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Biomedical subjects

B Schnyder

Publications and source records attributed to B Schnyder.

At least 19 recordsLinked to original sources
PubMed2000

Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals.

The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usually explained with the hapten-carrier model. However, recent investigations have revealed a MHC-restricted but processing- and metabolism-independent pathway of drug presentation. This suggested a labile, low-affinity binding of SMX to MHC-peptide complexes on APC. To study the role of covalent vs noncovalent drug presentation in SMX allergy, we analyzed the proliferative response of PBMC and T cell clones from patients with SMX allergy to SMX and its reactive oxidative metabolites SMX-hydroxylamine and nitroso-SMX. Although the great majority of T cell clones were specific for noncovalently bound SMX, PBMC and a small fraction of clones responded to nitroso-SMX-modified cells or were cross-reactive. Rapid down-regulation of TCR expression in T cell clones upon stimulation indicated a processing-independent activation irrespective of specificity for covalently or noncovalently presented Ag. In conclusion, our data show that recognition of SMX presented in covalent and noncovalent bound form is possible by the same TCR but that the former is the exception rather than the rule. The scarcity of cross-reactivity between covalently and noncovalently bound SMX suggests that the primary stimulation may be directed to the noncovalently bound SMX.

Anti-Infective Agents↗
PubMed2000

[Allergy to house dust mites].

The prevalence of atopic disease in Switzerland is 15-20%. About 30% of these patients have perennial symptoms and a substantial proportion are allergic to house-dust mite proteins. If absolute air humidity is lower than 7.0 g water per kg air, house-dust mites will not proliferate. This is why the occurrence of house-dust mites varies between different regions. About half of the patients with allergy to house-dust mites complain of rhinitis, a quarter of asthma and a quarter of asthma and rhinitis. The diagnosis is usually by history, skin prick tests and if necessary provocation. Therapy includes allergen avoidance (reduction of air humidity in dwellings by ventilation, encasing of mattresses and bedding), medication (mainly topical corticosteroids) and specific immunotherapy.

Animals↗
PubMed2000

[Urticaria].

Urticaria may affect as many as 25% of all people at some time during their lives. The hallmark of urticaria are transitory and completely reversible wheals (intracutaneous oedema). There are multiple causes of urticaria. It has various clinical expressions. Corresponding to the time course it is possible to differentiate between acute, acute relapsing and chronic urticaria. Acute and acute relapsing urticaria is often caused by an allergy or "pseudoallergy". Causal factors of chronic urticaria are usually elusive and therefore only a symptomatic treatment is possible. H1 antihistamines with a low potential for sedation are the most important first-line treatment.

Diagnosis, Differential↗
PubMed2000

Skin and laboratory tests in amoxicillin- and penicillin-induced morbilliform skin eruption.

BACKGROUND: Cutaneous amoxicillin- and penicillin-mediated reactions can be classified as immediate and delayed-type reactions. Immediate reactions are thought to involve IgE antibodies and have been studied extensively. In contrast only few data exist about delayed reactions such as morbilliform or maculopapular rash. OBJECTIVE: To assess the predictive value of immediate skin tests, skin-patch tests, specific IgE and lymphocyte transformation tests with regard to the diagnosis of delayed skin eruptions. METHODS: Skin and in vitro tests were performed in 18 subjects. Twelve subjects had penicillin- or amoxicillin-induced morbilliform exanthema and six were controls without hypersensitivity reaction, tested before and after exposure. RESULTS: Specific IgE to penicillin and immediate penicillin skin tests were negative in amoxicillin- or penicillin-induced delayed skin eruptions. In contrast, skin-patch testing and LTT were positive in 9/12 or 10/12, respectively, but negative in all six controls. CONCLUSION: These findings substantiate a T-cell-mediated immune pathomechanism in the majority of penicillin-induced delayed skin reaction. Moreover, they underline the necessity to adapt the test procedures to underlying pathomechanisms and support the diagnostic value of skin-patch testing and LTT in delayed cutaneous reactions to penicillins.

Adult↗
PubMed1999

[Food intolerance and food allergy].

Confirmed adverse reactions to foods may be caused by toxic, enzymatic, pharmacological, "pseudoallergic" or allergic mechanisms. True food allergies are mostly IgE-mediated and directed against one or only a few food proteins. They appear typically as eczema and gastrointestinal symptoms (vomiting, diarrhoea, abdominal cramps) among infants and as oral allergy syndrome, urticaria/angioedema, rhinoconjunctivitis or anaphylaxis among adults. The majority of food allergies among adults is caused by cross-reactivity of IgE against inhalative allergens also reacting with food proteins. This must be considered in investigations by skin-prick testing and/or specific IgE measurement, since the sensitivity of these tests for inhalative allergens is higher than for food proteins. The most frequent differential diagnoses of true allergies are pseudoallergic reactions to food additives or pharmacological reactions to biogenic amines. The diagnosis of these reactions can usually be based on the history and course under a corresponding diet. In clinical practice additional investigations by double-blind placebo-controlled food challenges are rarely required. A positive challenge test demonstrates only the cause-and-effect relationship of the foods and the patient's symptoms but does not demonstrate the underlying mechanism. The therapy of food intolerance is a corresponding diet. This requires a careful diagnosis and identification of the causative foods.

Adult↗
PubMed1999

[Drug allergy].

Drug reactions can be differentiated into immediate and delayed types. Immediate type reactions are life threatening or manifest themselves as urticaria /angioedema, asthma or anaphylaxis. They may be mediated by specific IgE antibodies or more frequently by non-immunological mechanisms (so-called "pseudoallergies"). Delayed type reactions are the most frequent immunological reactions. They appear mostly as maculo-papulous exanthema. Rarely they may become life threatening and lead to fever and involvement of visceral organs. In life threatening reactions further exposure to the causative drug should be strictly avoided. If the diagnosis of a drug allergy and of the causative drug is insecure, further allergological investigations are justified.

Drug Hypersensitivity↗
PubMed1999

Interaction of sulfonamide derivatives with the TCR of sulfamethoxazole-specific human alpha beta+ T cell clones.

Drugs like sulfamethoxazole (SMX) or lidocaine can be presented to specific human alphabeta+ T cell clones (TCC) by undergoing a noncovalent association with MHC-peptide complexes on HLA-matched APCs. For a better understanding of the molecular basis of the recognition of such drugs by specific TCC, we investigated 1) the fine specificity of the recognizing TCR, 2) the dose-response relationship for the induction of proliferation or cytokine production, and 3) the mechanism of TCR triggering. For that purpose, we tested the reactivity of 11 SMX-specific CD4+ TCC and 2 SMX-specific CD8+ TCC to a panel of 13 different sulfonamide derivatives bearing the same core structure. Five of 13 clones recognized only SMX, while all other clones were responding to as many as 6 different compounds. Some of the compounds needed up to two orders of magnitude higher concentrations than SMX to stimulate TCC, thereby displaying features of weak agonists. Different clones showed clear differences in the minimal drug concentration required for the induction of a proliferative response. Therefore, weaker or stronger agonistic properties were not a characteristic of a given sulfonamide derivative but rather an intrinsic property of the reacting TCR. Finally, the number of down-regulated TCRs was a logarithmic function of the ligand concentration, implicating that specific T cells were activated by serial TCR engagement. Our data demonstrate that, despite the special way of presentation, nonpeptide Ag like drugs appear to interact with the TCR of specific T cells in a similar way as peptide Ags.

Clone Cells↗
PubMed1999

Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice.

Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis. COX-2 is inducible and is the major isoform of inflammatory cells. COX-2-deficient mice were shown to have normal basal hematopoiesis and hematology. We hypothesized that COX-2 induction plays a role in the recovery phase of 5-fluorouracil (5-FU) induced bone marrow injury, because significant macrophage-driven phagocytic removal of necrotic debris and stromal cell reorganization of repopulating marrow occur after 5-FU induction of bone marrow necrosis. Hematologic recovery was markedly delayed with moderately severe leukopenia, thrombocytopenia and reticulocytopenia compared to heterozygotes on day 8 or 12 in Cox-2-/- mice. Mild anemia was present in 5-FU-treated Cox-2-/- and Cox-2+/- mice on days 8 and 12, which was more severe in Cox-2-/- mice. Cox-2-/- mice had markedly decreased bone marrow cell counts per femur and reduced numbers of erythroid and myeloid colony-forming cells compared to heterozygote mice on days 8 and 12 post 5-FU. Histologic examination of 5-FU-treated Cox-2-/- mice revealed a failure to repopulate the intact marrow stroma with hematopoietic cells. Accelerated erythropoiesis following phenylhydrazine-induced hemolytic anemia, however, was comparable between Cox-2-/- and Cox+/- mice, as were induced levels of renal erythropoietin mRNA. COX-2 induction is likely a central event in the accelerated hematopoiesis following myelotoxic injury, because recovery from 5-FU-induced myeloablation is markedly impaired in Cox-2-/- mice but is normal after phenylhydrazine induction of anemia.

Animals↗
PubMed1999

Regulation of blood pressure during long-term ouabain infusion in Long-Evans rats.

We tested whether ouabain, an inhibitor of the sodium pump, can lead to chronic hypertension in Long-Evans rats using sensitive 24-h measurements of blood pressure. After a control week of vehicle isotonic saline infusion (14.4 mL/day), ouabain was infused intravenously at 30 microg/kg/day in intact (2K) and uninephrectomized (1K) Long-Evans rats for a total of 4 weeks. Although plasma ouabain concentration rose to 0.97 +/- 0.15 nmol/L with ouabain infusion, mean arterial pressure did not change in either 2K (delta = -0.6 +/- 1.3 mm Hg) or 1K (delta = -1.2 +/- 0.7 mm Hg) rats. These data suggest that Long-Evans rats are insensitive to the hypertensive effects of ouabain.

Animals↗
PubMed1999

Recognition of local anesthetics by alphabeta+ T cells.

Patients with drug allergy show a specific immune response to drugs. Chemically nonreactive drugs like, for example, local anesthetics are directly recognized by alphabeta+ T cells in an HLA-DR restricted way, as neither drug metabolism nor protein processing is required for T cell stimulation. In this study we identified some of the structural requirements that determine cross-reactivity of T cells to local anesthetics, with the aim to improve the molecular basis for the selection of alternatives in individuals sensitized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine specific, three mepivacaine specific from two allergic donors) were analyzed. Stimulatory compounds induced a down-regulation of the T cell receptor, demonstrating that these non-peptide antigens are recognized by the T cell receptor itself. A consistent cross-reactivity between lidocaine and mepivacaine was found, as all except one lidocaine specific clone proliferated to both drugs tested. Sixteen chemically related local anesthetics (including ester local anesthetics, OH- and desalkylated metabolites) were used to identify structural requirements for T cell recognition. Each of the four clones examined in detail was uniquely sensitive to changes in the structures of the local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all OH-metabolites and other differently modified molecules. The broadly reactive clone OFB2 allowed us to propose a model, suggesting that the structure of the amine side chain of local anesthetics is essential for recognition by the T cell receptor.

Anesthetics, Local↗
PubMed1999

Chronic idiopathic urticaria: natural course and association with Helicobacter pylori infection.

BACKGROUND: Chronic urticaria is a common disease, though only few data on its natural course are available. In most cases the cause cannot be determined. Recently a relationship of chronic urticaria to infection with Helicobacter pylori (HP) has been postulated, but no controlled study has been performed to prove this association. METHODS: In this prospective study the clinical course and rate of HP infection in 46 patients with chronic 'idiopathic' urticaria were investigated. Infected patients were treated in a double-blind placebo-controlled crossover study with amoxycillin and lansoprazol. Eradication and clinical course were followed up 2 months after each treatment, respectively, 3 and 6 months after the first consultation. RESULTS: In 19/46 (41%) the chronic 'idiopathic' urticaria resolved within 6 months. 12 patients (24%) were infected with HP, which corresponds to the infection rate of the population at comparable ages without urticaria in Switzerland. Eradication of HP was achieved in 3, but only in 1 was the eradication associated with the resolution of urticaria. CONCLUSIONS: Our data show that in young patients with a rather short history of chronic urticaria frequently a rather favourable natural course of chronic idiopathic urticaria can be seen. No association between HP infection and chronic urticaria could be demonstrated.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Role of interleukin-8 phosphorylated kinases in stimulating neutrophil migration through fibrin gels.

Interleukin (IL)-8 elicits neutrophil migration in the early inflammatory response. This action of IL-8 is believed to involve mitogen-activated protein (MAP) kinase p44/42. In the present study, we used specific inhibitors to investigate the role of p44/42 kinase in stimulating neutrophil migration. The IL-8-guided migration through an imitation of inflammatory matrix, a fibrin gel, was impaired by 90% after treatment with 7 microM U0126, a specific inhibitor of the kinase of p44/42 kinase. Superoxide anion generation induced by high concentrations of bacterial signals was not impaired in the absence of functional p44/42. This anion generation could be decoupled from the p44/42 independency by priming the cells, a pretreatment with IL-8. The addition of U0126 inhibited by 60% the priming and subsequent superoxide anion generation triggered by low concentrations of bacterial signals. An impact on the priming effect and migration of neutrophils was found upon blockade (with wortmannin) of a further kinase event that converges on the p44/42 phosphorylation. Wortmannin blocked phosphatidylinositol 3-kinase and secondarily phosphorylation of p44/42 and of the p44/42-related MAP kinase p38. The overlapping functional consequences of a specific blockade of p38 MAP kinase (applying in vivo anti-inflammatory pyridinyl imidazole) further ascribed a migratory role to those signals culminating in p44/42 MAP kinase phosphorylation, and suggests a role in vivo.

Cell Movement↗
PubMed1998

HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.

T cell recognition of drugs is explained by the hapten-carrier model, implying covalent binding of chemically reactive drugs to carrier proteins. However, most drugs are nonreactive and their recognition by T cells is unclear. We generated T cell clones from allergic individuals specific to sulfamethoxazole, lidocaine (nonreactive drugs), and cef-triaxone (per se reactive beta-lactam antibiotic) and compared the increase of intracellular free calcium concentration ([Ca2+]i) and the kinetics of T cell receptor (TCR) downregulation of these clones by drug-specific stimulations. All drugs tested induced an MHC-restricted, dose- and antigen-presenting cell (APC)-dependent TCR downregulation on specific CD4(+) and CD8(+) T cell clones. Chemically nonreactive drugs elicited an immediate and sustained [Ca2+]i increase and a rapid TCR downregulation, but only when these drugs were added in solution to APC and clone. In contrast, the chemically reactive hapten ceftriaxone added in solution needed > 6 h to induce TCR downregulation. When APC were preincubated with ceftriaxone, a rapid downregulation of the TCR and cytokine secretion was observed, suggesting a stable presentation of a covalently modified peptide. Our data demonstrate two distinct pathways of drug presentation to activated specific T cells. The per se reactive ceftriaxone is presented after covalent binding to carrier peptides. Nonreactive drugs can be recognized by specific alphabeta+ T cells via a nonconventional presentation pathway based on a labile binding of the drug to MHC-peptide complexes.

Antigen Presentation↗
PubMed1998

Inhibition of kinases impairs neutrophil activation and killing of Staphylococcus aureus.

Intracellular phosphorylations polymorphonuclear neutrophils are mediated by kinases, including mitogen activated-protein (MAP) kinases and phosphatidylinositol 3-kinase. In the present study we demonstrate their effector functions upon both ligation of cell-surface seven-transmembrane-spanning receptors by bacterial peptide formylmethionyl-leucylphenylalanine as well as in the process of destruction of Staphylococcus aureus. To regulate neutrophil MAP kinases p38 and p44/42, specifically, we made use of their specific inhibitors 10 microM SK&F 86002 (for p38) and PD 098059 (for activating kinase of p44/42). SK&F 86002 was a potent inhibitor (by 70%) of induced antimicrobial oxygen-radical generation compared with PD 098059 (by 20%). SK&F 86002 and PD 098059 inhibited mobilization of a dominant neutrophil adhesion molecule, beta2 integrin, from cytoplasmic granules to the plasma membrane by 40 and 10% respectively, and the combination of the two drugs resulted in a 90% effect. The combined effect of both drugs was moderate inhibition of bacterial destruction, despite the fact that neither compound had detectable effect on bactericidal activity if applied individually. Bacterial destruction was also inhibited by wortmannin (0.1 microM), the specific inhibitor of phosphatidylinositol 3-kinase, which had previously been described to target various other activations of the neutrophil, including oxygen-radical generation. Although the relative contribution of p38 and p44/42 MAP kinases varied, the marked effects of the combined inhibition of the kinases revealed their concerted actions to be critical for normal neutrophil function.

Androstadienes↗
PubMed1998

T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction.

BACKGROUND: The incidence of skin rashes or erythema multiforme to sulfamethoxazole in exposed patients is about 3%. Among patients with acquired immunodeficiency syndrome the risk is approximately 10 times higher. The pathogenesis of these reactions and the reason for the increased frequency in HIV infections are not understood. OBJECTIVE: To investigate drug specific T-cell-mediated cytotoxicity in sulfamethoxazole- induced skin reactions. METHODS: Specific T-cell lines and T-cell clones generated from a donor who developed a skin rash to sulfamethoxazole were assessed with a standard 4 h 51Cr cytotoxicity assay in the presence or absence of soluble sulfamethoxazole. B lymphoblasts and keratinocytes with and without interferon gamma pretreatment were used as target cells. Selective blockers of FasL/Fas and perforin-mediated killing and immunostaining for perforin were used to evaluate the involvement of the different cytolytic pathways. RESULTS: CD4+ and CD8+ sulfamethoxazole specific T-cell clones showed a drug-specific and MHC-restricted cytotoxicity against autologous B lymphoblasts in the presence of soluble sulfamethoxazole. Keratinocytes, if pretreated with interferon gamma, were specifically killed predominantly by CD4+ T-cell clones. Specific T-cell clones of both CD4+ and CD8+ phenotype showed a strong immunoreactivity for perforin and the cytotoxicity was blocked by concanamycin A which suggests a perforin-mediated killing. CONCLUSION: Perforin-mediated killing of autologous keratinocytes in the presence of soluble sulfamethoxazole by drug-specific CD4+ lymphocytes may be a pathway for generalized drug-induced delayed skin reactions. The requirement of interferon gamma pretreatment of keratinocytes for efficient specific killing might explain the increased frequency of drug allergies in generalized viral infections like HIV, when interferon gamma levels are elevated.

CD4-Positive T-Lymphocytes↗
PubMed1998

Allele-unrestricted presentation of lidocaine by HLA-DR molecules to specific alphabeta+ T cell clones.

T cells recognize peptide and non-peptide antigens. Drugs represent typical examples of non-peptide antigens. The majority of drug-specific T cells are alphabeta+ TCR T cells and are MHC class I or II restricted. Here we show the existence of drug (lidocaine)-specific T cell clones which proliferate in the presence of antigen-presenting cells (APC) with different HLA alleles. Two clones (SFT24 and E20) were analyzed in detail. They show a narrow dose-dependent proliferation to lidocaine, but not to procaine. With the use of a panel of HLA-typed allogeneic APC, we observed that certain allogeneic APC plus lidocaine lead to a similar, others to partial and some to no proliferation of the lidocaine-specific T cell clones. An APC-independent proliferation could be excluded since both clones proliferated only marginally without APC and increasing the number of APC resulted in a higher proliferation. Blocking experiments with anti-DP, -DQ and -DR antibodies showed that lidocaine is presented in a HLA-DR-restricted way both with autologous or allogeneic APC. Mouse fibroblasts transfected with an allogeneic HLA-DRB1*01 but not HLA-DR-negative mouse fibroblasts could serve as presenting cells. Fixation of APC did not hamper drug presentation, but pulsing of APC with the drug was not possible, indicating that processing is not required and that lidocaine binds in an unstable way to the MHC-peptide complex. This degenerate drug recognition has certain features of superantigen recognition, such as the ability of drugs to bind from the outside to multiple HLA-DR alleles. Such features of drug recognition may open new therapeutic possibilities to intervene with TCR-MHC interactions in a selective way.

Adult↗