B. Lebel

Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species: II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts

The IgE response of patients only allergic to grass pollens differs from response of patients allergic to multiple-pollen species. The IgE immunoblots to orchard-grass pollens confirmed that polysensitized patients had more proteins revealed than patients only allergic to grass pollens. To determine if both groups of patients present a different response toward specific immunotherapy (IT), a double-blind, placebo-controlled study was performed in 70 patients. Patients receiving the active treatment had a rush IT with either a standardized orchard grass-pollen extract or with a standardized mixed-pollen extract prepared, depending on the sensitivity of the patients. The maintenance dose was defined as that dose effective in grass-pollen IT in previous experiments. The same equipotent maintenance dose was administered for all pollen species. Symptom-medication scores during the pollen season and nasal challenge with orchard grass-pollen grains demonstrated that grass pollen-allergic patients had a significantly improved efficacy by comparison to placebo treatment, whereas polysensitized patients had a nonsignificant improvement. Serum grass-pollen IgG was significantly increased after IT in both treated groups. This study demonstrate that the response toward specific IT differs in patients only allergic to grass pollens by comparison to polysensitized patients.

Correlation between symptoms and the threshold for release of mediators in nasal secretions during nasal challenge with grass-pollen grains

Nasal challenges with pollen grains represent one of the techniques of provocation. However, the clinical criteria of positivity are not clearly established. Nasal challenges with increasing numbers of orchard-grass pollen grains were performed in 60 patients allergic to grass pollens and 20 normal subjects. Before any challenge, the nose was washed three times with saline and then lactose, and 50, 150, 450, 1350, and 4050 orchard-grass pollen grains were insufflated into the nostrils until a symptom score of 5 was reached. This score was mainly based on major symptoms of allergic rhinitis, for example, rhinorrhea, nasal obstruction, sneezes, and to a lesser extent, on minor symptoms, such as pruritus, conjunctivitis, and pharyngitis. Nasal secretions were obtained after each challenge by lavage. Histamine was titrated by a radioimmunoassay with a monoclonal antibody against acylated histamine. Prostaglandin D2 (PGD2) was assayed with an enzyme immunoassay with a polyclonal antibody against PGD2 methoxamine. None of the normal subjects had a symptom score greater than 2; 55/60 patients had a positive challenge. The release of PGD2 was significantly (p less than 0.001, Kruskal-Wallis test) correlated with a symptom score of 5; 74.5% of patients had a significant release of PGD2 in nasal secretions. In contrast, although 58.2% of patients had a release of histamine in nasal secretions when the challenge was positive, the correlation with symptom scores was not significant. PGD2 in nasal secretions increased 3.7-fold after a positive nasal challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunotherapy with Fel d 1 peptides decreases IL-4 release by peripheral blood T cells of patients allergic to cats

BACKGROUND Cells producing a T(H2)-cytokine profile play an important role in the onset and maintenance of atopic diseases, and therefore specific immunotherapy is aimed to induce a switch to cells producing a T(H1)- or T(H0)-cytokine profile. Recently, a novel form of immunotherapy making use of synthetic peptides from the major cat allergen Fel d 1 has been developed, but its mechanisms of action are unknown. OBJECTIVES We examined the effects of immunotherapy with Fel d 1 peptides on the response to bronchial provocation tests (PD20FEV1) with a standardized Fel d 1 cat extract on Fel d 1-specific serum IgE and IgG levels and in vitro IL-4 and IFN-gamma production. METHODS Patients allergic to cats received 6 weekly injections of 7.5 micro(g) (low dose), 75 micro(g) (medium dose), or 750 micro(g) (high dose) of Fel d 1 peptides (25 patients) or a placebo (6 patients). RESULTS Six weeks after ending immunotherapy, posttreatment PD20FEV1 was not significantly different between the treated and placebo groups. However, in the medium- and high-dose groups there was a significant improvement between baseline and posttreatment days. IL-4 release was significantly reduced in the high dose-treated group (P <.005, Wilcoxon W test), whereas it was unchanged in the low or medium dose- and in the placebo-treated groups. In all groups, IFN-gamma, IgE, and IgG levels remained unchanged. CONCLUSION There was no correlation between the improvement of PD20FEV1 and the decrease in IL-4 production. These data suggest that peptide immunotherapy may act by shifting the Fel d 1-induced response of PBMCs in vitro from the T(H2)-like to the T(H0)-like phenotype.

Antiallergic activity of H1-receptor antagonists assessed by nasal challenge

Most oral drugs used for the treatment of allergic rhinitis are classified as H1-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H1-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insufflated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostaglandin D2 in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p less than 0.0023) and six when they were treated with terfenadine (p less than 0.01). Prostaglandin D2 release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H1 antagonists also possess antiallergic activities.

Different modulation by histamine of IL‐4 and interferon‐gamma (IFN‐γ) release according to the phenotype of human Th0, Th1 and Th2 clones

Histamine, an important inflammatory mediator in allergic diseases and asthma, has been reported to have modulator effects on T cells, suggesting that the bronchial microenvironment may regulate the function of resident T cells. We examined the effect of histamine on the release of the Th2‐associated cytokines IL‐4 and IL‐5 and the Th1‐associated cytokine IFN‐γ by 30 CD4+ T cell clones from peripheral blood or bronchial biopsy of one atopic subject. Based on the IL‐4/IFN‐γ ratio, the clones were ascribed to the Th2 (ratio >1), Th0 (ratio  0.1 and 1) or Th1 (ratio <0.1) phenotype. Histamine inhibited IFN‐γ production by Th1‐like cells (P<0.02, Kruskall–Wallis), especially from bronchial biopsy, but had no effect on IL‐4 release. Regarding Th0 clones, histamine inhibited IL‐4 production (P<0.02) in a dose‐dependent manner and slightly inhibited IFN‐γ production, but had no effect on Th2‐like cells. Histamine had a heterogeneous and insignificant effect on IL‐5 production. The H2‐receptor antagonist ranitidine completely reversed the inhibition of IL‐4 and IFN‐γ production, whereas the agonist dimaprit mimicked this effect. In contrast, H1‐ and H3‐receptor agonists and antagonists had no significant effect. These data demonstrate that histamine has different effects on IL‐4 and IFN‐γ release by T helper cells according to their phenotype via H2‐receptors. This study extends the immunomodulatory effects of histamine which may contribute to the perpetuation of airway inflammation in asthma.

Inhibition of mediator and cytokine release from dispersed nasal polyp cells by mizolastine

Background Mizolastine is a potent and selective H1‐receptor antagonist with antiallergic properties; in in‐vitro animal models, mizolastine was shown to inhibit 5‐lipoxygenase activity and to decrease the release of leukotrienes (LT) and tumor necrosis factor‐α (TNF‐α). This study investigated the effects of three concentrations of mizolastine (0.1, 1.0, 10 µM) on the release of LT (LTB4 and LTC4/D4) and prostaglandin D2 (PGD2) after stimulation by anti‐IgE, and on the spontaneous release of cytokines (TNF‐α and granulocyte/macrophage‐colony‐stimulating factor [GM‐CSF]), from dispersed cells obtained from surgically resected nasal polyps of patients with nasal polyposis.

Allergen-induced mediator release tests.

The diagnosis of allergic reactions in clinical practice is based on both clinical history and the determination of specific immunoglobulin E (IgE), either in the serum or on skin mast cells. However, for various reasons, identification of the causative factors is not possible in all the cases. Moreover, not all allergies are IgE‐dependent. In an attempt to find sensitive, specific and cost‐effective methods to investigate hypersensitivity reactions, in vitro tests were developed at a very early stage. Allergen‐induced mediator release assays analyze the mediator released from effector cells, mainly peripheral blood cells, when stimulated in vitro with serial dilutions of the putative allergens. Described initially as research tools, they could well become diagnostic tests. However, relatively few high quality reports have been published so far. In this review, we will detail allergen‐dependent histamine, tryptase, arachidonic acid metabolite, e.g. cysteinyl leukotrienes and 15‐hydroxyeicosatetraenoic mediator release tests.

Interleukins 1-beta, -8, and histamine increases in highly trained, exercising athletes.

PURPOSE Exercise-induced hypoxemia (EIH) in highly trained athletes is associated with an increase in histamine release (%H) during exercise. Certain cytokines, known as histamine-releasing factors, are capable of interacting with basophils and/or mast cells to cause the release of histamine. The aim of this study was to determine whether the increased histamine release in highly trained athletes is related to a high plasma level in interleukin-1 beta (IL-1beta), IL-3, or IL-8 in arterial blood. METHODS These parameters were measured in 11 endurance athletes (23.2 +/- 1.2 yr (mean +/- SEM)) known to develop exercise-induced hypoxemia and 11 control subjects (25.0 +/- 1.1 yr) at rest, during an incremental exhaustive exercise test, and at the fifth minute of recovery. RESULTS Histamine release increased between rest and maximal exercise in the athletes (P < 0.01), showing a strong correlation with EIH (r = 0.76, P < 0.01) and was unchanged in the controls. IL-3 plasma concentration was not altered with training and/or with exercise. Circulating IL-8 levels were not different between trained and untrained subjects at any testing level and increased at maximal exercise in both groups (P < 0.01). IL-1beta plasma levels were higher in athletes than in controls (P < 0.05) at each testing level and increased during exercise only in the athletes (P < 0.05). CONCLUSION An elevated concentration of IL-1beta in plasma and its association with increased IL-8 levels during exercise may partly explain the increase in %H associated with EIH in highly trained athletes. Histamine, IL-8, and IL-1beta releases during exercise reflect an inflammatory reaction, which is probably involved in EIH.

Spontaneous and non‐specific release of histamine and PGD2 by bronchoalveolar lavage cells from asthmatic and normal subjects: effect of nedocromil sodium

Mast cells have been implicated in the pathogenesis of allergic asthma but their role in non‐allergic asthma remains to be elucidated. The spontaneous and non‐specific release of histamine by suboptimal doses of calcium ionophore A23187 was studied in bronchoalveolar lavage cells obtained from nine asthmatic and seven healthy individuals. Bronchoalveolar lavage was performed with saline, and total cells were incubated without any secretagogue (spontaneous histamine release) or after addition of 1.25, 2.5 and 5 μm of A23187 for 30 min (net maximal release). Histamine was titrated by using a very sensitive radioimmunoassay using a monoclonal antibody against acylated histamine. The spontaneous release was similar in asthmatic (20.6±8.2%) and healthy individuals (17.4±8.4%). The net maximal release of histamine was significantly greater in asthmatic patients (28.1±17.4%) than in normal subjects (10.3±8.9%). The release of histamine was significantly correlated to the release of PGD2 measured by enzyme immunoassay using a polyclonal antibody against methoxamine‐PGD2 (Spearman rank test: 0.78, P<0.01). In eight subjects, the release of histamine by A23187 was studied in the presence of nedocromil sodium and it was observed that this drug significantly (P<0.05) decreased the net maximal release of histamine. This study shows that mast cells from asthmatic individuals have a greater releasability than those of normal subjects.

Experimental models in rhinitis

Nasal challenge with allergen or mediators is a useful model to understand the pathophysiology of allergic rhinitis. Some mechanisms have thereby been clearly clarified. Different methods have been proposed to mimic the natural allergen exposure and to measure the clinical and biological responses. Nasal challenges can also be used in clinical practice, mainly when there is a discrepancy between results of skin tests and in vitro or when occupational allergens are involved. Nasal challenges are also valuable to assess the efficacy of specific immunotherapy or some drugs.