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[Hyposensitization in pollinosis. Results of a 3-year controlled study with 2 depot-allergoid grass pollen extracts: aluminum hydroxide-adsorbed allergoid and tyrosine-adsorbed allergoid].

For controlled hyposensitization treatment over a period of three years 36 patients with confirmed grass pollen sensitization had been selected in 1986 and randomly distributed to receive preseasonal injection therapy: 23 patients were treated with an average of seven AGD (aluminium-adsorbed allergoid) injections, and 13 patients had received six TA (tyrosine-adsorbed allergoid) injections. Evaluation of the trial data collected during three years of preseasonal treatment showed the following results of tolerance and efficacy: Systemic side-reactions registered during therapy were only mild and transient and occurred in the average after 3% of the AGD injections and after 10% of the TA injections. Local reactions over 5 cm diameter were registered after 7% in the AGD group and after 9% in the TA group. Before therapy there was no significant difference (p greater than 0.05) between the groups; after three years of therapy the AGD injections had resulted in a mean net rise of specific IgG of 220% (significant, p = 0.001); during the same time, TA injections had resulted in a final net increase of 10% (not significant, p greater than 0.05). Both treatment forms did not lead to any statistically relevant changes of specific IgE values. After three years of hyposensitization treatment, patients of both groups had improved; but an advantage was documented for patients treated with AGD on the basis of scores for objective assessment as well as for registered symptom and medication scores.

Adult

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract.

Forty-five grass pollen-allergic patients were randomly assigned to three groups according to their skin test and RAST sensitivities and the severity of seasonal rhinitis. Eleven patients were treated with placebo (group 1), 19 patients (group 2) were treated with a six-mixed grass-pollen allergoid prepared by mild formalinization with a two-step procedure, and 15 other patients were treated with a standardized orchard grass-pollen extract (group 3). Because of a different immunotherapy schedule, only patients placed in groups 1 and 2 received the extracts in a double-blind fashion. Rush immunotherapy was performed in 3 to 6 days, and the maintenance dose was subsequently administered weekly for 4 weeks and every 2 weeks until the end of the grass-pollen season. During the season, a coseasonal treatment was administered. Systemic reactions occurred during the rush protocol in 36.8% of patients treated with allergoid and 20% of patients who received the standardized extract. Only patients treated with allergoid had systemic reactions during maintenance dose. The reactions observed with the standardized extract were more severe. Total doses of allergoid ranged from 2350 to 13,500 protein nitrogen units. Symptoms and medication scores during the peak of the season were analyzed. Patients treated with the standardized allergen had a significant reduction of the number of days of symptoms during the month of June (9.5 +/- 6.7 days; p less than 0.005) and of medication scores (1.3 +/- 1.4; p less than 0.01) compared to patients receiving placebo (19.4 +/- 8.1 days; medication score, 2.8 +/- 2.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid.

Specific immunotherapy is still widely used in grass-pollen allergy, but its side effects may limit its use. We tested the safety and efficacy of a formalinized high-molecular-weight allergoid prepared from a mixed grass-pollen extract with two injection schedules in a double-blind, placebo-controlled study. Eighteen patients received placebo, 19 received the low-dose schedule (maximal dose: 2000 PNU) and 20 received the high-dose schedule (maximal dose: 10,000 PNU). Only one patient presented a systemic reaction of moderate severity for a dose of 1200 PNU. Before the onset of the pollen season, patients had a nasal challenge with orchard grass-pollen grains, a skin test titration, and the titration of serum-specific IgG. Both groups of patients presented a significant reduction in nasal and skin sensitivities and a significant increase in IgG compared to placebo. Symptoms and medications for rhinitis and asthma were studied during the season, and both groups receiving allergoids had a significant reduction of symptom-medication scores for nasal and bronchial symptoms. There was a highly significant correlation between nasal symptom-medication scores during the season and the results of nasal challenges. High-molecular-weight allergoids are safe and effective.

Adolescent

Studies on allergoids from naturally occurring allergens. III. Preparation of ragweed pollen allergoids by aldehyde modification in two steps.

We have devised a new process for modifying heat-labile allergens, which employs a sequential "two-step" incubation at temperatures of 10 degree C and 30 degree to 32 degree C. This process was found to produce effective ragweed "allergoids" with low allergenicity and good immunogenicity, which makes them useful for the therapy of allergic humans. Modification with formaldehyde produced derivatives ("formallergoids") that were about 10-fold less allergenic in allergic humans (as measured by leukocyte histamine-release assay), and similarly or more immunogenic in guinea pigs, than glutaraldehyde-modified allergens ("glutarallergoids"). Further analysis by RAST inhibition showed that a ragweed formallergoid was sixfold less reactive than a glutarallergoid with a pool of human IgE antibodies. However, the formallergoid had retained the ability to induce a wide array of antibodies against native ragweed antigens, since rabbit anti-formallergoid serum was able to recognize at least 12 different ragweed antigens, including AgE. Gel-filtration experiments showed that both the formallergoid and glutarallergoid materials contained polymers having apparent molecular weights distributed around 260,000 and 230,000 daltons, respectively (approximate range 30,000 to 900,000 daltons). Our studies provide the immunochemical basis for the use of these allergoids in the therapy of allergic humans.

Aldehydes

Controlled evaluation of allergoid in the immunotherapy of ragweed hay fever.

Immunotherapy with ragweed allergoid administered in a clustered regimen, placebos in a clustered regimen, and unaltered ragweed extract (allergen) in a weekly regimen were compared in three groups of hay fever patients carefully matched for ragweed sensitivity. The allergoid and placebo comparison was performed double-blind and the unaltered ragweed extract comparison was single-blind. In terms of antigen E (AgE) equivalents, doses were about 50 times higher in the allergoid-treated group than in the allergen-treated group. Whereas there was no immunologic response to placebos, the allergoid regimen produced a more rapid serum IgG antibody response, with significantly higher posttreatment levels than those in the allergen regimen. Initial IgE antibody rises and subsequent slow declines were similar. Symptom-medication scores were similar in the two specifically treated groups and significantly less than scores reported by the placebo group (p less than 0.01). Due to an overestimate of the initial allergoid doses, systemic reactions occurred mostly in the early visits with allergoid treatment, whereas systemic reactions appeared late in the allergen treatment. The overall incidence was similar. In a second year, after 8 mo of no injections, a preseasonal booster regimen with both materials produced virtually no untoward reactions. During the period of no injections, IgG antibody declines were modest and, after boosters, IgG antibody levels rose promptly. Clinical results in both groups were again excellent, with an advantage for allergoid.

Allergens

Studies on allergen and allergoid preparations from purified timothy (Phleum pratense) pollen extracts. II. Anaphylaxis studies in rats and histamine release from human leukocytes.

In vivo and in vitro allergenic activities of allergen and allergoid preparations from partially purified timothy pollen extract were measured in three different systems. In heterologous PCA titration, the allergen preparation was found to be 32 times more allergenic than the allergoid preparation. By intravenous chaled that treatment of allergen preparations with formaldehyde led to a preparation with the properties of an allergoid. In addition, it was found that the carbohydrate fraction of the refined allergen preparation of timothy a reduction in blood pressure. Thus, the allergen preparation was at least 50 times more potent in inducing systemic anaphylaxis in sensitized rats than the allergoid preparation. In the histamine release assay of grass-sensitive human leukocytes, approximately 1,000 times more allergoid protein than allergen protein was required to achieve 30% histamine release. Although to different degrees, in all three test systems in could be demonstrated that treatment of allergen preparations with formaldehyde led to a preparation with the properties of an allergoid. In addition, it was found that the carbohydrate fraction of the refined allergen preparation of timothy pollen decreased the blood pressure even in nonsensitized animals. The effect of this carbohydrate fraction on blood pressure was immediate but short-lived and immunologically nonspecific.

Allergens

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecular-weight preparations in rhinoconjunctivitis and asthma.

Specific immunotherapy with unmodified formalinized allergoids is effective in grass-pollen allergy, but systemic reactions have been observed. A high-molecular-weight formalinized allergoid (HMW-GOID) was fractionated by gel filtration, retaining molecules of greater than 85,000 daltons in the expectation of improving safety without sacrificing efficacy. HMW-GOID and unfractionated allergoid (GOID) had a similar allergenic activity assessed by RAST inhibition, but the HMW-GOID preparation was 65 times less reactive when it was tested by skin prick test than the GOID preparation. A double-blind, placebo-controlled study was carried out in grass pollen-allergic patients with placebo (14 patients), GOID (15 patients), and HMW-GOID (13 patients). An additional group of 18 patients was treated by a rush schedule with a standardized orchard grass-pollen extract. A similar mean cumulative dose was administered with both allergoids. The fractionated allergoid only elicited minor systemic reactions similar to reactions elicited by placebo, whereas 20% of patients treated by GOID and 5.5% of patients receiving the standardized extract had a severe systemic reaction. For rhinitis, conjunctivitis, and asthma, the HMW-GOID and the standardized extract had a similar efficacy, significantly greater than placebo. GOID was less effective than the other two active treatments but was significantly more effective than placebo treatment for asthma and conjunctivitis.

Adolescent

Double-blind, placebo-controlled immunotherapy with a high-molecular-weight, formalinized allergoid in grass pollen allergy.

Specific immunotherapy is effective in grass pollen allergy with standardized extracts and formalinized allergoids; but systemic reactions are not uncommon. A high-molecular-weight (greater than 85,000 daltons), formalinized allergoid was investigated in a double-blind, placebo-controlled study to assess its safety and efficacy. Twenty patients received a placebo and 39 the allergoid using a rather aggressive protocol. Five patients developed a mild and transient systemic reaction with high doses of allergoid and one had a more severe reaction requiring treatment. Nasal challenges performed with orchard grass pollen grains showed that the threshold number of grains eliciting nasal symptoms was significantly (p less than 0.01) greater in the treated group. This group had significantly (p less than 0.01) less nasal symptoms during the season and specific IgG levels were significantly (p less than 0.01) elevated. There was a significant (p less than 0.01) correlation between nasal challenges and nasal symptoms during the season but no correlation between IgG and symptoms. There was no dose-dependent effect of allergoids.

Adolescent

[A comparative evaluation of the biological action of allergens and allergoids prepared from plant pollen by the double radial immunodiffusion method].

Antisera to allergens and allergoids prepared from timothy, orchard grass, birch and wormwood pollen have been obtained and used in the double radial immunodiffusion test. The preparations of the allergoid row have been found capable of inducing immune response in laboratory animals (rabbits). Both forms of pollen preparations, allergens and allergoids, have been shown to possess common antigenic determinants reacting with antibodies present in antisera to allergens and allergoids. The absence of identity in the ratio of manifestations of gel precipitation reactions for allergoid with respect to the initial forms of allergens of individual pollen preparation has been noted.

Allergens

Further evaluation of local intranasal immunotherapy with aqueous and allergoid grass extracts.

In a double-blind study, 45 grass-allergic patients received local nasal immunotherapy (LNIT) with either aqueous mixed-grass extract, formaldehyde-treated, mixed-grass extract (allergoid), or histamine placebo. Twenty-four patients received LNIT for a second successive year, and 21 patients received LNIT for the first year. The aqueous extract-treated patients had significantly lower symptom-medication scores than either allergoid- or placebo-treated subjects. There was no difference in symptom-medication scores in patients receiving allergoid and placebo treatment or in patients receiving 1 and 2 yr of LNIT. The aqueous extract stimulated a rise in serum grass-specific IgE. There was no serum or local antibody response after allergoid-extract treatment. Postseasonal rises in serum-IgE titers were observed in all three groups. These data suggest that LNIT with aqueous mixed-grass extract significantly reduces the symptoms of allergic rhinitis. The allergoid grass extract was ineffective in the second year of treatment. No cumulative effect of LNIT could be demonstrated in successive years of therapy.

Administration, Intranasal

Fractionation and immunological characterization of allergens and allergoids of Prosopis juliflora pollen.

Allergoids of Prosopis juliflora pollen were prepared by formalinization of crude allergen and glycoprotein. Fractionation of crude allergen and allergoids on Sephadex G-100 resulted in separation of proteins of varying molecular size and a glycoprotein of 81 to 13 KD. Allergoids prepared from the glycoprotein fractionated into two proteins of approximately 200 KD and more than 200 KD. Crossed immunoelectrophoresis indicated 12 and gel diffusion test 3 precipitating antigens incrude allergen extract; by these tests allergoids depicted 8 and 3 precipitin bands, respectively. The precipitin analysis showed heterogeneity of allergenic determinants and also variation in cross-immunogenicity of the formalinized derivatives. The skin prick and radioallergosorbent tests depicted greater activity of fractionated crude allergens than the allergoids. The above tests suggest altered and concealed antigenic determinants as result of formalinization of P. juliflora pollen which, however, showed reduced allergenic activity relative to the native allergen.

Allergens

Grass pollen allergoid. A 4-year follow-up study.

In an open comparative study with 31 grass pollen-allergic patients, two allergen extracts ('allergoid' extract/semi-depot extract) were examined. In the 1st year of treatment the allergoid group showed better results in relation to symptom score, drug consumption and IgG response, however, in the course of further treatment this difference was not evident anymore. Treatment was successful in both groups. A significant correlation between total antigen dose and IgG response was found. The better clinical results for the allergoid group in the first season after the 1st and 4th year of observation do indicate a better long-term therapeutic effect compared to the semi-depot group. This finding probably is due to the much higher antigen dose (4-fold) in the allergoid group.

Allergens

Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. II. Comparison between parameters assessing the efficacy of immunotherapy.

Specific immunotherapy is effective in alleviating symptoms in grass pollen-induced rhinitis, but there are no clear data demonstrating a correlation between symptom-medication scores and objective parameters. Twenty-five patients taking part in a double-blind, placebo-controlled immunotherapy with mixed grass pollen-formalinized allergoids were studied. All patients had the same investigations. Symptom-medication scores were significantly (p less than 0.005, Mann-Whitney U test) reduced in the treated group by comparison to the placebo-treated patients. Nasal challenges performed with threefold increasing numbers of orchard grass-pollen grains demonstrated that patients treated with allergoid tolerated a significantly (p less than 0.005, Wilcoxon W test) greater number of grains after treatment, whereas there was no mean difference in the placebo-treated patients. There was a significant (p less than 0.005, Spearman rank-correlation) correlation between nasal challenges and symptom scores during the season. The skin prick test end point was significantly (p less than 0.001, Wilcoxon W test) reduced after treatment in the allergoid-treated group and remained unchanged in the placebo-treated group. There was a significant (p less than 0.001) correlation between the skin prick test end point and symptom scores during the season. Serum grass-pollen IgG titrated by a solid-phase radioimmunoassay with Staphylococcus A protein was significantly (p less than 0.01, Wilcoxon W test) increased after treatment with allergoid, but there was no significant correlation between IgG titer and symptom scores during the season. Serum grass-pollen IgE increased (p less than 0.04, Wilcoxon W test) in the treated group but there was no correlation with symptom scores.

Adult

Frequency of booster injections of allergoids.

In 1982, 43 ragweed-sensitive patients receiving maintenance injections of full doses of ragweed allergoid were selected for a study of the immunologic and clinical efficacy of booster injections only four times a year. These patients had participated for 2 to 7 years as part of a trial of mixes of up to four allergoids to common pollens in the mid-Atlantic area tailored to each patient's skin test sensitivity. They were divided into a group (21 patients) to receive injections every 3 months and a group (22 patients) to receive injections about every 6 weeks (eight injections per year). Patients were rerandomized after 1 year so that half of each original group switched to the alternate treatment, and this program was continued until after the ragweed season of 1985. Thirty-four patients were still under study the last year. Doses, per injection, were 100 allergoid units (1 allergoid unit equals 100 PNU) of each allergen in the mixture. Symptom scores during the 8 weeks of each of the four ragweed seasons were not significantly higher in the 3-month treated group. IgG antibody levels to Amb a I (antigen E) were followed until early 1984 and were not significantly different in the two groups, even though the 6-week treated patients received a two times higher cumulative dose per year. Rates of local and systemic reactions (percent of injections eliciting reactions) were not different in the groups, which means that the 3-month treated group had about half as many reactions by virtue of taking half as many injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens

Biological characterization of a formulated allergoid from Dermatophagoides pteronyssinus.

A comparative study between the biological properties of the allergen Dermatophagoides pteronyssinus (Dp) and its formulated allergoid (DpHCHO) was performed. After immunizing rats with Dp or DpHCHO the serum level time course of IgE and IgG was determined by passive cutaneous anaphylaxis (PCA) and indirect-ELISA, respectively. The avidity for IgE (PCA and PCA-inhibition) or IgG (indirect ELISA and ELISA inhibition) and the ability to induce anaphylactic shock were also determined. Serum IgE pattern differs between Dp and DpHCHO while IgG levels were greater after DpHCHO. The allergoid has lost the ability to bind IgE while its avidity for IgG falls 5-6 times. The allergoid, but not the allergen, fails to induce anaphylactic shock. A schedule for assaying the biological characteristics of allergoids is presented.

Allergens

[A comparative immunochemical analysis of allergoids and allergens].

In comparison with allergens having protein fragments with a molecular weight not exceeding 110 kD, allergoids have been found to consist of larger fragments with a molecular weight of 10-150 kD. Allergoids have less charged components than initial allergens and less antigenic components. Allergoids retain their capacity for stimulating the production of antibodies, specific to all antigenic components.

Allergens

Specific immunotherapy with allergoids in atopic subjects, hyporeactive to other vaccines.

Allergoids comply with the therapeutic requirement to reach high doses of the injected allergen, since the modifications of the allergens cause a loss of allergenicity, though the immunogenicity is being retained. Considering that it is possible to use a starting dose 40 times higher in comparison with retard vaccines, we thought it very expedient to treat with allergoids 18 patients allergic to parietaria, and 12 patients allergic to grass pollen, who had shown no clinical improvement after immunotherapy, lasting for at least three years with retard vaccines. The therapeutic results obtained are the following: improvement in 66% of the parietaria allergic patients after the first year, and of the 72% in the second year, of the 75% of the grass pollen allergic patients after the first year and of the 83% in the second year. They can be interpreted as due to the fact that such patients are always poorly reactive to the doses of allergens commonly present in retard vaccines. On the contrary, they do react to allergoids, both due to the high amount of allergen administered, and to the fact that polymerization brings about a stronger epitopic expression matched by a higher immunogenic activity. Moreover, the data are also indicative for a good relationship between the antibody titer of antigen-specific blocking IgG and the clinical effectiveness valued by means of symptom and medication scores.

Humans

The clinical and immunologic efficacy of immunotherapy with modified ragweed extract (allergoid) for ragweed hay fever.

A double-blind study comparing formaldahyde modified ragweed allergen (allergoid) and placebo in the treatment of allergic rhinitis was carried out. Twenty ragweed-sensitive patients were studied, ten receiving 10,710 PNU of allergoid pre-seasonally and ten receiving placebo injections. Daily symptom score sheets were kept by each patient during August and September of 1983. A significant difference in average daily symptom scores (P = 0.01) between the two groups was noted. Significant differences were also observed in symptom scores for individual weeks during the ragweed season. Post-treatment allergen-specific IgG blocking antibody was significantly higher (P = 0.001) in the treatment group compared to pre-treatment levels and when compared to the control group (P = 0.01). No significant local or systemic reactions occurred. The results suggest that the dosage protocol used in this study is appropriate as an initial treatment schedule in clinical practice.

Adult