Anti-IL-5 immunomodulates the effect of Staphylococcus aureus enterotoxin on T cell response in nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a T helper-2 (Th2) inflammatory disease with considerable impact on the quality of life. Staphylococcus aureus enterotoxins (SAEs) can induce and/or amplify inflammation. In this study, we investigated the immunomodulatory effect of SAEs on cytokine production by T cell obtained from nasal polyps (NPs) and examined whether neutralizing interleukin 5 (IL-5) can reverse the immunological effect mediated by those toxins. METHODS: NP tissues were obtained from all patients who underwent endoscopic sinus surgery for CRSwNP. NP cells were isolated and stimulated in vitro with SAEs in the presence or absence of anti-IL-5. Flow cytometry (FACS) analyses were performed to measure specific T lymphocyte cytokine production. RESULTS: Seventeen patients (mean age 48 years) were enrolled. SAEs significantly increased the IL-4, IL-5 (Th2) and interferon (INF)-γ (Th1) cytokines released from T lymphocytes of NPs. The addition of anti-IL-5 suppressed IL-4 and INF-γ release, which was most evident on NP tissue with high basal levels of IL-5. CONCLUSIONS: Neutralizing IL-5 is a potential therapeutic modality in patients with NPs, the effect of which is dependent on IL-5 levels.

Expression of inducible nitric oxide synthase in a mouse model of anaphylaxis.

BACKGROUND: The generation of large quantities of nitric oxide (NO) is implicated in the pathogenesis of anaphylactic shock. The source of NO, however, has not been established and conflicting results have been obtained when investigators have tried to inhibit its production in anaphylaxis. OBJECTIVE: The aim of this study was to analyze the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in a mouse model of anaphylaxis. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to induce anaphylaxis. Tissues were removed from the heart and lungs, and blood was drawn at different time points during the first 48 hours after induction of anaphylaxis. The Griess assay was used to measure nitric oxide generation. Nitric oxide synthase expression was examined by reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: A significant increase in iNOS mRNA expression and nitric oxide production was evident as early as 10 to 30 minutes after allergen challenge in both heart and lungs. In contrast, expression of eNOS mRNA was not altered during the course of the experiment. CONCLUSION: Our results support involvement of iNOS in the immediate physiological response of anaphylaxis.

Effect of montelukast pretreatment on inducible nitric oxide synthase mRNA expression in the lungs of antigen-challenged allergic mice.

BACKGROUND: Growing evidence suggests that inducible nitric oxide synthase (iNOS) is the main source of the high output of exhaled nitric oxide (NO) in asthma. Treatment of asthmatic patients with glucocorticoids reduces high levels of exhaled NO mainly by inhibiting the transcription of iNOS. A similar reduction in exhaled NO was recently observed in patients treated with the leukotriene receptor antagonists, but the exact interaction between these drugs and iNOS remains obscure. OBJECTIVE: The purpose of this study was to evaluate the effect of a leukotriene receptor antagonist, montelukast, on the expression and activity of iNOS in a murine model of allergic asthma. METHODS: Twenty-four BALB/c mice were sensitized to OVA and were equally divided into 3 groups (Groups 1-3). Eight additional mice were sham sensitized and served as a negative control group (Group 4). Group 1 received montelukast 1 mg/kg/day in their drinking water, Group 2 received dexamethasone 1 mg/kg/day in their drinking water and Groups 3 and 4 received plain tap water. After 1 week, the animals were challenged by inhalation of OVA and, 3 h later, they were killed and their lung cells were isolated by enzymatic tissue digestion. NO generation was measured by a Griess assay, and iNOS mRNA was studied by RT-PCR. RESULTS: A significant increase in iNOS mRNA expression and in NO generation was evident after allergen challenge compared with the controls. Pretreatment with montelukast mildly decreased NO production without producing a concomitant significant decrease in iNOS mRNA expression. CONCLUSION: Unlike pretreatment with glucocorticoids, we failed to find compelling evidence for a major role for montelukast treatment in the modulation of iNOS mRNA in a murine model of acute asthma.

The effect of specific immunotherapy on T-cell receptor repertoire in patients with allergy to house-dust mite.

BACKGROUND: The precise mechanism of specific immunotherapy (SIT), long used for treating allergic diseases, remains undefined. SIT was shown to act by modifying the immune response of T lymphocytes to antigens. We examined the effect of SIT on the expression and use V-alpha, -beta, -gamma and -delta chains of T-cell receptors (TCR) in patients allergic to house-dust mite. METHODS: Peripheral venous blood was taken for lymphocyte TCR analysis from 10 house-dust mite (HDM) allergic adults before initiating SIT and 6 months after initiating the treatment. Twelve similarly allergic patients without SIT served as controls. TCR chains were identified by fluorescence-activated cell sorter (FACS) using the following monoclonal antibodies: CD3, CD14, CD8, pan alpha-beta, pan gamma-delta, V-alpha2, V-alpha12.1, V-beta5a, V-beta5b, V-beta5c, V-beta8a, V-beta8b, V-beta3.1, V-beta13, V-beta12, V-beta6.7, V-delta1, V-delta2, V-gamma9, and V-gamma4. RESULTS: Analyzed before and 6 months after SIT initiation, lymphocyte TCR showed significantly increased V-beta5b, V-beta12 and V-alpha12.1 values compared to controls (without significant changes in other markers). CONCLUSIONS: SIT caused selective expansion of certain V-beta- and V-alpha-expressing T cells in patients allergic to HDM. Our results support the notion that the effect of SIT in patients with allergic rhinitis may be achieved by modifying the T lymphocyte response through the modulation of TCR usage.

The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital.

BACKGROUND: Penicillin allergy poses a major problem in the management of infectious diseases. OBJECTIVE: We estimated the costs and usage of antibiotic treatment of 'penicillin-allergic' patients in comparison to non-allergic patients in a tertiary care hospital. MATERIALS AND METHODS: The study was based on the records of 118 randomly chosen in-hospital patients labelled as being 'allergic to penicillin' and who were treated with antibiotics. The antibiotic selection and cost of the patients with alleged penicillin allergy were compared to 118 matched patients without an antibiotic allergy (controls). RESULTS: During in-hospital treatment, the mean antibiotic cost for penicillin-allergic patients was 63% higher than the cost for the controls. In addition, there was a 38% higher cost of the recommended anti-microbial treatment regimen to be followed upon discharge by the former compared to the latter. CONCLUSIONS: Penicillin-allergic patients were more likely to receive broader spectrum antibiotics compared to the non-allergic ones. Since many of the patients who are labelled as being 'allergic to penicillin' are, in fact, not allergic to it, inaccurate reporting of penicillin allergies may have costly economic and epidemiologic repercussions in addition to more toxic effects which can occur when choosing alternative drugs in case of penicillin allergy.

Epidemiology of bronchial asthma and chronic rhinitis in schoolchildren of different ethnic origins from two neighboring towns in Israel.

Allergic diseases have increased significantly in developed countries for reasons yet to be determined. We studied the epidemiology of bronchial asthma (B.A.) and chronic rhinitis (Ch.R.) among Israeli school children from two neighboring towns, one Jewish (Zichron Yaakov, school population = 585) and the other Arab (Paradis, school population = 658). The children (age range 8-17 years, 567 males, 676 females) shared the same climate and had similar demographic characteristics. They received similar medical care and had the same rates of hospitalization and emergency room visits. The Jewish children had a higher prevalence of B.A. (13.7% vs. 9.4%), Ch.R. (19.7% vs. 9.7%), and stuffy nose (31% vs. 14%) than their Arab counterparts. In addition to ethnicity, parental smoking habits were the major differentiating factor between the two groups: 20% of the mothers and 29% of the fathers from Zichron Yaakov and 2% of the mothers and 60% of the fathers from Paradis were smokers. Smoking fathers increased the rate of B.A. in both towns as well as emergency room visits, but not the rate of Ch.R. or stuffy nose. A familial history of B.A. was the main determinant for having childhood asthma or chronic rhinitis. We conclude that in addition to family history and ethnicity, smoking among mothers was the major contributing factor for the higher prevalence of atopic diseases among Jewish schoolchildren compared to their Arab counterparts.

[Systemic mastocytosis].

Mastocytosis has a highly variable clinical expression, and systemic mastocytosis is occasionally associated with a myeloproliferative or a myelodysplastic disorder. These patients often present without skin involvement and have a very poor prognosis. We report a 72-year-old man with this condition who had spells of flushing and dyspnea, myelofibrosis, and high serum and urine histamine levels.

Time course of lipopolysaccharide-induced nitric oxide synthase mRNA expression in rat glomeruli.

The decrease in glomerular filtration rate that is characteristic of sepsis has been shown to result from the local glomerular inhibition of endothelial nitric oxide synthase (NOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). iNOS activation depends on de novo synthesis of both RNA and protein. Therefore it is assumed that several hours are required for its full activation. Yet the renal hemodynamic response in sepsis has been documented as early as 60 minutes after lipopolysaccharide (LPS) administration. Experiments were designed to determine the time course of LPS-induced glomerular iNOS mRNA expression and activity in rats. Rats were treated with LPS (2 mg/kg body weight IP). Kidneys were removed after 1,2, 4, 6, and 16 hours. Glomeruli were isolated and incubated. Nitric oxide generation was measured with a Griess assay, and iNOS mRNA was studied by reverse transcriptase-polymerase chain reaction. Similar time course experiments were repeated in glomeruli isolated from normal rats and exposed to LPS in vitro. A significant increase in iNOS mRNA expression was evident as early as 60 minutes after both in vivo and in vitro administration of LPS. The quantity of iNOS mRNA reached its peak between 2 to 4 hours after administration and declined to baseline levels after 16 hours. Immunohistochemical studies were remarkable for a significant increase in the staining for iNOS in glomeruli 2 hours after the in vivo administration of LPS. Plasma nitric oxide concentration after the in vivo administration of LPS increased from a baseline level of 11.25 +/- 0.8 micromol/L to a peak level of 62.9 +/- 3.8 micromol/L (P < .05 vs baseline) at 4 hours and then decreased to 17.5 +/-1.9 micromol/L at 16 hours. Similar results were obtained when the glomerular generation of nitric oxide after in vivo administration of LPS was measured (2.6 +/- 0.8 pmol/h/microg tissue, 17.2 +/- 2.1 pmol/h/microg tissue (P < .05 vs baseline), and 0.4 +/- 0.65 pmol/h/microg tissue, respectively). These results provide evidence of the rapid activation of glomerular iNOS after in vivo and ex vivo administration of LPS and thus support the role of nitric oxide in the early renal hemodynamic response to LPS.