Functional interaction between various glutamate receptors

The interaction of glutamate with various receptors in glutamatergic neurons and functional interaction between glutamate receptors are reviewed. It is hypothesized that metabotropic receptors perform defensive functions in the brain by protecting neurons from neurotoxic effects caused by excessive glutamate release. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, 130, No. 9, pp. 244–251, September, 2000     

Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes

Background: Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects. Objective: We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86). Methods: Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents. Results: Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% ± 14.8% vs 1.4% ± 1.2%; P < .001), whereas no difference was observed in CD86 expression (2.0% ± 2.3% vs 1.1% ± 0.6; P > .1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner. Conclusion: Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects. (J Allergy Clin Immunol 1999;103:1136-42.)     

Functional interaction between various glutamate receptors

The interaction of glutamate with various receptors in glutamatergic neurons and functional interaction between glutamate receptors are reviewed. It is hypothesized that metabotropic receptors perform defensive functions in the brain by protecting neurons from neurotoxic effects caused by excessive glutamate release. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, 130, No. 9, pp. 244–251, September, 2000     

Lipopolysaccharide augments IgG and IgE responses of mice to the latex allergen Hev b 5

Background: LPS is a common contaminant in the health care environment and in latex examination gloves. Objective: We sought to investigate the role of LPS in enhancing the immune responses of mice to inhaled latex allergen. Methods: As our model allergen, we used a fusion protein containing the potent latex allergen Hev b 5. BALB/c mice were lightly anesthetized and given repeated intranasal doses of saline, LPS, and/or Hev b 5. The doses were given in 2 courses separated by a 6-week period, with the first course consisting of 6 doses and the second consisting of 3 doses. Results: After the first set of immunizations, mice given Hev b 5 alone had no detectable IgG1 or IgE responses to Hev b 5, whereas mice given the antigen along with LPS had significant responses (IgG1, 0.73 U ± 0.05; IgE, 0.88 U ± 0.2). No enhancement of specific IgG2a was observed. A stimulatory effect of LPS on all 3 immunoglobulin types was apparent after the second course. Lymphocytes from mice immunized with LPS and Hev b 5 had increased proliferation to Hev b 5 and its fusion partner. Conclusions: LPS may be an important immunoadjuvant for the development of allergic reactions to latex protein allergens. (J Allergy Clin Immunol 199;102:977-83.)     

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.     

T lymphocytes that infiltrate nasal polyps have a specialized phenotype and produce a mixed TH1 /TH2 pattern of cytokines

Background: Nasal polyps (NPs) are inflammatory reactions in the nasal mucosa the etiology and pathogenesis of which remains unknown. Objective: The purpose of this study was to study in detail the phenotype and function of T lymphocytes infiltrating NPs by analyzing the expression of surface markers and cytokine secretion. Methods: NP tissue samples and peripheral blood were obtained from 18 patients. Mononuclear cells were purified from these samples, and their phenotype was investigated by triple-color immunofluorescence and flow cytometric analysis. Cytokine production was determined in cultures by using an ELISA technique. Results: NP lymphoid cells mainly consisted of T lymphocytes. These T lymphocytes showed a CD45RO+CD45RA– phenotype and expressed pan-T cell molecules; the CD8+ subset was predominant. NP T cells showed a lower density of CD28, CD3, and TCR-αβ compared with T cells from peripheral blood. NP T lymphocytes expressed the activation markers DR and CD69 and exhibited the adhesion molecule profile CD54+, CD62L–, and CD103+ CD49d^low . Virtually all NP T cells bore CD95 (FAS), but they did not undergo apoptosis, either spontaneously or induced by CD95 cross-linking with the mAb CH11. The pattern of cytokines secreted by NP T lymphocytes was characterized by the spontaneous and simultaneous production of IFN-γ and IL-5. Neither IL-2 nor IL-4 were detectable in nonstimulated cultures. Conclusion: This study defines the T lymphocytes that infiltrate NPs as memory T cells in an activated status, with homing properties related to the mucosal immune system. They are resistant to anti-CD95-mediated apoptosis and produced a mixed T_H1 /T_H2 cytokine pattern as defined by the simultaneous production of IFN-γ and IL-5. (J Allergy Clin Immunol 1998;102:953-60.)     

Suppression of hemopoiesis during CCl4-induced hepatic fibrosis: Role of systemic endotoxemia

CCl₄-induced hepatic fibrosis in mice was accompanied by insufficiency of bone marrow myelo- and erythropoiesis. Polymyxin B completely abolished these changes. This phenomenon can be explained by the development of macrophage endotoxin tolerance during hepatic fibrosis. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 172–175, August, 2000     

Specific IgE to cross-reactive carbohydrate determinants strongly affect the in vitro diagnosis of allergic diseases

BACKGROUND: Cross-reacting carbohydrate determinants (CCDs) are antigenic structures shared by allergenic components from taxonomically distant sources. The case history of a patient with a great discrepancy between skin test and specific IgE results led us to investigate the role of these determinants in his specific case and in an allergic population. OBJECTIVE: We sought to determine the role of CCDs in causing false-positive and clinically irrelevant results in in vitro tests. METHODS: The involvement of CCDs was studied by specific IgE inhibition by using glycoproteins with a known carbohydrate structure. Direct and inhibition assays were performed by commercially available systems, in-house ELISA, and the immunoblotting technique. The binding to the periodate-oxidated carbohydrate structure of glycoproteins and allergenic extracts was also evaluated. A comparative study between skin test and specific IgE responses to the antigens studied was carried out in 428 consecutive allergic subjects. RESULTS: All the tests performed suggested that cross-reacting carbohydrate epitopes were the cause of false-positive specific IgE results in one of the commercial systems and the high reactivity in all the solid-phase in vitro tests. None of the cross-reacting carbohydrate allergens yielded a positive skin test response. Periodate treatment caused variable degrees of reduction of IgE binding to the different antigens studied, indicating that CCDs played a different role in each of them. About 41% of patients allergic to pollen had specific IgE for a glycoprotein, without a positive skin test response to the same molecule. CONCLUSIONS: CCDs must be taken into account when evaluating the clinical relevance of positive results in in vitro specific IgE assays, at least in the diagnosis of patients with pollen allergy. Commercial systems should be carefully assessed for the ability to detect specific IgE for carbohydrate determinants to avoid false-positive or clinically irrelevant results.     

School as a risk environment for children allergic to cats and a site for transfer of cat allergen to homes

BACKGROUND: Many children are allergic to furred pets and avoid direct pet contact. The school may be a site of indirect exposure to pet allergens, which may induce or maintain symptoms of allergic diseases. OBJECTIVE: We sought to investigate airborne levels of cat allergen (Fel d 1) at schools and in homes with or without cats and to study clothes as a route for dissemination of allergens between homes and school. METHODS: Airborne cat allergen was collected with personal samplers from (1) children attending classes with many (>25%) or few (<10%) cat owners and (2) homes with or without cats. A recently developed amplified ELISA assay, which detects low levels of airborne cat allergen in pet-free environments, was used. Dust samples were collected from clothes and mattresses. RESULTS: There was a 5-fold difference in the median levels of airborne cat allergen between classes with many and few cat owners (2.94 vs 0.59 ng/m3; P <.001). The median airborne cat allergen concentration in classes with many cat owners was significantly higher than that found in the homes of non-cat owners (P <.001) but lower than that found in homes with cats (P <.001). Allergen levels in non-cat owners' clothes increased after a school day (P <.001). Non-cat owners in classes with many cat owners had higher levels of mattress-bound cat allergen (P =.01). CONCLUSION: The results indicate significant exposure to cat allergen at school. Allergen is spread through clothing from homes with cats to classrooms. There the allergen is dispersed in air and contaminates the clothes of children without cats. The allergen levels in non-cat owners' homes correlate with exposure to cat allergen at school.     

Six-hour trimethoprim-sulfamethoxazole–graded challenge in HIV-infected patients

Background: Hypersensitivity reactions to trimethoprim-sulfamethoxazole (TMP-SMX) are very common in HIV-infected patients, leading to drug discontinuation. However, it is the drug of choice as prophylaxis for Pneumocystis carinii pneumonia. Objectives: We sought to determine the safety and long-term efficacy of a 6-hour TMP-SMX–graded challenge in a group of hypersensitive HIV-infected patients. Methods: Forty-four consecutive HIV-infected patients with documented TMP-SMX hypersensitivity were seen in our outpatient allergy department. They ingested 12 doses of increasing amounts of TMP-SMX at half-hour intervals. Thereafter, they took 80/400 mg TMP-SMX daily and were advised to “treat through” every nonbullous cutaneous adverse reaction. Results: All 44 patients tolerated the procedure without any adverse reactions during the day of challenge. Eleven of the 44 patients experienced mild hypersensitivity reactions on days 1 to 2 (8 patients) and 8 to 10 (3 patients), consisting mainly on a 1-day pruritic maculopapular eruption. Two patients stopped TMP-SMX at day 1, and 2 stopped it at days 10 and 15, giving an overall success rate at 1 month of 91% (40 of 44). Two were successfully rechallenged late. After a median follow-up of 10 months, 42 patients were taking TMP-SMX without any adverse reaction, giving an overall success rate of 95%. Conclusions: A 6-hour graded challenge with cautious “treating through” of mild reactions enables more patients to take TMP-SMX and is safe and effective. (J Allergy Clin Immunol 1998;102:1033-6.)     

Effects of topical corticosteroids on inflammatory mediator–induced eicosanoid release by human airway epithelial cells

Background: Airway epithelial cells are among the first cells to come in contact with aerosolized corticosteroids. However, the relative potencies and time course of action of the several commonly used aerosolized corticosteroids on eicosanoid production by airway epithelial cells are unknown. Objectives: This study compared the effects of fluticasone, budesonide, and triamcinolone on eicosanoid output by human airway epithelial cells in vitro. We also determined the spectrum of eicosanoids affected and the mechanism for corticosteroid action. Methods: Cultured BEAS-2B airway epithelial cells (a transformed cell line) were exposed to corticosteroids (1 nmol/L to 1 μmol/L) for 2 to 48 hours and then assayed for basal- and bradykinin (BK)-stimulated eicosanoid output. The eicosanoid profile was identified by HPLC in tritiated arachidonic acid prelabelled cells, and PGE₂, the major eicosanoid product, was quantitated by RIA. The effect of corticosteroids on the immunoreactivity of key proteins involved in eicosanoid metabolism (ie, cyclooxygenase [COX], phospholipase A2 [PLA₂], and Clara cell protein, a PLA₂ inhibitor) was determined by Western blotting. Results: Eicosanoid output was largely confined to prostaglandins with values of 5 ± 2 and 82 ± 35 ng PGE₂/10⁶ cells for basal- and BK stimulation, respectively (n = 8). All 3 corticosteroids inhibited basal- and BK-induced PGE₂ output in a dose- and time-dependent manner. Fluticasone and budesonide completely eliminated PGE₂ output in nanomolar concentrations in contrast to triamcinolone, which required micromolar concentration. The rank order of potency was: fluticasone = budesonide > triamcinolone. The time course of action for PGE₂ inhibition also differed, with budesonide acting more slowly than the other 2 corticosteroids (P = .04). All 3 corticosteroids markedly reduced COX2 with little effect on COX1, cPLA₂ (Type IV), or iPLA₂ (Type VI) immunoreactivity or their relative distribution in cytosol versus membrane fractions. Clara cell protein immunoreactivity was undetectable in control and corticosteroid-treated cell lysates. Conclusion: These results show that in a human airway epithelial cell line, the 3 inhaled corticosteroids commonly used to treat asthma differ in onsets of action as inhibitors of prostaglandin synthesis and vary considerably in potency. All 3 corticosteroids act mechanistically in similar fashion by inhibiting COX2 synthesis. (J Allergy Clin Immunol 1999;103:1081-91.)     

Role of Thy 1.2+ cells in hemopoietic regulation in cytostatic-induced hemosuppression

Effect of Thy 1.2⁺ cells (direct and mediated by stromal elements) on the growth of granulomonocyte and erythroid colonies in the bone marrow is studied on CBA mice with cytostatic disease induced by single injection of adriamycin, cyclophosphamide, and 5-fluorouracil in maximum permissible doses. It is shown that Thy 1.2⁺ cells stimulate colony formation in regenerating bone marrow, the effect depending on functional activity of hemopoiesis-inducing microenvironment. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol 125, No. 5, pp. 509–513, May, 1998     

A cross-sectional survey of sensitization to Aspergillus oryzae–derived lactase in pharmaceutical workers

BACKGROUND: The presence of IgE-mediated occupational respiratory sensitization to microbial enzymes has been well documented in a variety of industries. Aspergillus oryzae -derived lactase is used as a dietary aid for patients with lactose intolerance. OBJECTIVE: In 1993, a cross-sectional survey of 94 pharmaceutical workers exposed to lactase for a mean duration of 23 months and 24 nonexposed recently hired employees was initiated to identify lactase-sensitized workers and potential risk factors that could be used in making recommendations for preventing future cases of lactase sensitization. METHODS: The survey included a physician-administered questionnaire, skin prick testing to lactase enzyme and a panel of common aeroallergens, and spirometry. RESULTS: Twenty-seven of 94 lactase-exposed workers (29%) had positive skin test responses to lactase. These workers were 9 times more likely to have upper or lower respiratory symptoms compared with workers with negative skin test responses. Atopic workers were 4 times more likely to have lactase skin sensitivity than nonatopic workers. However, atopy was not a risk factor for the development of upper and/or lower respiratory symptoms. Lactase skin reactivity was not observed in the 24 nonexposed employees. CONCLUSION: This cross-sectional survey revealed that atopic workers were more likely to have lactase sensitization and that lactase-sensitized workers were more likely to have upper and/or lower respiratory symptoms, but atopy was not a risk factor for upper or lower respiratory symptoms. In spite of these findings, the company allowed only nonatopic, nonlactase-sensitized workers to continue working in high lactase-exposure areas with careful symptom monitoring and use of protective clothing. Although this strategy was successful in total prevention of new cases of occupational respiratory disease after 5 years, the results of this cross-sectional survey do not support exclusion of atopic workers from working with industrial enzymes.     

Food allergy. Part 2: Diagnosis and management

Patients with food-induced allergic disorders may be first seen with a variety of symptoms affecting the skin, respiratory tract, gastrointestinal tract, and/or cardiovascular system. The skin and respiratory tract are most often affected by IgE-mediated food-induced allergic reactions, whereas isolated gastrointestinal disorders are most often caused by non-IgE-mediated reactions. When evaluating possible food-induced allergic disorders, it is often useful to categorize disorders into IgE- and non-IgE-mediated syndromes. The initial history and physical examination are essentially identical for IgE- and non-IgE-mediated disorders, but the subsequent evaluation differs substantially. Proper diagnoses often require screening tests for evidence of food-specific IgE and proof of reactivity through elimination diets and oral food challenges. Once properly diagnosed, strict avoidance of the implicated food or foods is the only proven form of treatment. Clinical tolerance to food allergens will develop in many patients over time, and therefore follow-up food challenges are often indicated. However, a number of novel immunomodulatory strategies are in the developmental stage and should provide more definitive treatment for some of these food-induced allergic disorders in the next several years.     

Comparison of the efficacy of budesonide and fluticasone propionate aqueous nasal spray for once daily treatment of perennial allergic rhinitis

Background: Intranasal corticosteroids, such as budesonide and fluticasone propionate, are widely prescribed in the treatment of perennial allergic rhinitis. Once daily budesonide dry powder and fluticasone propionate aqueous suspension have been found to provide similar efficacy in controlling symptoms of perennial allergic rhinitis. Objective: The purpose of this study was to assess the efficacy and safety of treatment with once daily budesonide aqueous nasal spray. Methods: This study involved a multicenter, blinded, randomized, parallel-group, placebo-controlled trial of adults with perrenial allergic rhinitis. Patients (n = 273) recorded daily nasal symptoms for 8 to 14 days (baseline) and 6 weeks (treatment). Results: Budesonide decreased combined symptoms to a significantly greater extent than did fluticasone (P = .03); both treatments significantly decreased mean combined nasal symptoms scores compared with placebo. Of the 3 nasal symptoms assessed (ie, nasal blockage, runny nose, and sneezing), nasal blockage was significantly (P = .009) more decreased with budesonide compared with fluticasone. Both treatments also significantly improved runny nose and sneezing compared with placebo. Improvement in combined nasal symptom scores of the budesonide-treated group reached statistical significance within 36 hours compared with placebo (P = .01); in those patients treated with fluticasone, significant improvement compared with placebo was first observed within 60 hours. Adverse events were mild and transient. Conclusions: Once daily budesonide aqueous nasal spray, 256 μg, was significantly better in controlling the symptoms of perrenial allergic rhinitis than once daily fluticasone propionate, 200 μg, especially nasal blockage. Both treatments were superior to placebo. Budesonide may have a faster onset of action than fluticasone. (J Allergy Clin Immunol 1998;102:902-8.)     

IL-4–induced apoptosis in peripheral blood eosinophils

Background: The regulation of eosinophil survival and apoptosis may play a major role in diseases demonstrating increased numbers of circulating and tissue eosinophils such as allergic reactions. Because few promoters of eosinophil apoptosis have been described so far, the objective of this study was to elucidate the role of endogenous factors on eosinophil survival and apoptosis. Methods and Results: Highly purified peripheral blood eosinophils were analyzed in the time course from 24 up to 144 hours in culture. Eosinophil survival was assessed with trypan blue dye exclusion and apoptosis was determined by DNA fragmentation gel analysis and ELISA technique with anti-histone antibodies. We confirmed previous results demonstrating prolonged eosinophil survival and inhibited apoptosis by IL-3, IL-5, and GM-CSF. In contrast, eosinophil apoptosis was significantly enhanced by corticosteroids, particularly dexamethasone and hydrocortisone. However, IL-1β, IL-8, IL-12, platelet-activating factor, TNF-α, and eotaxin had no effect on eosinophil survival or apoptosis when compared with culture medium alone. In contrast, IL-4 at concentrations of 100 U/mL or more inhibited eosinophil survival and induced apoptosis. This effect was time dependent and abrogated by preincubation with neutralizing anti–IL-4 antibodies. However, after 96 hours in coincubation, IL-4 did overcome the survival-prolonging effect of IL-3, IL-5, and GM-CSF. IL-4 did not enhance eosinophil surface expression of APO-1/Fas antigen (CD95). In assessing IL-4–mediated effects on eosinophil function, we found no response by means of the release of eosinophil cationic protein or reactive oxygen species. Conclusions: Taken together, our data present direct evidence for the presence of functional IL-4 receptors on human eosinophils and indicate that IL-4 may lead to resolution of chronic inflammation by induction of eosinophil apoptosis. (J Allergy Clin Immunol 1998;102:1013-20)     

Hevein-like protein domains as a possible cause for allergen cross-reactivity between latex and banana

Background: Patients allergic to natural rubber latex (NRL) frequently exhibit immediate hypersensitivity reactions to banana, but the molecular basis of these putative cross-reactions is unknown. Objective: We wanted to examine whether proteins resembling hevein, a major NRL allergen, exist in banana and whether coexisting allergy to NRL and banana can be explained by IgE cross-reactivity to these proteins. Methods: Allergens in banana cross-reacting with hevein were identified by IgE immunoblot inhibition. The cross-reacting proteins were purified by reversed-phase chromatography and characterized by amino acid sequencing. Allergen cross-reactivity was further assessed by IgE ELISA, IgE ELISA inhibition, and skin prick testing. Results: In immunoblotting, 9 of 15 sera from patients allergic to NRL with IgE to hevein showed IgE binding to 32- and 33-kd banana proteins. These 2 protein bands were also targets to IgG from a hevein-immunized rabbit. IgE binding to both 32- and 33-kd protein bands was totally inhibited by hevein (10 ng/mL) in all 5 sera from patients allergic to NRL sera studied. N-terminal sequencing of the purified 32- and 33-kd proteins revealed 80% identity to the N-terminus of hevein. An internal peptide (19 amino acids) of the 33-kd protein gave over 90% identity to endochitinases of several plants. In ELISA all 15 sera from patients allergic to NRL had IgE to the purified 32-kd banana protein. In ELISA inhibition hevein (10 ng/mL) inhibited approximately 50% of IgE binding to the solid-phase 32-kd banana protein in a pool of sera from patients allergic to NRL. Conclusion: These results suggest that the commonly occurring hypersensitivity to banana in patients allergic to NRL could be explained by cross-reacting IgE antibodies binding to epitopes in hevein and in a hevein-like domain of a previously undescribed endochitinase in banana. (J Allergy Clin Immunol 1998;102:1005-12.)     

A comparative study of the effects of dimebon,obsidan, finoptin,and cordaron on the functional state of ischemic focus and size of necrotic zone in experimental myocardial infarction

Dimebon, an antihistamine agent, exerts a moderate antianginal effect, improving the function of ischemic focus in the myocardium and decreasing the necrotic zone in experimental myocardial infarction. Dimebon is less active than obsidan, finoptin (except for the size of the necrotic zone), and cordaron. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 12, pp. 642–644, December, 1996