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PubMed1998

Nasal allergen challenge and immunotherapy control.

Nasal allergen challenges, despite not reproducing exactly natural allergen exposure, are a very useful method to understand the complex cellular kinetics and cellular interactions that occur in allergic rhinitis. Cell-specific soluble mediator measurements can give useful diagnosis information as well as complementary information regarding the monitoring of specific immunotherapy. In this article we present data concerning eosinophil cationic protein and tryptase measurements after nasal allergen and the influence of specific immunotherapy on nasal peak flow before and 1, 2 and 3 years after starting immunotherapy.

Allergens↗
PubMed1998

[Allergic immunobiology and anesthesiology].

A protocol has been produced for the study of anaphylactic accidents that occur post-operatively that allows definition of the anaphylactic origin, and so reactions that are mediated by IgE in post-operative accidents. This protocol occurs in two stages, the first is done in the minutes and hours that follow the anaphylactic accident, and the second a month or 6 weeks afterwards. At first, we evaluate the sequential study of the liberation of the mediators of anaphylaxis, plasma histamine, serum tryptase, urinary methylhistamine and, more recently, leucotriene E4. The second study is devoted to reactions that are mediated by IgE, essentially, specific serum IgE, tests of activation of basophils by flow cytometry, measurement of leucotriene C4 and skin tests. A study on 16 subjects has evaluated and validated the protocol and shown a significant level of correspondence of results between the sequential measurement of mediators on one hand and on the other the search for IgE-mediated reactions every time that there was an anaphylactic reaction.

Adolescent↗
PubMed1998

[Importance of the urinary leukotriene E4 level. Preliminary study].

Post-anesthesia anaphylactic reactions or those seen during drug provocation tests with a systemic clinical reaction may be confirmed by the sequential release into blood of plasma histamine, tryptase and leukotriene C4 and into urine of urinary methylhistamine and leukotriene E4.

Acetaminophen↗
PubMed1998

[Mastocyte proteinase].

Recent studies have led to a rapid expansion of knowledge concerning the structure and biology of mast cells neutral proteinases. Therefore, in this paper tryptases, chymases, carboxypeptidases and cathepsin G have been described and their biological roles have been discussed.

Animals↗
PubMed1998

Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients.

Metachromatic cells in the peripheral blood of patients with asthma, allergy, or an allergic drug reaction were evaluated for their nuclear morphology, surface expression of the mast cell (MC) marker c-kit, surface expression of the basophil marker Bsp-1, and granule expression of MC proteases. Consistent with previous findings by others, Bsp-1+/metachromatic cells represented <1% of the cells in the peripheral blood of normal individuals. These cells generally contained segmented nuclei. Very little, if any, tryptase (Try), chymase (Chy), or carboxypeptidase A (CPA) was found in their granules, and very little, if any, c-kit was observed on their surfaces. The number of metachromatic cells increased in the peripheral blood of the three groups of patients. Like the basophils in normal individuals, most of these metachromatic cells contained segmented nuclei and expressed Bsp-1. However, in contrast to the basophils in normal individuals, many of the metachromatic cells in the three patient groups expressed c-kit, Try, Chy, and/or CPA. That the metachromatic cells in the blood of our patients have some features of MCs and some features of basophils suggests that human basophils and MCs are derived from a common progenitor. As assessed by the chloroacetate esterase cytochemical assay, the immunoreactive Chy in the peripheral blood of these patients is enzymatically active. Because MC proteases regulate numerous immunologic and other biologic systems, the expression of Try, Chy, and/or CPA in a peripheral blood-localized cell in an individual having asthma, allergy, or an allergic drug reaction has important clinical implications.

Acute Disease↗
PubMed2004

Differential expression of cytokines in UV-B-exposed skin of patients with polymorphous light eruption: correlation with Langerhans cell migration and immunosuppression.

BACKGROUND: Disturbances in UV-induced Langerhans cell migration and T helper (T(H)) 2 cell responses could be early steps in the pathogenesis of PLE. OBJECTIVE: To establish whether UV-B exposure induces aberrant cytokine expression in the uninvolved skin of patients with polymorphous light eruption (PLE). DESIGN: Immunohistochemical staining and comparison of microscopic sections of skin irradiated with 6 times the minimal dose of UV-B causing erythema and the unirradiated skin of patients with PLE and of healthy individuals. SETTING: University Medical Center (Dutch National Center for Photodermatoses). Patients Patients with PLE (n = 6) with clinically proven pathological responses to UV-B exposure and normal erythemal sensitivity. Healthy volunteers (n = 5) were recruited among students and hospital staff. MAIN OUTCOME MEASURES: Expression of cytokines related to Langerhans cell migration (interleukin [IL] 1, IL-18,and tumor necrosis factor [TNF] alpha); T(H)2 responses (IL-4 and IL-10); and T(H)1 responses (IL-6, IL-12, and interferon gamma). Double staining was performed for elastase (neutrophils), tryptase (mast cells), and CD36 (macrophages). RESULTS: The number of cells expressing IL-1beta and TNF-alpha was reduced in the UV-B-exposed skin of patients with PLE compared with the skin of healthy individuals (P<.05 for TNF-alpha). No differences were observed in the expression of T(H)1-related cytokines but fewer cells expressing IL-4 infiltrated the epidermis of patients with PLE 24 hours after irradiation (P =.03). After UV exposure TNF-alpha, IL-4, and, to a lesser extent, IL-10 were predominantly expressed by neutrophils. CONCLUSIONS: The reduced expression of TNF-alpha, IL-4, and IL-10 in the UV-B-irradiated skin of patients with PLE appears largely attributable to a lack of neutrophils, and is indicative of reduced Langerhans cell migration and reduced T(H)2 skewing. An impairment of these mechanisms underlying UV-B-induced immunosuppression may be important in the pathogenesis of PLE.

Adult↗
PubMed1999

Human conjunctival mast cells: expression of Fc epsilonRI, c-kit, ICAM-1, and IgE.

OBJECTIVE: To characterize the expression and regulation of conjunctival mast cell surface receptors important in allergic inflammation. METHODS: Mast cells were isolated from human conjunctival tissues of cadavers. Mast cell surface markers were identified using flow cytometry with antibodies to IgE, Fc epsilonRI, c-kit, and intercellular adhesion molecule-1 (ICAM-1). We evaluated the effect of 24-hour tumor necrosis factor alpha (TNF-alpha) or interleukin 4 (IL-4) incubation on the expression of mast cell c-kit, ICAM-1, and surface-bound IgE. RESULTS: Staining of mast cells (c-kit and/or tryptase positive) yielded positive results for all of the variables measured. The intensity of mast cell c-kit staining increased with TNF-alpha incubation, but decreased below that of unstimulated mast cells when incubated with IL-4. Anti-ICAM-1 and anti-IgE staining were increased over that of unstimulated cells when incubated with TNF-alpha or IL-4. CONCLUSIONS: In this model, TNF-alpha up-regulates mast cell surface receptors and cell-bound IgE. Interleukin 4 up-regulates mast cell ICAM-1 and cell-bound IgE, but down-regulates c-kit. CLINICAL RELEVANCE: Conjunctival mast cells play a critical role in the pathogenesis of atopic ocular disease. Characterization of the expression and regulation of mast cell surface receptors is important to the development of potential novel treatments for ocular inflammation.

Cell Separation↗
PubMed1996

Effects of loratadine and terfenadine on the induced nasal allergic reaction.

OBJECTIVE: To evaluate the effect of terfenadine and loratadine on the early nasal allergic response to challenge and the subsequent cellular influx and hyperresponsiveness. DESIGN: Double-blind, placebo-controlled, triple-crossover study. SUBJECTS: Fourteen, asymptomatic, allergic volunteers. INTERVENTIONS: After an initial challenge with methacholine chloride, subjects received treatment with placebo, loratadine (10 mg by mouth daily), or terfenadine (60 mg by mouth twice daily) for 1 week, followed by a nasal allergen challenge with lavages; 24 hours later, while the subjects were still receiving medication, the quantity of cells in the nasal lavage was determined, and another challenge with methacholine was done. Mediator levels were quantified in the nasal lavages after the allergen c hallenge, and the weight of the methacholine-induced nasal secretions was measured. RESULTS: Both loratadine and terfenadine treatment resulted in significant reductions in allergen-induced sneezing and the levels of histamine, kinins, albumin, and N-alpha-tosyl-L-arginine methyl ester-esterase activity in recovered nasal lavages compared with the reductions that resulted from placebo treatment, with no significant difference among the treatments. Treatment had no effect on the levels of tryptase, prostaglandin D2 or leukotriene C4. A significant eosinophil influx into nasal secretions 24 hours after the allergen challenge in patients who were receiving placebo (P=.006) was not affected by loratidine or terfenadine treatment. Comparing methacholine-induced secretions between screening challenges and challenges with the patients who were being treated with either loratadine or terfenadine, there was a significant decrease in secretions after the use of these antihistamines (P<.05). CONCLUSION: Both loratadine and terfenadine partially inhibit the early nasal response to allergen challenge and the subsequent reactivity to a challenge with methacholine without affecting the influx of eosinophils into nasal secretions.

Adult↗
PubMedDate not supplied

Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.

CONTEXT: Long-acting beta(2)-agonists are prescribed for patients with persistent asthma and are sometimes used without inhaled corticosteroids (ICSs). No evidence exists, however, to support their use as monotherapy in adults with persistent asthma. OBJECTIVE: To examine the effectiveness of salmeterol xinafoate, a long-acting beta(2)-agonist, as replacement therapy in patients whose asthma is well controlled by low-dose triamcinolone acetonide, an ICS. DESIGN AND SETTING: A 28-week, randomized, blinded, placebo-controlled, parallel group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 to January 1999. PARTICIPANTS: One hundred sixty-four patients aged 12 through 65 years with persistent asthma that was well controlled during a 6-week run-in period of treatment with inhaled triamcinolone (400 microg twice per day). INTERVENTIONS: Patients were randomly assigned to continue triamcinolone therapy (400 microg twice per day; n = 54) or switch to salmeterol (42 microg twice per day; n = 54) or to placebo (n = 56) for 16 weeks, after which all patients received placebo for an additional 6-week run-out period. MAIN OUTCOME MEASURES: Change in morning and evening peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV(1)), self-assessed asthma symptom scores, rescue albuterol use, asthma-specific quality-of-life scores, treatment failure, asthma exacerbation, bronchial reactivity, and markers of airway inflammation, compared among the 3 treatment groups. RESULTS: During the 16-week randomized treatment period, no significant differences between the salmeterol and triamcinolone groups were observed for conventional outcomes of clinical studies of asthma therapy-morning PEF, evening PEF, asthma symptom scores, rescue albuterol sulfate use, or quality of life. Both active treatments were superior to placebo. However, the salmeterol group had more treatment failures than the triamcinolone group (13/54 [24%] vs 3/54 [6%]; P =.004), as well as more asthma exacerbations (11/54 [20%] vs 4/54 [7%]; P =.04), greater increases in median (interquartile range) sputum eosinophils (2.4% [0.0% to 10.6%] vs -0.1% [-0.7% to 0.3%]; P<.001), eosinophil cationic protein (71 [-2 to 430] U/L vs -4 [-31 to 56] U/L; P =.005), and tryptase (3.1 [2.1 to 7.6] ng/mL vs 0.0 [0.0 to 0.7] ng/mL; P<.001). The duration of benefit when patients were switched from active treatment to placebo after 22 weeks of randomized treatment was not significantly longer in the triamcinolone group than in the salmeterol group. CONCLUSIONS: Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.

Administration, Inhalation↗
PubMed1999

The detection of mast cell subpopulations in formalin-fixed human tissues using a new monoclonal antibody specific for chymase.

Chymase is an important marker for human mast cells as well as a mediator of inflammation and matrix remodelling, but research into chymase-containing mast cell subpopulations has been hampered by the lack of reagents suitable for use with formalin-fixed tissue. A monoclonal antibody to chymase (designated CC1) was prepared by immunizing a mouse with chymase purified from human skin, fusing the splenocytes with NS-1 myeloma cells, and screening the hybridoma supernatants by ELISA with recombinant human prochymase isolated from a baculovirus expression system. This antibody bound to chymase in western blots and bound selectively to cells with the morphology and distribution of mast cells in paraffin wax sections of skin, synovium, lung, and heart. In sequential sections and with double-labelling experiments, chymase was localized to cells which contained mast cell tryptase; in contrast to previous reports, no evidence was found for its presence in endothelial cells or any other cell type. The antibody permitted chymase-containing mast cells to be detected in formalin-fixed tissues, and the numbers identified were similar to those in tissues fixed with Carnoy's or ethanol fixatives. Immunocytochemistry with antibody CC1 provides for the first time a sensitive and specific means for the detection of chymase in routinely fixed tissues and should prove valuable in studying mast cell subsets in disease.

Animals↗
PubMed1998

SP220K is a novel matrix serine proteinase.

Matrix proteinases play a critical role in extracellular matrix remodeling, which is particularly involved in cancer invasion and metastasis. We have previously characterized and purified a new tetrameric serine proteinase (SP220K) from human kidney clear cell carcinoma plasma membranes. Here, we report that SP220K exhibits gelatinase activity as assessed both in solution and by zymography. Optimum gelatinase activity ranges between pH 7.5 to pH 9.0. Fibronectin and type I collagen were hydrolyzed by SP220K, at variance with laminin and type IV collagen. Like other trypsin-like fibronectin degrading proteinases, SP220K released the 29-kDa N-terminal heparin-binding domain of fibronectin. By using a panel of proteinase inhibitors, we found that the inhibition profile of SP220K was different from that of other known serine proteinases such as thrombin, trypsin, plasmin, plasminogen activators and tryptase. Altogether, our results indicate that SP220K corresponds to a novel matrix proteinase that exhibits a marked specificity for fibronectin and type I collagen.

Collagen↗
PubMed1998

Biomarkers of nasal inflammation in wood-surface coating industry workers.

Upper airway symptoms in workers employed in the manufacture of wood products using ultraviolet radiation curing or acid curing of surface coating have been reported. In this study, workers were divided into groups according to exposure: (1) UV-surface coating line, (2) acid curing surface coating line, (3) finishing processes of UV-cured acrylate coated products, (4) finishing processes of of both UV- and acid cured coated wood products, and (5) control group. The workers were examined with nasal lavage in order to investigate inflammatory signs (ECP, tryptase, albumin and microscopy with cell differential counting). UV-line workers and finishers had significantly increased levels of ECP in nasal lavage. There was a positive correlation between exposure time and ECP and albumin levels. Workers with general nasal complaints and atopics had increased levels of ECP. In this study there were findings indicating an inflammatory process in the nasal mucosa in workers exposed to UV radiation curing multifunctional acrylate coatings. The findings indicate an unspecific inflammation and, therefore, a correlation between occupational exposure to acrylate coatings and nasal inflammation seems probable.

Acrylates↗
PubMed1996

Role of adenosine in asthma.

Several lines of evidence support the hypothesis that adenosine contributes to asthma. Inhaled adenosine provokes bronchoconstriction in asthmatics, but not in nonasthmatics. This process appears to be mediated by mast cell activation, because it can be blocked by antihistamines and inhibitors of mast cell activation. Inhaled adenosine evokes release of mast cell mediators in bronchoalveolar lavage fluid, including histamine, prostaglandin D2, and tryptase, a specific mast cell marker. Also, adenosine potentiates the immunological activation of mast cells in vitro, including rat peritoneal mast cells, mouse bone marrow-derived mast cells, human lung mast cells, and the human mast cell line HMC-1. The receptor subtype that mediates this activation differs between mast cell type, but preliminary evidence suggests that human lung mast cells express A2B receptors. An argument against the contribution of adenosine in asthma has been the "enprofylline paradox." This xanthine (3-(n-propylyl)xanthine) is as effective an antiasthmatic as theophylline (1,3-dimethyl xanthine) but was initially thought not to be an adenosine receptor antagonist. More recent evidence has confirmed that enprofylline blocks A2B receptors with a Ki (7 microM) similar to that of theophylline (13 microM) and well within its therapeutic plasma levels (5-25 microM). This finding, we believe, resolves the enprofylline paradox and supports the hypothesis that adenosine, through A2B receptor activation, contributes to asthma. Preliminary evidence suggests that A2B receptors are indeed present in human lung mast cells. A2B receptors, therefore, may be a potential target for the development of antiasthmatic drugs.

Adenosine↗
PubMed1995

Acute basophilic leukemia in a child. Anaphylactoid reaction and coagulopathy secondary to vincristine-mediated degranulation.

BACKGROUND: Acute de novo basophilic leukemia (ABL) is uncommon in adults, and extremely rare in children. To the authors' knowledge, there have been no previous reports of anaphylactoid reactions from basophilic degranulation in children with this condition. METHODS: This report describes the clinicopathologic profile and complications of a patient with de novo ABL. RESULTS: Immediately after the first induction dose of intravenous vincristine, the patient developed an anaphylactoid reaction and disseminated intravascular coagulation with massive pulmonary hemorrhage. A normal serum tryptase level suggested that this life-threatening event was secondary to tumor lysis (basophilic degranulation), rather than to a mast-cell mediated anaphylactic reaction to vincristine. This interpretation is supported by the coagulation studies, which suggested release of heparin from the blast granules. CONCLUSIONS: Although de novo ABL is rare, it should be considered when cytoplasmic basophilic granules are seen in the leukemic cells of patients with what otherwise appears to be undifferentiated leukemia, and the pertinent diagnostic procedures should be undertaken. During the treatment of ABL, potential complications related to basophilic degranulation should be anticipated, and antihistamine prophylaxis may be of value.

Anaphylaxis↗
PubMed1997

Asthma: a dynamic disease of inflammation and repair.

It is now widely accepted that asthma in its varied forms is an inflammatory disorder of the airways in which mediator release from activated mast cells and eosinophils plays a major role. T lymphocytes take a primary role in orchestrating these processes through their capacity to generate a range of cytokines of the interleukin 4 gene cluster encoded on the long arm of chromosome 5. Additional cytokines derived from mast cells and eosinophils also play a key role, especially tumour necrosis factor alpha, which is responsible for initiating the up-regulation of vascular adhesion molecules involved in the recruitment of eosinophils and other inflammatory cells from the circulation. The importance of C-X-C and C-C chemokines as local chemoattractants and activating stimuli is also recognized. In addition to releasing an array of pharmacologically active autacoids, the inflammatory response in asthma results in the generation of proteolytic activities from mast cells (tryptase, chymase), eosinophils (MMP-9) and the epithelium itself (MMP-2, MMP-9), which exert tissue-destructive and cell-signalling effects. The epithelium is also highly activated, as evidenced by the up-regulation of cytokine production, inducible enzymes and soluble mediators. Increased surface expression of the epithelial isoform of CD44 (9v) and subepithelial proliferation of myofibroblasts are indicative of a simultaneous active repair process and the laying down of new interstitial collagens. Together, inflammatory and repair processes create the complex phenotype that characterizes asthma and its progression.

Asthma↗
PubMed1993

Controlled short-time terpene exposure induces an increase of the macrophages and the mast cells in bronchoalveolar lavage fluid.

Eight healthy nonsmoking volunteers underwent terpene exposure (450 mg/m3 air) on 4 different occasions within a 2 week period. Total exposure time was 12 hours. Before and after the sequences of exposure, bronchoalveolar lavage was performed. Twenty hours after the exposure there was a significant (p < 0.05) increase of the alveolar cell concentration (median pre-exposure value 76 x 10(6) cells/L, post-exposure value 126 x 10(6) cells/L), predominantly due to an increment of the macrophages (from 72 x 10(6) cells/L to 121 x 10(6) cells/L). The mast cells also increased from 1/10 to 5/10 visual fields. No elevated concentrations of albumin, fibronectin, hyaluronan (hyaluronic acid), and tryptase were observed. We conclude that terpene exposure, in a concentration regarded as moderate, induces an acute alveolar cellular reaction in healthy subjects.

Adult↗
PubMed2006

Lymphocyte-independent connective tissue mast cells populate murine synovium.

OBJECTIVE: Mast cells (MCs) are a heterogeneous population of tissue-resident bone marrow-derived cells; distinct MC subpopulations are situated at specific microanatomic locations. The phenotype of the murine synovial MC remains undefined. Since MCs have been implicated in the pathogenesis of inflammatory arthritis, we sought to define the phenotype of the murine synovial MC population in normal and arthritic joints. We also examined the contribution of lymphocytes to synovial MC physiology. METHODS: The MC phenotype in healthy and K/BxN serum transfer-induced arthritic synovial tissue was defined using immunohistochemical staining of prototypic MC-specific proteases (murine MC proteases [mMCP] 1, 2, 4, 5, 6, and 7) (chymases and tryptases). MC numbers and density were determined by histomorphometry in healthy and arthritic synovia. The lymphocyte contribution to MC populations was assessed using RAG-null mice. RESULTS: We found that synovial MCs display a connective tissue mast cell (CTMC) phenotype in both normal and arthritic synovial tissue, which expresses mMCP-4, -5, -6, and -7, but not mMCP-1 or mMCP-2. In addition, MC hyperplasia was seen in the arthritic synovium. In RAG-null mice, the phenotype and degree of MC hyperplasia were identical to those observed in normal mice with and without arthritis. Furthermore, in contrast to skin CTMCs, all synovial MCs expressed mMCP-6, demonstrating discrete differences between synovial CTMCs and other anatomic CTMC populations. CONCLUSION: Our findings demonstrate that the murine synovial MC population is composed of lymphocyte-independent CTMCs and identify arthritic synovium as a model system by which to gain insight into the poorly understood physiology of CTMCs in chronic inflammation.

Animals↗
PubMed1994

Human granzyme B is essential for DNA fragmentation of susceptible target cells.

We have partially characterized the granules of the human NK cell line, YT-INDY, and assessed granule-mediated lysis and DNA fragmentation of assorted targets. Biochemical studies demonstrated significant quantities of granzyme B (asp-ase) and a heretofore undescribed chymase but no tryptase (i.e., granzyme A or 3) or distinct met-ase. YT-INDY expressed mRNA for granzyme B, perforin and CCPX. The existence of perforin was confirmed by immunoblot. The granules lysed both human and murine NK-sensitive and NK-resistant targets. YT-INDY and NK3.3, two human cytotoxic cells, were also lysed. EGTA reduced lysis by only 50%, suggesting that a perforin-independent lytic pathway is associated with the granules. In addition, 4-(2-aminoethyl) benzenesulfonylfluoride hydrochloride (AEBSF), an inhibitor that selectively blocked the chymase and 3,4-dichloroisocoumarin (DCI), an inhibitor that inactivated both chymase and asp-ase activities, marginally affected lysis. By gel electrophoresis and 125I-labeled deoxyuridine release assay, only murine cells (SP2/0 and YAC-1) underwent DNA fragmentation, and cleavage was completely inhibited by DCI, whereas EGTA, AEBSF and aurintricarboxylic acid (ATA) had no effect. The results, therefore, underscore the central role of granzyme B in granule-mediated DNA fragmentation, emphasize that the protease acts via an ATA-resistant endonuclease pathway and stress that nucleolysis does not invariably accompany granule-mediated cytolysis. Finally, ATA inhibited the asp-ase activity of isolated but not granule-associated granzyme B. ATA, therefore, is not a specific endonuclease inhibitor and results obtained with ATA should be viewed cautiously.

Animals↗