Ragweed-sensitive Patients Research Articles

Innovation in immunotherapy

Innovation in immunotherapy

Local Induction of a Specific Th1 Immune Response by Allergen Linked Immunostimulatory DNA in the Nasal Explants of Ragweed- Allergic Subjects

Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS. Tissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-alpha and IFN-gamma mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry. RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+ cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNgamma-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged. AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals.

Amb a 1-immunostimulatory Oligodeoxynucleotide Conjugate Immunotherapy Increases CD4+CD25+ T Cells in the Nasal Mucosa of Subjects with Allergic Rhinitis

We have previously shown that short-course treatment with Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) before the ragweed season modifies the response of the nasal mucosa to allergen challenge in ragweed-sensitive patients by increasing Th1 cytokines and decreasing both Th2 cytokines and eosinophilia after the ragweed season. The effect of AIC immunotherapy on CD4+CD25+ T cell expression in the nasal mucosa is unknown. To determine the in vivo effect of short-course AIC immunotherapy on CD4+CD25+ regulatory T cells in the nasal mucosa of ragweed-sensitive subjects. 19 ragweed-sensitive patients with allergic rhinitis were randomly assigned to receive either 6 escalating doses of AIC (0.06-12microg; n = 12) or placebo (n = 7) at weekly intervals immediately before the 2001 ragweed season. Nasal biopsies were taken at baseline prior to immunization and again post immunization 24 hours after ragweed allergen challenge at the start and end of the ragweed season. The expression of T regulatory cells, IL-10 and TGF-beta was assessed at each time point by immunohistochemistry. The numbers of allergen-induced CD4+-, CD4+CD25+-, IL-10- and TGF-beta-positive cells in the nasal mucosa after AIC immunization before the ragweed season did not differ between the two groups. Repeat challenge after the ragweed season led to a significant increase in CD4+CD25+ cells in AIC-compared with placebo-treated subjects. A trend toward an increase in IL-10-positive cells in the AIC-treated group did not reach statistical significance. Short-course AIC immunotherapy increases CD4+CD25+ regulatory T cell infiltration in the nasal mucosa following allergen challenge after seasonal ragweed-pollen exposure.

Ocular Efficacy of a Novel, Enhanced Affinity Corticosteroid, Fluticasone Furoate∗ Nasal Spray, in Ragweed-Sensitive Patients ∗USAN-approved name

RATIONALE: Inconsistent results have been reported for the ocular efficacy of nasally administered corticosteroids in treating seasonal allergic rhinitis (SAR). This study evaluated the effects of a novel, enhanced-affinity corticosteroid, fluticasone furoate nasal spray (FFNS), on ocular symptoms caused by ragweed.

Amb a 1–immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response

Background Amb a 1–immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) is a novel immunotherapeutic compound consisting of purified Amb a 1 from short ragweed proteins covalently linked to an immunostimulatory phosphorothioate oligodeoxyribonucleotide. In sensitized animals AIC can stimulate an Amb a 1–specific T H1 response and decrease pulmonary reactivity to ragweed challenge. Clinical trials have documented reduced allergic response to AIC in comparison with licensed ragweed extract. Objectives We sought to determine the in vivo effect of short-course immunotherapy with AIC on eosinophilia and cytokine mRNA expression in the nasal mucosa of ragweed-sensitive patients. Methods Ragweed-sensitive patients with allergic rhinitis were treated with 6 escalating doses of AIC (0.06-12 μg, n = 28) or placebo (n = 29) at weekly intervals immediately before the 2001 ragweed season. Symptom scores and medication use were recorded for the 2001 and 2002 ragweed seasons for all patients. A subset of patients (12 receiving AIC and 7 receiving placebo) consented to have nasal biopsy specimens taken before immunization and before and after the first ragweed season. The preseason and postseason biopsy specimens were taken 24 hours after ragweed allergen challenge and compared with the initial unchallenged biopsy specimen to assess cytokine and inflammatory cell responses by using immunocytochemistry and in situ hybridization. Results AIC was safe and well tolerated by all patients. There was no difference between the AIC and placebo groups in the number of allergen-induced major basic protein–, IL-4–, IL-5–, or IFN-γ–positive cells in the mucosa in the first weeks after AIC immunization. On rechallenge and rebiopsy after the end of the 2001 ragweed season, however, AIC-treated patients had a significantly reduced increase in eosinophils and IL-4 mRNA-positive cells and an increased number of IFN-γ mRNA-positive cells compared with placebo-treated patients. No difference between treatment groups was observed in symptom scores or medication use during the first ragweed season. During the second ragweed season, however, there was a significant decrease in chest symptoms and a trend toward reduced nasal symptoms in the AIC-treated group. Conclusion Short-course immunotherapy with AIC can modify the response of nasal mucosa to allergen challenge by increasing T H1 cytokine production and decreasing T H2 cytokine production and eosinophilia. This modification was not immediate but was observed 4 to 5 months after completion of immunotherapy and seasonal ragweed-pollen exposure. The T-cell subset shift after immunization and seasonal exposure was followed by evidence of clinical efficacy in the second ragweed season without additional AIC immunizations.

Role of microbial toxins in the induction of glucocorticoid receptor beta expression in an explant model of rhinosinusitis.

Glucocorticoids (GCs) are the most potent agents currently available for relieving the symptoms of chronic rhinosinusitis. The pathogenesis and molecular basis of GC insensitivity in allergic rhinosinusitis are unknown. Studies done on patients with GC-insensitive asthma demonstrated an overexpression of GC receptor beta (GRbeta), an abnormal splice variant and an endogenous inhibitor of the classic GC receptor alpha. The mechanisms that induce the overexpression of GRbeta remain poorly understood. To study the role of Staphylococcus-derived enterotoxin in inducing GRbeta in a human explant model of rhinosinusitis. Nasal tissue was obtained from inferior turbinates of nonatopic and ragweed-sensitive patients. Tissue samples from nonatopic patients were incubated in the presence and absence of superantigen (SAg) of staphylococcal enterotoxin. In addition, tissue samples from ragweed-sensitive patients were incubated with and without ragweed allergen in the presence or absence of SAg. The expression of GRbeta was assessed by immunocytochemistry using a specific polyclonal antibody to GRbeta. SAg increased the expression of GRbeta in both atopic and nonatopic tissue. The highest increase in the expression of GRbeta occurred when atopic nasal tissue was incubated with both ragweed and SAg. SAg-induced GRbeta is an important modulator of steroid sensitivity in chronic rhinosinusitis.

Altered allergen binding capacities of Amb a 1-specific IgE and IgG4 from ragweed-sensitive patients receiving immunotherapy

The mechanisms for the effectiveness of allergen immunotherapy (IT) are not well understood. The binding potential for immunoglobulins is a function of both antibody concentration and affinity (K(A)). The purpose was to perform a cross-sectional preliminary study to investigate any differences in allergen-specific antibody affinity and concentration following ragweed immunotherapy by introducing a new concept of antibody binding capacity ([Ig] X K(A)). The binding capacity of allergen-specific IgE and IgG4 was determined for ragweed-allergic individuals undergoing ragweed immunotherapy and compared with the capacity of ragweed-specific IgE and IgG4 for allergic individuals not receiving immunotherapy. The mean binding capacity for IgG4 after long-term immunotherapy was 1.6 log units higher (P < .0001) than for individuals not receiving IT. The binding capacity for allergen-specific IgE was 1.2 log units lower following long-term immunotherapy (P < .0001) compared with individuals not receiving ragweed IT. We hypothesize that a primary effect of immunotherapy is to increase IgG4 binding capacity and concomitantly decrease IgE binding capacity.

Immunologic changes associated with allergen immunotherapy

Specific allergen injection immunotherapy is highly effective in selected patients with IgE-mediated disease, including respiratory allergy and venom anaphylaxis. Research in this area provides insight into the immunologic basis of allergic disease and may assist in the development of more highly targeted treatment. Immunotherapy reduces immediate allergen-induced symptoms and concentrations of inflammatory mediators, including histamine and prostaglandin D 2, in ragweed-sensitive patients. Similarly, nasal epithelial mast cell numbers are decreased. A characteristic feature of immunotherapy is its ability to inhibit late-phase responses. In the nose it is accompanied by a decrease in eosinophil numbers in lavage during late responses. Characteristic changes in serum immunoglobulins are found, with an initial increase in IgE followed by a blunting of seasonal increases in IgE in pollen-sensitive patients and a gradual decline in allergen-specific IgE levels over several years. This is accompanied by an increase in allergen-specific IgG (blocking antibodies), although neither appear to correlate closely with the clinical response to immunotherapy. One way in which immunotherapy may act is by modifying the T-lymphocyte response to subsequent natural allergen exposure. Studies in peripheral blood and within the target organ have demonstrated a shift in the balance of T-cell subsets away from T H2-type (producing particularly IL-4 and IL-5) in favor of a T H1-type T-lymphocyte response (with the preferential production of IFN-γ). Studies of the nasal mucosa before and after immunotherapy have demonstrated suppression of the late nasal response and increases in the numbers of cells expressing mRNA for IFN-γ. It is not clear whether this immune deviation is due to anergy of T H2/T H0 cells or increases in T H0/T H1 T-lymphocyte responses. An alternative may be amplification of suppressor CD8+ T cells, which may have a downregulatory effect. Novel approaches currently being explored include the use of T-cell reactive peptides, which might circumvent the risk of anaphylaxis, and the use of adjuvants such as IL-12 or mycobacterial vaccines to potentiate the effects of allergen in inducing immune deviation. (J Allergy Clin Immunol 1998;102:157-64.)

Neurochemical coding in the small intestine of patients with Crohn's disease.

There have been conflicting results regarding the effect of Crohn's disease on the neurochemical composition of the enteric nervous system. To examine the effect of Crohn's disease on the neurochemical composition of enteric nerve fibres and cell bodies using whole mount preparations of human ileum. Whole wall ileum from seven normal subjects and nine patients with Crohn's disease was used to investigate the neurochemical composition of neurones and nerve fibres in the myenteric plexus, circular muscle, and serosa layer of ileum using immunohistochemical techniques. Increased tyrosine hydroxylase, 5-hydroxytryptamine, and neuropeptide Y immunoreactivity was exclusively seen in the myenteric plexus. There was increased neurofilament immunoreactivity in the myenteric plexus and nerve fibres of the circular muscle layer, and thick bundles of immunoreactive nerve fibres in the serosa layer. Increased vasoactive intestinal polypeptide, nitric oxide synthase, and pituitary adenylate cyclase activating peptide immunoreactivity was seen in the myenteric plexus and nerve fibres of the circular muscle layer, and aggregates of inflammatory cells in the serosa layer of the afflicted segment of Crohn's ileum. In addition, there was a chaotic display of nerve fibres containing some of the neuroactive substances with a high frequency of enlarged varicosities in the myenteric ganglia and/or nerve fibres of the circular muscle layer of Crohn's ileum. Results show quantitative as well as qualitative changes in the neurochemical composition of enteric nerve fibres and nerve cell bodies of Crohn's ileum. These changes and the presence of nitric oxide synthase and peptides immunoreactive inflammatory cells in the serosa layer suggest that nerve-immune interactions may have a significant role in the process of the inflammatory changes seen in Crohn's ileitis.

The Effect of Cetirizine on Nasal Allergic Response

The effect of cetirizine on both early and late nasal allergic response was assessed in 15 ragweed sensitive patients. All patients were challenged before treatment and after 7 days of cetirizine 10 mg qd. Clinical assessments and measurements of mediators were performed at baseline, after positive challenge, 1 and 2 hours later, and repeated 7 and 8 hours later. There was a significant change (P &lt; 0.0001) in the early response threshold to ragweed challenges after cetirizine. There were early phase elevations of prostaglandin D2, leukotriene C4, and eosinophil cationic protein both pre and post-treatment. Late phase changes were difficult to detect, but a statistically significant rise of both prostaglandin D2 and histamine was diminished after cetirizine treatment. Cetirizine clinically inhibited the early response to nasal allergen challenge, but early mediators were not affected. An effect on the late phase could not be clearly demonstrated.

Antigenic relationship between mugwort and ragweed pollens by crossed immunoelectrophoresis.

Mugwort and ragweed pollens have been considered as important respiratory allergens in Korea. These two pollens are abundant in the air of Seoul from August through October. Many ragweed-sensitive patients have shown concurrent sensitivities to mugwort pollen. However the antigenic relationship between these two pollens has not been clarified. To observe the cross-reactivity between them, we developed polyclonal anti-mugwort and anti-ragweed antibodies by immunization on New Zealand white rabbits, and performed crossed immunoelectrophoresis(CIE) with two pollen extracts. Five precipitation lines were formed by mugwort and anti-mugwort antibody. One precipitation line was formed by ragweed and anti-ragweed antibody. There was no reaction from mugwort and anti-ragweed antibody, and from ragweed and anti-mugwort antibody. These results indicate that there is no cross-antigenicity between mugwort and ragweed pollens.

Allergenic cross-reactivity between Parthenium and ragweed pollen allergens.

Cross-reactivity of allergens from the pollen of the Compositae weeds, Parthenium hysterophorus (American feverfew) and Ambrosia (ragweed), in 2 groups of patients with different geographic distributions was studied. Parthenium-sensitive Indian patients, who were never exposed to ragweed, elicited positive skin reactions with ragweed pollen extracts. A significant correlation in the RAST scores of Parthenium and ragweed-specific IgE was observed with the sera of Parthenium and ragweed-sensitive Indian and US patients, respectively. RAST inhibition experiments demonstrated that the binding of IgE antibodies in the sera of ragweed-sensitive patients to short (W1) and giant (W3) ragweed allergen discs could be inhibited by up to 94% by Parthenium pollen extracts. Similar inhibition (up to 82%) was obtained when the sera of Parthenium rhinitis patients were incubated with ragweed allergen extracts. A dose-dependent proliferation of lymphocytes from a Parthenium-sensitive rhinitis patient with elevated levels of both Parthenium and ragweed-specific IgE was observed when incubated with Parthenium and ragweed pollen extracts. A 1.6-fold higher proliferation, however, was observed with Parthenium pollen extract at a concentration of 100 micrograms/ml. These results suggest that shared epitopes present on Parthenium and ragweed pollen allergens are recognized by both Indian and US patients sensitized by exposure to Parthenium and ragweed pollen, respectively. The high degree of cross-reactivity between Parthenium and ragweed pollen allergens suggests that individuals sensitized to Parthenium may develop type-I hypersensitivity reactions to ragweed and vice versa when they travel to regions infested with the weed to which they had not been previously exposed.

Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis

The objective of this study was to develop and test a health-related quality of life questionnaire for clinical trials in rhinoconjunctivitis. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was developed by asking patients to identify areas of their lives affected by rhinoconjunctivitis. The resultant RQLQ was tested for reproducibility, responsiveness and validity in a randomized, double-blind trial of regular versus 'as required' aqueous beclomethasone dipropionate (BDP) nasal spray in ragweed pollen-induced rhinoconjunctivitis. Eighty-five patients from previous rhinoconjunctivitis studies participated in the developmental survey. Sixty ragweed-sensitive patients, from previous trials and media notices, were enrolled in the clinical trial. Aqueous BDP (800 micrograms) nasal spray was administered regularly or 'as required' throughout the ragweed pollen season. The survey revealed that, in addition to local symptoms of rhinoconjunctivitis, patients experienced impairment of quality of life through systemic symptoms, sleep disturbance, practical problems, activity limitations and emotional problems. The RQLQ includes 28 questions related to these dimensions. Repeated administration of the RQLQ demonstrated good reproducibility. During the clinical trial, the RQLQ proved responsive in its ability to distinguish between regular and 'as required' medication use. Validity was shown by moderate to strong relations between changes in symptom diary scores and changes in RQLQ scores. In conclusion the RQLQ is likely to prove useful as a measure of health-related quality of life in clinical trials in both rhinoconjunctivitis and rhinitis.

T Cell Receptor Variable Gene Expression: Analysis in Ragweed-Sensitive Patients during Allergen Exposure

Four monoclonal antibodies (MAb) to V region determinants of the alpha/beta-chain of the T cell antigen receptor (TCR) were used, by cytofluorography, to detect discrete populations of peripheral blood T cells (PBT). Together they identify 10-15% of circulating CD3+ T cells. Each MAb is known to detect specific V regions of the beta-chain. Thus V beta 5 gene products are recognized by MAb C37, V beta 6 by OT145, V beta 8 by Ti3a, and V beta 12 by MAb S511. In previous studies, we found that the percentages of PBT detected by these MAb show little variation over time in normal individuals. In order to determine if there is a change in TCR V gene usage during an immune response to an environmental antigen, 12 atopic patients with known ragweed sensitivity by history and skin test were followed for a 6-month period encompassing the ragweed season. No shifts in V gene usage that could be correlated with the ragweed season were consistently observed. The patients could be arbitrarily divided into two groups: in group I little variation over time was observed in the T cell populations identified by the MAb used, while group II was characterized by marked variation of the same T cell populations over time. In group II individuals, the population of Ti3a+ T cells showed the most variation over time. Failure to observe shifts in PBT subpopulations, identified by expression of different TCR V regions, during exposure to an allergen to which an IgE response has been made may mean that such shifts do not occur or that they occur primarily at the tissue site of antigen exposure and not in the peripheral circulation or that they occur in T cell subpopulations not identified by the reagents used.

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. We conclude that maintenance treatment with large doses of mixed allergoid preparations maintains effective treatment when it is administered only four times per year.

Airway Hyperresponsiveness in Allergic Rhinitis: A Risk Factor for Asthma

In order to study whether the methacholine inhalation challenge could predict which patients with allergic rhinitis were at risk to develop asthma, we prospectively studied a group of ragweed-sensitive patients over a four to five year period. On the initial study, 16 of 40 patients (40 percent) were found to be hyperresponsive to methacholine. On the follow-up study, three of these 16 patients (19 percent) were found to have developed asthma from one and one-half to five years after the initial testing. Each had greater methacholine responsiveness on repeat study. The degree of methacholine hyperresponsiveness, judged by the PD20, could not predict which of the initial responders would develop asthma. Twenty-four (60 percent) of our patients showed normal responses to methacholine on initial study; none developed asthma and 88 percent remained nonresponders on repeat study. Our study shows that allergic rhinitis patients hyperresponsive to methacholine are at greater risk to develop asthma than those with normal bronchial challenges (p less than 0.05).

Allergic Reactivity of &lt;i&gt;Parthenium hysterophorus&lt;/i&gt; (Santa Maria Feverfew) Pollen: An Unrecognized Allergen

Parthenium hysterophorus (PH), a member of the Asteraceae, is a ubiquitous weed found in great profusion in the United States Gulf coast area. A plant survey carried out in Texas Gulf coast demonstrated that around Corpus Christi, PH is the most prevalent weed. We have studied known ragweed-sensitive patients living in Austin and Corpus Christi, by radioallergosorbent test (RAST) analysis for PH and Ambrosia psilostachya (AP; western ragweed). Nine of ten patients from Austin were RAST-positive to PH and AP; 8 of the 10 patients had positive scores to both pollen extracts. All of the 8 patients from Corpus Christi were positive to both PH and AP. The Austin group showed a significant correlation between AP and PH RAST scores while no correlation between RAST values was seen in the Corpus Christi group. RAST inhibition analysis in this highly selected population did reveal patients that had true sensitivity to PH pollen alone or who were sensitive to both PH and AP pollen. This suggests that in areas where it is highly prevalent PH pollen is an overlooked cause of allergic disease.

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.

Persistence of efficacy after a brief course of polymerized ragweed allergen: A controlled study

Immunotherapy with PRW has been demonstrated to be safe and effective. To determine whether the efficacy would remain in successive ragweed seasons without further therapy, a trial was conducted comparing PRW to histamine placebo therapy in patients that had received courses of PRW previously. Those patients were also compared to previously untreated ragweed-sensitive patients. In a double-blind fashion, 21 previously treated patients were treated before the 1982 ragweed season with four weekly injections of PRW therapy, whereas 21 previously treated patients were treated with four injections of placebo therapy. An additional control group of 21 previously untreated ragweed-sensitive patients received no injections. Daily symptom and medication score sheets were completed by patients each day of the ragweed season. Blocking antibody rose elevenfold with treatment ( p < 0.0001) in the PRW group. There was a statistically significant difference in symptom score mean between untreated patients (1007 ± 174) and previously treated patients whether they received supplemental injections (554 ± 180) ( p < 0.01) or whether they did not (650 ± 168) ( p < 0.03). In summary the efficacy of 15 injections of PRW immunotherapy persists at least several years without need for supplemental immunotherapy.

Studies of the mechanism of passive anaphylaxis in human airway smooth muscle.

This investigation was carried out to study allergic contraction of passively sensitized human airway smooth muscle in response to specific antigen challenge. We attempted to determine the role played by histamine, slow reaction substances (SRSs), and cyclooxygenase products in the mediation of this response in tracheal smooth muscle. Tissues were passively sensitized with serum from ragweed-sensitive patients (15 h, 4 degrees C). Subsequent challenge with ragweed antigen produced a slowly developing contraction. The peak contraction to a dose producing a maximal response was 37 +/- 6% of the carbachol maximum. Mepyramine (5 X 10(-6) M) did not alter the contraction. Methylprednisolone (2 X 10(-5) M) attenuated the response to antigen but had no significant effect on the contractile response to arachidonic acid. Indomethacin (5.6-28 X 10(-6) M) enhanced the peak antigen-induced contractions by 25 +/- 11% whereas 5,8,11,14-eicosatetraynoic acid (6.4 X 10(-5) M) selectively attenuated the antigen-induced contraction by 86 +/- 12%. Nordihydroguarietic acid (6-12 X 10(-6) M) attenuated both the antigen plus arachidonate induced responses. FPL-55712 (1-2 X 10(-6) M) antagonized the contractions to antigen. Compound 48/80 and goat antihuman immunoglobulin E produced similar slowly developing contractions in sensitized and in some nonsensitized tissues. These responses, except for an early component of the response to 48/80, were independent of histamine and were reversed by FPL-55712. These findings suggest that arachidonic acid metabolites mediate (slow reacting substances) and modulate (prostaglandins) allergic contraction of human airway smooth muscle while any histamine released contributes little or nothing to the contraction in the larger airways.