoic acid (cleavage at X-Cys). Electrophoretic analysis of the two pools showed that none of the major components of the whole extract remained intact. Characterisation of the two fragment pools by radioimmunoassay showed that whilst they both lost the ability to bind to human anti-rye IgE antibodies, they largely retained their reactivity towards both human and mouse anti-rye IgG antibodies. In addition, the higher molecular weight pool retained its ability to stimulate extract-specific T cells, after accessory cell processing. This separation of the immunological properties of rye grass pollen extract by chemical cleavage is seen as a basis for the development of novel immunotherapy agents.

Animals↗
PubMed1988

Induction of allergen-specific T cells by conjugates of N-formyl-methionyl-leucyl-phenylalanine and rye grass pollen extract.

A conjugate of the biologically active peptide N-formyl-methionyl-leucyl-phenylalanine and rye grass pollen extract (F-MLP/rye), previously shown to react with rye grass pollen extract-specific T cells, induced the formation of allergen-specific T cells in mice. Lymph node cells prepared from mice immunized with either native extract or F-MLP/rye gave an enhanced response to unmodified rye grass pollen allergens in vitro. Syngeneic spleen macrophages were able to present the unmodified allergens to T cells obtained from both groups of mice causing their proliferation in vitro. Conjugation of the peptide into the extract brought about an extensive reduction in its reactivity with grass pollen-specific human IgE, and a loss of its ability to induce specific IgG antibody in guinea-pigs. A state of delayed hypersensitivity specific for rye grass pollen extract was produced in guinea-pigs by immunization with either the F-MLP/rye or unmodified extract. It is concluded that conjugates such as F-MLP/rye or other T' allergoids could be used as probes to investigate whether changes in T cell activity are important in immunotherapy.

Allergens↗
PubMed1988

Retained T-cell reactivity of rye grass pollen extract following cleavage with cyanogen bromide and nitrothiocyanobenzoic acid.

Rye grass pollen extract was fragmented by sequential treatments with cyanogen bromide and 2-nitro-5-thiocyanobenzoic acid, and a fraction containing fragments of molecular weight greater than 10,000 Mr was isolated. The in vitro reactivity of the extract with specific IgE was extensively reduced by fragmentation. Less reduction in activity was shown either by skin testing or by inhibition of an extract-specific IgG-binding assay. Reactivity with, and ability to induce, extract-specific mouse T cells were retained by the fragment preparation, and the ability to cause transformation of lymphocytes from atopic donors was unchanged. Fragments did not induce extract-specific IgG antibody in mice, were unable to stimulate the production of T-helper cells which could collaborate in an adoptive cell-transfer system, and did not induce delayed hypersensitivity reactions in guinea pigs. The possibility that such T-cell-reactive modified allergens (T'allergoids) might be used to stimulate selectively T-cell subsets and, therefore, could be used to advantage in immunotherapy is discussed.

Animals↗
PubMed1988

Induction of T-helper cell activity by fragments of rye grass pollen extract produced by digestion with chymotrypsin.

Rye grass pollen extract was digested by chymotrypsin to produce fragments with a molecular weight below 10,000, as demonstrated by polyacrylamide gel electrophoresis. Chymotryptic fragments did not react with either human or mouse IgG antibodies specific for rye grass pollen, nor did they induce an antibody response in mice with specificity for the parent extract. However, macrophage-presented fragments retained the ability to react with rye-specific T cells in a lymphoproliferation assay. Furthermore, these fragments induced the development of splenocytes capable of supporting dinitrophenyl specific antibody production. This implies that the fragments still react with, and induce, rye grass pollen extract-specific T-helper cells. The possibility that such fragments might have potential for use in immunotherapy for the specific treatment of allergy is discussed.

Adjuvants, Immunologic↗
PubMed1987

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. V. By intranasal administration.

Serum IgE antibody responses were generated in mice by intranasal exposure to grass pollen extract. Primary IgE responses were suppressed by the concomitant intranasal administration of a conjugate of polysarcosine and pollen extract which has been shown to be a potent tolerogen when given parenterally. Partial suppression of boosted IgE responses was observed when the conjugate was applied intranasally with a secondary challenge of unmodified extract. The data suggest that clinical schedules of intranasal application of tolerogenic conjugates can be devised to bring about specific IgE suppression.

Administration, Intranasal↗
PubMed1987

Immunogenicity in guinea pigs and tolerance in grass pollen-sensitive volunteers of enteric-coated grass pollen allergens.

An acid-insoluble, methacrylic acid, methyl methacrylate copolymer (Eudragit L-100) was used to give an enteric coating to a grass pollen extract in order to protect it against gastric degradation. Substantial protection against the degradative effects of simulated gastric secretion was demonstrated using this preparation which was well tolerated by grass pollen-allergic volunteers. The enteric-coated allergen induced a greater secondary antibody response than did an aqueous presentation when administered orally to guinea pigs which had been primed previously by subcutaneous injection. This result indicates that an effective hyposensitisation regimen could consist of a short series of initial parenteral injections, followed by an oral course of the protected allergen.

Acrylic Resins↗
PubMed1987

T cell reactivity of conjugates of N-formyl-methionyl-leucyl-phenylalanine and rye-grass pollen allergens.

Conjugates of rye-grass pollen extract and N-formyl-methionyl-leucyl-phenylalanine were prepared using an activated form of the tripeptide. Introduction of the peptide into the extract brought about an extensive reduction of reactivity with grass-pollen-specific IgE, as measured by RAST inhibition. Despite this loss, guinea pig alveolar macrophages and murine splenic macrophages readily presented the conjugates to T lymphocytes specific for grass pollen allergens and caused their proliferation in vitro.

Animals↗
PubMed1987

Oral hyposensitisation with enteric-coated allergens as extension therapy following a basic subcutaneous course of injections.

We investigated in grass-pollen-sensitive adults the efficacy and safety of a therapeutic hyposensitisation regimen consisting of a basic pre-seasonal course of tyrosine-absorbed glutaraldehyde-modified grass pollen extract (Pollinex), followed by oral extension treatment using encapsulated, particulate, enteric-coated grass pollen allergen. The daily recorded symptom scores both of these patients and of others treated with complete basic and extension courses of Pollinex indicated that both sets of patients had fared better during the grass pollen season than control patients who had received only the basic Pollinex injections.

Administration, Oral↗
PubMed1986

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. III. Activity in vitro.

Conjugates of poly-N-methylglycine (polysarcosine) and grass pollen allergen extracts, which have been previously shown to suppress murine IgE responses, were examined for their ability to modify lymphocyte activity in vitro. Allergen-specific T lymphocytes obtained from Balb/c mice gave a reduced response to syngeneic accessory cells pulsed with conjugates of polysarcosine-allergen compared with the response found using equivalent concentrations of native extract. Pretreatment of accessory cells with either polysarcosine or polysarcosine-allergen conjugates did not impair their subsequent ability to present grass pollen extract to immune T cells. Incubation of allergen-specific spleen cells with polysarcosine-allergen conjugates, but not with polysarcosine or allergen alone, resulted in specific cell-mediated suppression which significantly reduced proliferation in vitro. This activity was sensitive to treatment of cells with anti-T-lymphocyte antisera plus complement. Spleen cells obtained from animals immunised with allergen and taken 21 days after intravenous treatment with polysarcosine-allergen conjugates, a regimen that suppressed IgE antibody production, did not proliferate in the presence of grass pollen extract and failed to suppress a secondary lymphoproliferative response in vitro. Spleen cells obtained from similarly treated animals 3 days after the final polysarcosine-allergen injection responded to pollen extract in culture and, additionally, impaired a secondary response. The results suggest that the reduced IgE response found in animals treated with polysarcosine-allergen conjugates may be due, in part, to the generation of a short-lived antigen-specific T cell suppression.

Allergens↗
PubMed1986

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. IV. Suppressive activities in established IgE model systems.

Conjugates of poly-N-methylglycine (polysarcosine) and grass pollen extracts, previously found to be capable of suppressing immature IgE antibody responses in mice, were shown to be highly effective at inhibiting the capacity of immune splenocytes to produce a secondary response in sub-lethally irradiated recipient animals. Anamnestic IgE responses in mice primed without adjuvant were also suppressed, but the effects were modest and of short duration. The predictive value of murine models for selecting clinically appropriate specific IgE suppressive agents and treatment schedules that might be successfully employed for clinical use are discussed.

Allergens↗
PubMed1985

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. I. Preparation of poly-(N-methylglycine)/grass pollen extract conjugates using 4-(methylmercapto)phenyl-succinimidyl succinate as coupling reagent.

A procedure utilising the latent activating potential of the 4-(methylmercapto)phenyl ester group has been developed for the controlled, reproducible preparation of macromolecular conjugates. This ester, as part of a succinyl-bridging group, was used to couple the water-soluble, amino acid polymer, poly-(N-methylglycine) (polysarcosine), via its N-terminal secondary amine, with the nucleophilic components of the aqueous extract of a mixture of grass pollens. The products exhibit a reproducible, antigen-specific suppressive effect on the in vivo synthesis of IgE in mice.

Allergens↗
PubMed1985

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. II. Suppressive activities in adjuvant-induced IgE responses.

Treatment with conjugates of polysarcosine and grass pollen allergen extracts efficiently suppressed the induction of IgE responses in mice. The suppressive activity was shown to be allergen-specific and required covalent linking of the polysarcosine. Inhibitory effects could be overcome by booster injections of native allergen when these were given 3-4 weeks after treatment with conjugates. Administration of conjugates had only marginal effects on established IgE responses. The variance of these results with those of other studies on IgE suppression and the suitability of murine models for investigating reaginic antibody suppression are discussed.

Adjuvants, Immunologic↗
PubMed1985

Differential suppressive influence of intranasal application of rye grass pollen extract on IgE antibody production in the mouse.

Serum antibody responses to a ubiquitous aero-allergen, rye grass pollen extract, have been monitored in BALB/c and BD1 mice following intranasal and parenteral administration. Parenteral treatments were shown to trigger antibody production while topical administration of low doses of allergen extract preferentially suppressed reaginic antibody production. However, higher doses of extract administered to the respiratory tract were found to induce the formation of IgE antibody. Thus in mice antigen administered intranasally can influence the immune response in a qualitatively different manner to parenteral exposure.

Agglutination Tests↗
PubMed1984

Adjuvant properties of hydrophobic derivatives prepared from L-tyrosine.

The capacity of various N-acyl, O-acyl, amide and ester derivatives of L-tyrosine to promote the induction of antibodies to grass pollen extracts has been studied in guinea pigs. Antibody production was generally found to be enhanced when these derivatised materials were used as adsorbate vehicles compared with either L-tyrosine or simple aqueous presentations. Increases in alkyl chain length were found to parallel increased adjuvant activity. Unlike L-tyrosine, however, these hydrophobic materials tended to produce tissue lesions in experimental animals at concentrations which displayed apparent adjuvant advantages.

Adjuvants, Immunologic↗
PubMed1982

l-Tyrosine as an immunological adjuvant.

A series of experiments has been carried out to investigate the adjuvant properties of the amino acid L-tyrosine in laboratory animals. Adsorption of various allergenic materials to L-tyrosine was found to enhance the induction of IgG antibodies, but no unusual propensity to stimulate IgE antibody or delayed hypersensitivity was observed. Administration of the amino acid at a site remote from the allergen was found not to augment antibody production. This, together with evidence of reduced bioavailability of the tyrosine-adsorbed allergen, suggested that the adjuvant activity observed resulted from a short-term depot effect.

Adjuvants, Immunologic↗
PubMed1978

A comparative study of an aqueous grass pollen extract and glutaraldehyde-treated grass pollen-tyrosine adsorbate in the treatment of pollenosis.

Hyposensitization therapy gave a subjective improvement in 84% of grass pollen-sensitive patients receiving an eighteen dose course of aqueous pollen extract (SDV) and in 69% of patients receiving a three dose course of glutaraldehyde-treated pollentyrosine adsorbate (Pollinex). Systemic reactions to treatment were considerably more frequent with the aqueous course, but virtually absent with the short adsorbate course, which seems therefore more convenient for the patient. The SDV treatment induced a more pronounced IgG antibody response both in patients and in guinea-pigs receiving the clinical dosage schedule. The Pollinex treatment showed a tendency to enhance the IgE antibody response in new patients.

Adult↗
PubMed1977

Chemical modification of crude timothy grass pollen extract. III. The effect of glutaraldehyde-induced aggregation on antigenic and immunogenic properties.

Timothy pollen extracts have been reacted with glutaraldehyde under conditions leading to different degrees of aggregation of the product. Aggregation tends to enhance the previously demonstrated effects of glutaraldehyde in that reactivity with human IgE antibody, and ability to induce IgE antibody in the Bordetella pertussis-treated rat, are further reduced. Ability to induce IgG antibody with specificity for unmodified extract is substantially retained in all aggregated products.

Aldehydes↗