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Biomedical subjects

A W Wheeler

Publications and source records attributed to A W Wheeler.

At least 19 recordsLinked to original sources
PubMed2001

Safety evaluation of a glutaraldehyde modified tyrosine adsorbed housedust mite extract containing monophosphoryl lipid A (MPL) adjuvant: a new allergy vaccine for dust mite allergy.

A new allergy vaccine is currently under clinical evaluation for the prevention or relief of symptoms caused by specific housedust mites. It consists of a 50:50 mixture of the mite Dermatophagoides pteronyssinus and D. farinae protein derived from aqueous extracts of the mites which is chemically modified by glutaraldehyde and adsorbed onto L-tyrosine with addition of the immunostimulatory adjuvant, monophosphoryl lipid A (MPL) "Polymite". A specific preclinical safety testing strategy was developed to support clinical use and comprised single and repeat dose toxicity, reproduction toxicity and local tolerance studies. Dose levels of up to 0.5ml for the mouse and up to 1ml for both the rat and the rabbit were used. Overall, the product was shown to produce no toxicological findings of significance at levels greatly in excess to those proposed for clinical use. A not unexpected, but relatively minor, immunostimulatory effect was seen following repeated dosing (once weekly for 13 weeks) at 1ml per rat; the Polymite formulation also resulted in injection site reaction which can largely be attributed to the presence of tyrosine. No reproduction toxicity was found.

Adjuvants, Immunologic↗
PubMed2001

A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections.

BACKGROUND: We present data showing that a Th1-inducing adjuvant can reduce the number of injections required for allergy vaccination. Allergy vaccination is the only treatment for type 1 hypersensitivity that can alter the underlying disease process. A switch of specific T-cell activity from Th2 >Th1 to Th1 >Th2 is believed to be an important change seen after long-term vaccination therapy. An immunologic adjuvant that enhances such a switch could be used to reduce the number of injections required. This would improve compliance with the treatment and provide pharmacoeconomic advantages. Such an adjuvant is 3-deacylated monophosphoryl lipid A (MPL adjuvant, Corixa). METHODS: A multicentre, placebo-controlled, randomized, double-blind clinical study was performed with a new standardized allergy vaccine comprising a tyrosine-adsorbed glutaraldehyde-modified grass pollen extract containing MPL adjuvant. Four subcutaneous injections of the active product were given preseasonally to 81 grass pollen-sensitive subjects, and 60 received placebo injections (tyrosine alone). Diary cards were used to record symptoms and medication taken during approximately 30 days of the grass pollen season. RESULTS: There was a statistical advantage in favour of the active treatment for nasal (P = 0.016) and ocular (P = 0.003) symptoms and combined symptom and medication scores (P=0.013). Titrated skin prick testing revealed a significant reduction of skin sensitivity in the active group compared to placebo (P = 0.04). Grass-pollen-specific IgG antibody was raised by active treatment (P < 0.01). A rise in IgE antibody was seen in the placebo group during the season (P < 0.01). The first year's treatment rise of IgE was not seen in the active group, and no rise occurred during the pollen season. More local adverse events were seen in the active group. There was no difference in generalized adverse events. CONCLUSION: A new, well-tolerated allergy vaccine, incorporating a Th1-inducing adjuvant, MPL, was efficacious and after only four preseasonal injections produced antibody changes normally associated with long injection schedules. This may encourage wider application of allergy vaccination. The vaccine is now available in a number of countries as Pollinex Quattro.

Adjuvants, Immunologic↗
PubMed2001

A Th1-inducing adjuvant, MPL, enhances antibody profiles in experimental animals suggesting it has the potential to improve the efficacy of allergy vaccines.

BACKGROUND: Monophosphoryl lipid A (MPL) is a detoxified derivative of the lipopolysaccharide (LPS) moiety of Salmonella minnesota R595, which has retained immunostimulatory activities. MPL has been administered to many subjects in clinical trials as an adjuvant component of infectious disease vaccines and is currently a component of a licensed cancer vaccine, Melacine (Corixa Inc., Schering Plough). MPL has, in particular, been shown to promote Th1-type antigen specific responses. L-tyrosine is a depot adjuvant which is fully metabolisable and has been successfully employed in allergy vaccines for a number of years. METHODS: Mice were immunised with MPL adjuvant in conjunction with separate preparations of either ovalbumin or glutaraldehyde-modified ragweed pollen extract both coprecipitated with L-tyrosine. The specific antibody isotypes IgG1, IgG2a, IgG2b and also IgE were measured. Rats received booster injections of keyhole limpet haemocyanin (KLH) in conjunction with MPL adjuvant following priming with KLH in alum alone. KLH-specific antibody responses were measured. RESULTS: It was shown that a combination of L-tyrosine and MPL were synergistic in enhancing murine antigen specific IgG antibody responses without enhancing antigen specific IgE responses. Furthermore, this adjuvant combination promoted strong IgG2 antigen specific responses indicative of a Th1 directed response. In KLH sensitised rats, treatment with MPL was shown to prevent a secondary IgE antibody response when injected with booster injections of antigen. CONCLUSIONS: Immunisation of mice with two different antigens adsorbed to L-tyrosine induced a Th1-skewed primary response when in conjunction with MPL adjuvant which also generally enhances a specific IgG response. Incorporation of MPL adjuvant in the immunisation of rats prevented a secondary specific IgE response. These results suggest that the employment of this new adjuvant in clinical allergy vaccination formulations may result in an improved efficacy which could be utilised in various ways to improve compliance.

Adjuvants, Immunologic↗
PubMed1996

Design of an optimally-diagnostic skin test solution for diagnosis of sensitivity to timothy grass (Phleum pratense) pollen.

BACKGROUND: Although most of the common allergen extracts that are used for diagnosis of type 1 hypersensitivity are now well standardized, this gives no assurance that they are within the concentration range that gives the best chance of a true diagnosis. OBJECTIVE: The objective of this study was to identify the most appropriate concentration range of timothy grass pollen Phleum pratense extract to diagnose sensitivity to this pollen correctly through skin-testing. METHODS: Dilutions of a well-standardized extract were made and used to skin test "true' positive and "true' negative populations of subjects as identified by case history, challenge tests and radioallergosorbent test (RAST). Weal diameters were measured and the data were submitted to receiver operating characteristics (ROC) analysis. For any particular weal size cut-off, the optimal diagnostic concentration (ODC) range was thus calculated. RESULTS: A 3 mm weal diameter cut-off was chosen as an appropriate size for routine diagnosis. Therefore the ODC range at this diameter was used to establish a product target concentration and specification for formulation of the diagnostic reagent. This method of allergen extract standardization can lead to a true-biological unitage that can be used for labelling purposes. CONCLUSION: The optimum concentration range at which to formulate an allergen extract, in terms of an in vitro immunologically based assay, can be determined by carrying out ROC analysis of the results of clinical studies as described in this communication. Diagnostic units (DU), are now used by us for labelling of such final formulations which conveys the information that the product is at the most appropriate concentration for diagnosis.

Allergens↗
PubMed1993

Grass pollen specific antibody in the plasma of normal dogs.

An investigation carried out with healthy beagle dogs showed that their plasmas contained detectable levels of grass pollen specific IgG antibody, as measured by a radiometric assay involving the binding of IgG to radio-iodinated staphylococcal protein A. These samples did not, however, contain detectable homocytotropic-type antibodies specific for grass pollen extract.

Animals↗
PubMed1991

IgE-mediated sensitization to English plantain pollen in seasonal respiratory allergy: identification and partial characterisation of its allergenic components.

Characterisation by SDS-PAGE immunoblotting of plantain pollen extract showed that components of 16,000-20,000 M(r) were frequently reactive with IgE antibody in the sera of subjects with seasonal respiratory allergy. Other, more weakly IgE-binding allergens were seen in the range of 40,000-60,000 M(r). HPLC followed by RAST inhibition demonstrated that components of approximately 17,000 M(r) were also responsible for much of the IgE-binding activity of the extract. These components appeared to have pI values between 4.5 and 5.2. RAST inhibition showed that there were no common IgE-binding epitopes in grass pollen and plantain pollen extracts, indicating that skin test responses should not necessarily be interpreted in terms of cross-reaction. 82 subjects with a clinical history of seasonal, respiratory allergy were screened in a skin prick test survey. 28% were skin test positive to plantain pollen extract. The frequency of positive skin test reactions to plantain pollen extract was greater than that to Betula (23%) and Artemisa (16%), both which are considered to be important allergens. In a larger survey positive RAST scores to plantain pollen were given by 34% of sera from subjects with respiratory allergy. Plantain pollen sensitivity should therefore be considered during diagnosis of seasonal allergy.

Allergens↗
PubMed1991

Hyposensitization therapy of Parietaria-sensitive patients with a tyrosine adsorbed allergoid, Pollinex Parietaria (Bencard Parietaria).

Thirty patients suffering from allergy to Parietaria pollen were treated with either a new tyrosine-adsorbed allergoid of Parietaria judaica pollen (Pollinex Parietaria) or a commercially available alum-adsorbed extract (Alavac) as control. A reduced response to nasal provocation was seen in 7 out of 11 patients following treatment with Pollinex and 1 out of 10 after control treatment. 9 out of 11 and 3 out of 10, respectively, showed reduced skin test activity. Patients who received Pollinex tended to have fewer nasal symptoms during the pollen season. Pollinex induced larger increases in P. judaica-specific IgG antibody than did the control product. Side effects of therapy were similar between the two groups of patients. Pollinex Parietaria thus shows good potential for the control of allergy to Parietaria pollen.

Adult↗
PubMed1991

Pollinex Parietaria (Bencard Parietaria), a new allergoid for treatment of patients sensitive to Parietaria pollen.

Two matching groups each of eleven patients suffering from allergy to Parietaria pollen were treated either with tyrosine-adsorbed glutaraldehyde-modified extract of Parietaria judaica pollen (Bencard Parietaria/Pollinex Parietaria) or with alum-adsorbed pyridine-extract (Alavac). The side effects of therapy were similar in both groups and were mostly local in nature. Nasal symptoms were significantly less at the end of treatment in the group of patients treated with Pollinex. P. judaica-specific IgG levels were significantly higher in patients following treatment with Pollinex. The majority of patients in both groups showed reduced nasal and/or skin sensitivity following therapy as measured by provocation testing. The results indicate that Pollinex Parietaria is an effective vaccine for the treatment of immediate hypersensitivity to Parietaria pollen.

Adult↗
PubMed1990

Heterogeneity of a major allergen from olive (Olea europea) pollen.

Studies were carried out in order to confirm and extend knowledge of the physico-chemical properties of an allergenic material found in the pollen of the olive tree (Olea europea). The sera from 88% of patients who were sensitive to olive pollen contained IgE that reacted with a 19,000 Mr component and many also reacted to a 17,000 Mr band as shown by SDS-PAGE immunoblotting. A monoclonal antibody (OL-1) produced to the 19,000 Mr component also reacted with the 17,000 Mr band, and with bands at 21,000 and 41,000 under non-reduced conditions. HPLC separation followed by SDS-PAGE and immunoblotting of the fractions indicated that the allergen fraction from which the 19,000 and 17,000 components were derived had a mol. wt between 50 and 60 kD. Isoelectricfocusing followed by immunoblotting and development with (OL-1) indicated heterogeneity of the allergen with respect to pI values. Two of the strongest components of the six identified which reacted with (OL-1) had pIs of about 5.0 and 6.0 confirming the published data. The study therefore showed that olive pollen contains a number of allergenic components, with various mol. wts and pI values, with some epitopes in common, which may in the native state be bound together or aggregated.

Allergens↗
PubMed1990

Reactivity of mast-cell-bound IgE idiotypes with anti-idiotypic antibody: mediator release or inhibition of antigen-induced mediator release?

When anti-idiotypic antibodies specific for idiotopes on IgE antibodies react with mast-cell-bound IgE antibody, the reaction may be expected to lead either to mediator release or to inhibition of allergen-induced release. This study was carried out to determine which would occur. Anti-idiotype antiserum (anti-Ids) was raised in syngeneic mice by immunisation with affinity-purified DNP-specific mouse monoclonal IgE. Sera from these immunised mice and from a similarly immunised rabbit inhibited the binding of the monoclonal IgE to radio-iodinated dinitrophenylated (DNP) ovalbumin, whereas a high concentration of affinity-purified rabbit antimouse epsilon-chain-specific antibody was unable to inhibit even though it was shown to bind to the monoclonal IgE. The mouse anti-Ids did not give a positive passive cutaneous anaphylactic reaction in rats sensitised with high-titre grass-pollen-specific IgE-containing antiserum, whereas it gave a positive result in rats sensitised with the DNP-specific monoclonal IgE. Rabbit antimonoclonal antiserum and rabbit anti-epsilon-chain antibody both gave positive results in these two assays. The results indicated that anti-idiotypic antibodies specific for idiotopes on IgE antibody can react and release mediators from IgE-sensitised mast cells. The significance of this in view of the increased levels of anti-idiotypes that can occur during immunotherapy is discussed.

Animals↗
PubMed1989

Demonstration of human, rye grass pollen extract-specific, helper and suppressor stimulating activity of modified allergens by effects on in vitro hapten-specific antibody production.

An in vivo system is described in which penicilloyl antibody was produced from peripheral leucocytes of a grass pollen-sensitive patient who had received penicillin therapy, by challenge of the cells with penicilloyl-grass pollen extract conjugate. Incubation of these leucocytes with a number of modified preparations of grass pollen extract with various T-cell-stimulating properties was shown to affect penicilloyl antibody production. Both chymotryptically fragmented rye grass pollen extract and a conjugate of f met-leu-phe and rye grass pollen extract enhanced penicilloyl-specific antibody similarly to the enhancement induced by unmodified extract, though at high concentration some suppression was seen. A conjugate of polysarcosine and rye grass pollen extract, previously shown to cause antibody suppression in mice, was similarly suppressive for penicilloyl-specific antibody. The system therefore shows potential for the evaluation of the effects of modified allergen treatment on antibody levels via T-cell mechanisms.

Allergens↗
PubMed1989

Induction of polyclonal and monoclonal antibodies with a single allergen separated from birch pollen extract by SDS-PAGE and nitrocellulose blots.

A Gold staining allergenic band, Bet v 1, was excised from a nitrocellulose blot following SDS-PAGE of birch pollen extract. This was used to raise a polyclonal rabbit antiserum and monoclonal mouse antibodies specific only for the Bet v 1. The method offers practical advantages for the production of antibodies to individual allergens in complex extract mixtures, without laborious purification methods.

Allergens↗