Peter S. Creticos

Peptide leukotriene release after antigen challenge in patients sensitive to ragweed.

Slow-reacting substance of anaphylaxis (composed of leukotrienes C, D, and E) is released in vitro by the interaction of antigen and IgE antibody on human mast cells and basophils. When we challenged ragweed-sensitive patients intranasally with pollen grains, their clinical response was significantly correlated with the release of the peptide leukotrienes (P less than 0.001). Nonallergic subjects had neither symptoms nor leukotriene release. The leukotrienes were released in a dose-dependent fashion, with a peak mean level of 827 +/- 234 pg per 0.1 ml of a 10-ml nasal wash. High-performance liquid chromatography revealed the presence of leukotrienes C, D, and E, suggesting that nasal cells or fluids had the ability to degrade leukotriene C enzymatically. The in vivo release of these potent inflammatory mediators after exposure to pollen suggests that leukotrienes may have an important role in human allergic reactions.

Ragweed Immunotherapy in Adult Asthma

BACKGROUND Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. METHODS We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. RESULTS During the observation phase, the mean (+/- SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 +/- 20 liters per minute in the immunotherapy group and 444 +/- 16 liters per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 +/- 16 liters per minute, vs. 453 +/- 17 in the placebo group [P = 0.06] during the first year, and 480 +/- 12 liters per minute, vs. 461 +/- 13 in the placebo group [P = 0.03] during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (P = 0.01) but did not differ in the two groups during the second year (P = 0.7). Asthma-symptom scores were similar in the two groups (P = 0.08 in year 1 and P = 0.3 in year 2). The immunotherapy group had reduced hay-fever symptoms, skin-test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. CONCLUSIONS Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.

Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy.

Challenge of the nasal mucosa of allergic subjects with specific allergen induces not only the expected sneezing and rhinorrhea, but also the appearance in nasal secretions of mediators commonly associated with activation of mast cells or basophils: histamine, leukotrienes, prostaglandin D2 (PGD2), kinins, and TAME ([3H]-N-alpha-tosyl-L-arginine methyl ester)-esterase. To determine whether specific immunotherapy alters mediator release in vivo, nasal pollen challenge was used to compare 27 untreated highly sensitive ragweed (RW)-allergic subjects with 12 similarly sensitive patients receiving long-term immunotherapy (3-5 yr) with RW extract (median dose, 6 micrograms RW antigen E). The two groups were equally sensitive based on skin tests and basophil histamine release. The immunized group had a diminished response as demonstrated by (a) the treated group required higher pollen doses to excite sneezing or mediator release; (b) significantly fewer subjects in the treated group released mediators at any dose (TAME-esterase [P = 0.005], PGD2 [P = 0.04]), and (c) the treated group released 3-5-fold less mediator (TAME-esterase [P = 0.01], and histamine [P = 0.02]).

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.

BACKGROUND Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. OBJECTIVE We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. METHODS Four hundred thirty-nine adults with grass pollen-induced ARC with or without asthma were randomized to once-daily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 standardized quality tablet, containing approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5-specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. RESULTS Relative to placebo, grass AIT treatment improved total combined scores by 20% (P = .005), daily symptom scores by 18% (P = .02), and RQLQ(S) scores by 17% (P = .02). Daily medication scores were improved by 26% and trended toward significance (P = .08). Phl p 5-specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (P < .001). Grass AIT treatment was safe and well tolerated. The majority of AEs were transient mild local reactions with no investigator-diagnosed grass AIT-related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). CONCLUSIONS Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen-induced ARC.

Dose response of IgE and IgG antibodies during ragweed immunotherapy

We studied the detailed dose-response relationship for ragweed (RW) antibody responses in 51 patients who received maximal-dose immunotherapy with crude RW extract. Serum RW-IgG and RW-IgE levels were determined by solid-phase radioimmunoassay at frequent intervals during initiation and maintenance of immunotherapy. Pretreatment RW-IgE ranged from 0.94 to 974 ng/ml (median 105); 45/51 patients had insignificant levels (less than 250 ng/ml) of RW-IgG. The maximal doses given ranged from 0.19 to 93.5 micrograms of RW antigen E per injection. All patients produced a significant IgG response (median peak 3462 ng/ml, range 689 to 24,395), and 46/51 had significant increases in IgE antibody (median peak 231 ng/ml, range 12 to 1528). A threshold dose was defined for each patients IgG and IgE response as that dose level which initiated a persistent increment in immunoglobulin to greater than or equal to 25% of pretreatment levels. The median threshold dose for IgE was 0.13 micrograms of antigen E, which was achieved in a median time of 42 days. The threshold dose for IgG was significantly higher (median 0.56 micrograms of antigen E; p = 0.001) and occurred significantly later (median 79 days; p = 0.003). Despite variability over 3 orders of magnitude, the thresholds for IgE and IgG responses were significantly correlated for individual patients (r = 0.487; p = 0.002). The maximum RW-IgE response occurred in a median of 107 days, after which IgE antibodies declined in 46 of 49 patients. The maximal IgG response occurred significantly later (median 245 days; p less than 0.001) and then plateaued or declined modestly. The doses required to achieve maximal IgE and IgG responses were significantly correlated (r = 0.638; p less than 0.001). The maximum IgG response was positively correlated with the maximal dose of RW antigen E received (r = 0592; p less than 0.001). In 28 of the 51 patients, the incremental rise in total serum IgE was more than twice that observed for RW-IgE at the time of the maximum response, suggesting a nonspecific effect of RW immunotherapy on total serum IgE levels. This discrepancy could not be accounted for by environmental stimulation from other known allergens, as assessed by skin testing, or by pretreatment levels of RW-IgE or total IgE. These observations indicate that the human IgE antibody response during high-dose RW immunotherapy is more sensitive to both stimulation and suppression by continuous allergen administration than is the IgG response.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity☆☆☆

We investigated the effect of immunotherapy (IT) on eosinophil (EOS) migration into the nasal cavity after nasal provocation with ragweed antigen and during seasonal exposure. In the first study, three groups of subjects participated: one group with no treatment (N = 19), one group with 10 months of IT, reaching maintenance at 2 micrograms of Amb a I (antigen E) (N = 15), and one group with 22 months of IT, reaching maintenance at 24 micrograms of Amb a I (N = 10). The percent of EOSs in nasal lavages performed during December before and 24 hours after nasal challenge with ragweed extract was determined. No significant difference between groups existed before challenge. The no treatment group demonstrated a significant increase in the percent of EOSs from 26% to 69.5% (p less than 0.008), whereas the treated groups demonstrated no significant change. In the second study, 45 patients were divided into four groups based on maintenance dose in micrograms of Amb a I and duration of treatment: (1) no treatment (N = 15), (2) 1 year at 2 micrograms (N = 13), (3) 2 years at 2 micrograms (N = 11), and (4) 3 years at 24 micrograms (N = 9). Nasal mucosal brushings were done during the ragweed season. A significantly smaller percentage of EOSs in 3-year IT-treated individuals was obtained compared to the control group (18 versus 8.4; p less than 0.04). The smaller dose of IT, regardless of duration, did not reveal a reduction compared to that in the no-treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of immunotherapy on the early, late, and rechallenge nasal reaction to provocation with allergen: Changes in inflammatory mediators and cells

We investigated the effects of immunotherapy (IT) on the early (ER), late (LPR), and rechallenge reactions (RCRs) to nasal challenge with antigen as well as on the cutaneous ER and LPR to intradermal skin challenge. Our expectation was that IT would have a preferential effect on the LPR, and our aim was to understand the mechanism. Twenty-one ragweed hay fever-sensitive subjects were treated with a moderate dose of antigen extract (maintenance dose of 1.94 micrograms of antigen E (Amb a I)) during a period of 8 months (total dose equivalent to 24 micrograms of antigen E), and 20 matched subjects received placebo injections in a double-blind manner. Both groups underwent identical nasal challenges and intradermal skin tests with ragweed-antigen extract both before (1985) and during (1986) IT. Symptom and medication diaries, recorded during seasonal exposure, and changes in specific serum IgE and IgG antibodies confirmed the efficacy of the administered IT dose. Between-group analysis revealed that IT significantly reduced the levels of histamine, TAME-esterase activity, and kinins, as well as symptoms of rhinorrhea and congestion generated during the ER to nasal challenge. Within-group paired analysis demonstrated ER, LPR, and RCR mediators and symptoms also to be reduced by IT. Surprisingly, the placebo-treated group demonstrated an increase in the ER. There was no decrease of the LPR without an antecedent decrease of the ER. IT did not clearly change the late cellular inflammatory response. In the case of skin challenge, IT significantly reduced the cutaneous ER. The reduction of the cutaneous LPR was more pronounced. We speculate that moderate-dose IT ameliorates seasonal symptoms of allergic rhinitis by reducing the ER, LPR, and RCR to antigen challenge but does not preferentially reduce the nasal LPR.

Role of human basophils and mast cells in the pathogenesis of allergic diseases

The role of human basophils and mast cells in the pathogenesis of allergic diseases has been analyzed. Purified human basophils and mast cells release several known mediators of allergic reactions, including histamine, sulfidopeptide leukotrienes, kinin-forming enzymes, and, in the case of the mast cell, PGD2. These same mediators are released in vivo after experimental challenge in the upper airways with either allergen or cold, dry air, a stimulus used to simulate exercise-induced bronchospasm. The appearance of mast cell mediators in vivo after such challenges further implicates mast cells in the pathogenesis of allergic diseases of the airways that occur as a result of exposure to allergen or physical stimuli. During the LPR after experimental challenge of the upper airways, the pattern of mediators released (i.e., histamine, leukotrienes, and others, but no PGD2) suggests that basophils may contribute to the LPR. Antiallergic drugs that prevent mediator release in vitro, such as antihistamines, also prevent the appearance of mediators in vivo, strengthening both the validity of the in vitro test as a model of the disease and the hypothesis that mediator release is an essential element of the disease process. A model discussing the pathogenetic mechanism is presented.

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults

BACKGROUND In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration. OBJECTIVES This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy. METHODS Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration. RESULTS During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred. CONCLUSIONS In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

Clinical aspects of allergic disease: A double-blind study of the discontinuation of ragweed immunotherapy

BACKGROUND Immunotherapy effectively treats the symptoms of allergic rhinitis and improves its pathophysiology. We studied whether the effects of immunotherapy on the early response to nasal challenge with antigen and seasonal symptoms persist after discontinuation. METHODS Twenty subjects with ragweed allergy who were receiving immunotherapy and who had nasal challenges performed before initiation of treatment were selected. The patients had been receiving maintenance therapy with aqueous ragweed extract at a dose of 12 microg of Amb a 1 equivalent for a minimum of 3 years, at which point they were randomized to receive either placebo injections or to continue with the maintenance dose. Nasal challenges were performed before and 1 year after randomization. Nasal challenges were monitored by counting the number of sneezes and measuring histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and kinins in recovered nasal lavages. In the same year symptom diaries were collected during the ragweed season. RESULTS The initial immunotherapy significantly reduced responses to nasal challenge in both groups. The group continuing to receive active treatment showed no significant changes from the response before randomization. In contrast, the group randomized to placebo treatment showed a partial return of histamine, kinins, and N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions and the numbers of sneezes. IgG antibodies to ragweed declined only in the group switched to placebo treatment. Seasonal rises of IgE antibodies to ragweed did not return during the first season after treatment was stopped. Symptoms reported during the ragweed season were not different between the groups. CONCLUSIONS One year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.