Giorgio Ciprandi

Antiallergic drugs and the immune response. Interactions and possible clinical relevance.

Since the pharmacological treatment of allergic diseases is used in patients with alteration of the immune response due to atopy and possible concomitant infections, we have investigated the possible effects of such drugs as cromolyn, theophylline, ketotifen, oxatomide, astemizole, fenoterol, pirenzepine, and rosaprostol on the in vitro immune response, in order to obtain experimental data and, as a consequence, clinical conclusions. In a series of investigations by our group and other authors the following immunological parameters have been considered: T cell activation induced by different pathways (i.e. autologous stimulation, PHA, anti‐CD3, ‐CD2 and ‐CD28 monoclonal antibodies), and lymphokine production (i.e. IL‐1, IL‐2 and gamma‐IFN). For a more detailed experimental model the experiments have been performed both in bulk culture and by using T cell clones derived from the peripheral blood. The results show cromolyn to have an enhancing effect, theophylline and ketotifen a suppressing effect, whereas the remainder show no effect on the immune response. These data are considered and discussed from the aspect of their possible clinical relevance and also in light of the in vivo data previously reported.

Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy

The natural exposure to house dust mites causes sensitization in genetically susceptible patients. Persistent exposure of sensitized patients causes chronic inflammation, and consequently, hyperreactivity, thus promoting the development of clinical features. Recently, intercellular adhesion molecule-1 (ICAM-1)/CD54 expression on epithelial cells triggered by allergen has been demonstrated and related to the inflammation caused by the allergic reaction. Therefore we evaluated the possible presence of inflammation (i.e., inflammatory cell infiltrate and ICAM-1/CD54 expression on epithelium) at conjunctival and nasal levels in patients with asymptomatic allergic rhinitis caused by mites, in their relatives living in the same environment, and in healthy volunteers. In addition, the possible relationship between inflammation and house dust mite allergen exposure was evaluated. Conjunctival and nasal scrapings of allergic subjects enrolled in the study showed many inflammatory cells. A mild ICAM-1/CD54 expression on conjunctival and nasal epithelium was detectable in allergic subjects, whereas relatives and healthy volunteers showed few inflammatory cells and no ICAM-1/CD54 expression on epithelial cells. A detectable level of house dust mite, sufficient to cause sensitization, was found in all houses. This study demonstrates a minimal persistent inflammation at conjunctival and nasal levels constantly detectable in patients without symptoms who are sensitized to mites and continuously exposed to the natural allergens.

Cetirizine reduces inflammatory cell recruitment and ICAM-1 (or CD54) expression on conjunctival epithelium in both early- and late-phase reactions after allergen-specific challenge ☆ ☆☆ ★ ★★

BACKGROUND Allergen-specific conjunctival challenge (ASCC) is a safe and reproducible experimental model of allergic conjunctivitis and a useful tool in the evaluation of effectiveness and possible mechanisms of action of drugs commonly used in the treatment of allergic diseases. OBJECTIVE The protective effect of cetirizine on inflammatory changes after ASCC was assessed in 12 patients with rhinoconjunctivitis caused by Parietaria judaica in a double-blind study. METHODS After a screening ASCC was performed, patients were randomized into two treatment groups; each patient was given cetirizine (oral tablets) 10 mg twice daily, or matching placebo for 3 1/2 days in off-pollen season. Clinical evaluation (itching, hyperemia, lacrimation, and swelling of eyelids) and cytologic assessment (number of inflammatory cells in conjunctival scraping and evaluation of intercellular adhesion molecule-1 (ICAM-1)/CD54 expression on epithelial cells) were performed at baseline, 30 minutes (i.e., early-phase reaction [EPR]), 6 hours, and 24 hours (i.e., late-phase reaction [LPR]) after ASCC, before and after treatment. RESULTS The EPR clinical events and the EPR total number of inflammatory cells were significantly reduced by cetirizine compared with placebo. The LPR clinical events and inflammatory cell recruitment were reduced by cetirizine in a similar manner. Both eosinophil and neutrophil numbers were decreased by active drug in EPR and LPR. Furthermore, ICAM-1/CD54 expression was significantly reduced by cetirizine in both the EPR and LPR compared with placebo. CONCLUSIONS This study shows that cetirizine has a protective effect on clinical and cellular EPR and LPR events (including ICAM-1/CD54 expression on epithelium) induced by ASCC.

Allergic subjects express intercellular adhesion molecule — 1 (ICAMA or CD54) on epithelial cells of conjunctiva after allergen challenge

BACKGROUND Allergic inflammation can be experimentally reproduced in vivo in humans, by means of the conjunctival provocation test with allergen. The allergen stimulation triggers an early clinical response and an almost simultaneous cellular infiltrate. Among the factors that can contribute to the local cellular recruitment, we postulate a possible early involvement of CD54 in the development of inflammation caused by the allergic reaction. METHODS We used a sensitive immunocytochemical immunoenzymatic alkaline phosphatase-monoclonal antialkaline phosphatase technique to detect the possible expression of CD54 molecule on epithelial cells of conjunctiva in 15 allergic subjects and in 15 healthy individuals in basal conditions and after allergen challenge (Parietaria judaica) during the off-pollen season. RESULTS At baseline all studied individuals did not evidence CD54 expression on epithelial cells; 30 minutes after allergen challenge, all the allergic individuals showed a marked expression of CD54 on conjunctival epithelium, whereas none of healthy subjects showed any CD54 expression. First, CD54 expression on conjunctival epithelium after specific provocation test appeared as a specific phenomenon occurring only in sensitized subjects; moreover, it is an immediate event concomitant with the local inflammatory infiltrate. Therefore conjunctival epithelium unexpectedly appeared to be more than a bystander in the allergic reaction; it may be perceived as an active participant interacting with the inflammatory infiltrate. CONCLUSIONS These findings indicate that CD54 may play a central role in the allergic inflammation and strongly support the concept that maneuvers designed to interact with the adhesion machinery expressed on inflammatory cells and epithelium may be a helpful therapeutic approach.

Seasonal and perennial allergic rhinitis: is this classification adherent to real life?

Background:  Allergic rhinitis is traditionally subdivided into seasonal (SAR) and perennial (PAR), although the new definitions of persistent and intermittent were recently proposed. We assessed the validity of the traditional classification in a large group of subjects suffering from allergic rhinitis alone.

Induction of interleukin 10 by sublingual immunotherapy for house dust mites: a preliminary report

BACKGROUND Subcutaneous specific immunotherapy has been demonstrated to be capable of inducing T-cell regulatory response. Interleukin 10 (IL-10) plays a crucial role in inducing allergen-specific tolerance; however, no previous studies have examined IL-10 production after sublingual immunotherapy (SLIT). OBJECTIVE To evaluate T-cell proliferation and IL-10 production in patients successfully treated with SLIT for house dust mites (HDMs). METHODS Peripheral blood mononuclear cells were isolated from patients after at least 3 years of successful HDM SLIT and from matched untreated allergic patients and healthy control subjects. After 3 and 6 days of in vitro stimulation with phytohemagglutinin (PHA), Candida albicans, and Dermatophagoides farinae, proliferation and production of IL-10 were measured. RESULTS Patients treated with SLIT showed a significant reduction of proliferation induced by C albicans compared with untreated atopic patients (P < .001), but a significant reduction was also demonstrated in healthy controls compared with untreated atopic patients (P < .001). Patients treated with SLIT also showed a significant increase of IL-10 production after Candida and PHA stimuli compared with patients with untreated rhinitis (P < .001 for both). Patients with untreated rhinitis did not produce IL-10. CONCLUSION This preliminary study confirms reduced T-cell proliferation and preliminarily provides the first evidence, to our knowledge, of peripheral IL-10 production in allergic patients successfully treated with HDM SLIT.

Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: An antiallergic activity

BACKGROUND It is well known that allergen-specific nasal challenge (ASNC) is a fruitful tool with which to evaluate antiallergic activity exerted by a drug. Azelastine is a new antihistamine also available in topical form (i.e., nasal spray). OBJECTIVE The aim of the study was to evaluate the effects of azelastine nasal spray on inflammatory changes after ASNC in both the early-phase reaction and the late-phase reaction. METHODS The study had a double-blind, placebo-controlled, randomized, and parallel-group design. Twenty patients with pollen allergy were enrolled out of pollen season. ASNC was performed at baseline (TO) and after 1 week of washout (T7). At T7, 10 patients sprayed azelastine (1 puff) into their nostrils, and 10 patients used placebo. ASNC was performed after 30 minutes. The considered parameters (evaluated during early- and late-phase reactions) were: (1) clinical signs and symptoms, (2) cytologic assessment (neutrophils and eosinophils), (3) assay-of mediators (eosinophil cationic protein and myeloperoxidase), and (4) expression of intercellular adhesion molecule-1 (ICAM-1) on nasal epithelial cells. We focused our attention on ICAM-1 because it is the natural ligand of leukocyte functional associated antigen-1 and Mac-1, expressed on eosinophils. In addition, ICAM-1 is expressed on epithelial cells only on allergen exposure (both natural and experimental). RESULTS Placebo did not exert any modification on the considered parameters. After azelastine administration, significant decreases in total symptom score, eosinophilic and neutrophilic infiltration, and ICAM-1 expression were observed during both early- and late-phase reactions. Furthermore, serum eosinophil cationic protein levels decreased during the late-phase reaction, whereas myeloperoxidase was not affected by the treatment. These findings were confirmed by the powerful Kochs split-plot statistical analysis. CONCLUSION Azelastine exerts antiallergic activity, mainly affecting eosinophil function and downregulating ICAM-1 expression, on nasal epithelial cells.

Increase of Asthma and Allergic Rhinitis Prevalence in Young Italian Men

Our previous studies have reported that the prevalence of asthma was 2.89% and of allergic rhinitis 1.54% in Ligurian conscripts for the army during 1983. Since several authors reported an increasing prevalence of these diseases in different geographic areas, the aim of the present study was to evaluate the trend of prevalence rates in a same homogeneous group of Ligurian conscripts. The prevalence of asthma and allergic rhinitis was assessed in a group of 4310 young Ligurian men (18 years old) who had undergone medical examination for call-up to the navy during 1993, 1994 and 1995. Subjects were investigated by history, clinic visit, spirometry, metacholine bronchial challenge and skin prick test. The prevalence of asthma is 4.39% and of allergic rhinitis 2.2%. Comparing these results with previous data, a significant increase appears in this area 12 years later (respectively, p < 0.001 and p < 0.006). In addition, the association with asthma in allergic rhinitics increases from 41 to 77%, as well as an increasing trend appears for perennial allergens (i.e. mites and cat) and the polysensitizations increase from 48 to 67%. Possible explanations for these phenomena might be due to environmental factors (i.e. pollutants, viral infections, changes in domestic microenvironment).

Serum interleukin-17 levels are related to clinical severity in allergic rhinitis.

Background:  T helper (Th)‐17 cells are a subset of T helper lymphocytes that exert regulatory activities. Recently, it has been reported that serum interleukin (IL)‐17 levels are high in the most severe cases of birch allergy studied outside the pollen season.

Minimal persistent inflammation is also present in patients with seasonal allergic rhinitis

BACKGROUND The allergic reaction is characterized by an inflammatory response, which is correlated to the allergen exposure, and is detectable in mite allergic patients, even when symptoms are absent. OBJECTIVE The study was aimed at assessing the presence of inflammation in patients with pollen allergy during a long observation period. METHODS Six patients, sensitized only to Betula alba, were enrolled. Evaluated parameters were (1) nasal symptoms, (2) inflammatory markers (ie, neutrophil and eosinophil number and intercellular adhesion molecule-1 expression on nasal epithelial cells), and (3) pollen count. Patients were examined during the pollen season every 4 days for 40 days and were observed 3 times after the pollen season. RESULTS A significant inflammatory reaction was evident throughout the pollen season, even during the days with a low pollen count and low or absent symptoms. CONCLUSIONS The results of this study indicate that the global therapeutic strategy for allergic rhinitis should be revised and targeted to inflammatory phenomena rather than to symptoms alone.