There is a long tradition of attempts to derive the Libyco-Berber script from the Phoenician one ... more There is a long tradition of attempts to derive the Libyco-Berber script from the Phoenician one (Halévy 1874, Meinhof 1931, Bates 1914, Prasse 1972, Chaker 1984, Iliffe 1997, Pichler 2007), comparatively few colleagues favoured the Punic thesis (Février 1959, O' ...
Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimula... more Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimulations are not antigen-driven, but due to non-covalent drug-protein binding. The drugs may bind to immune receptors like HLA or TCR which elicits a strong T cell reaction (p-i concept), the binding may enhance the affinity of antibodies (enhanced affinity model), or drug binding may occur on soluble proteins which imitate a true antigen (fake antigen model). These novel models of DH could have a major impact on how to perform risk assessments in drug development. Herein, we discuss the difficulties of detecting such non-covalent, labile and reversible, but immunologically relevant drug-protein interactions early on in drug development. The enormous diversity of the immune system, varying interactions, and heterogeneous functional consequences make it to a challenging task. We propose that a realistic approach to detect clinically relevant non-covalent drug interactions for a new drug coul...
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Extensive formation of nonfollicular sterile pustules on erythematous background combined with fe... more Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease , showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells , differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4-and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis , to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease , in particular for the formation of vesicles. The data reveal that drug-specific CD4 ؉ as well as CD8 ؉ T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.
Drug side eVects are common. They are usually classified as type A reactions if they are related ... more Drug side eVects are common. They are usually classified as type A reactions if they are related to the pharmacological activity of the drug, and type B reactions if unrelated to the pharmacological activity. Immune mediated side eVects are type B reactions and account for about one seventh of all drug related side eVects. Their frequency is, however, highly dependent on the type of drug. Some drugs are notorious for their allergic side eVects—for example, some antibiotics and antiepileptics— while other drugs are seldom related to allergies. The diagnosis of drug allergy is diYcult for various reasons. Firstly, the clinical manifestations of drug allergies are very heterogeneous. Drug allergic reactions imitate diseases, causing symptoms similar to infectious, autoimmune, or superantigen triggered diseases. If no skin symptoms are present, drug induced allergic reactions such as hepatitis or interstitial lung diseases are likely to be underdiagnosed. Moreover, viral infections such...
Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well establ... more Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are (a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. (b) Some noncovalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-protein adducts. Such drug-protein complexes represent so-called "fake antigens," as they are unable to induce immunity, but may react with and cross-link preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. (c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE-mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.
Swiss Medical Forum ‒ Schweizerisches Medizin-Forum, 2008
Herzlichen Dank, dass Sie sich Zeit genommen haben, in den Schlaglichtern des SMF Ihre Ansicht zu... more Herzlichen Dank, dass Sie sich Zeit genommen haben, in den Schlaglichtern des SMF Ihre Ansicht zu Sicherheit von Medikamenten darzustellen. Sie beklagen, dass die Zulassungsbehörden wie z.B. die FDA aufgrund von politischem Druck die Sicherheitsfrage von Medikamenten so interpretieren, dass eine Nulltoleranz-Politik entwickelt und die Nutzen-Nebenwirkungsabwägung den Ärzten entzogen werden. Dies führt dazu, dass wirksame Medikamente wegen potentieller Gefahren in einer Subgruppe nicht mehr zugelassen und als Folge davon bald gar nicht mehr entwickelt werden.
Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including s... more Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10 −9) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10 −9) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
International Journal of Basic and Clinical Pharmacology, 2016
This patient had a two-month history of four clinical manifestations of drug hypersensitivity rea... more This patient had a two-month history of four clinical manifestations of drug hypersensitivity reactions (DHR): maculo papular eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN). The eliciting drugs were rifampicin, possibly gabapentin, levofloxacin, meropenam and/or colistin. Thus, the patient might develop a multiple drug hypersensitivity syndrome. The TEN-like lesion appeared after stopping drugs for two days. A different manifestation of DHR in dependence of drug use suggests that the distinct manifestations of DHRs are due to the stimulation of T cells with distinct functions. The simultaneous appearance of AGEP and DRESS symptoms might be due to the simultaneous stimulation of two (or more) different T cell subsets, which are functionally dominant. Lastly, the appearance and further propagation of symptoms after therapy-stop is a common but somewhat neglected problem in DHR, which raises questions regarding the cause of persisting T cell activation.
Current opinion in allergy and clinical immunology, 2010
Vychází díky edukačnímu grantu firmy Medical Tribune CZ, s. r. o., má výhradní právo na překlady ... more Vychází díky edukačnímu grantu firmy Medical Tribune CZ, s. r. o., má výhradní právo na překlady a publikaci článků z časopisu Current Opinion in Allergy and Clinical Immunology a Current Opinion in Pulmonary Medicine. Pořizování kopií jakéhokoli článku nebo jeho části a jejich šíření v jakékoli formě bez předchozího souhlasu nakladatelství Lippincott Williams & Wilkins a Medical Tribune CZ, s. r. o. je zakázáno. Redakce neodpovídá za obsah uveřejněné reklamy.
The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usually explained with the... more 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...
More than 70% of birch-pollen-allergic patients suffer from an oral allergy syndrome (OAS) to fru... more More than 70% of birch-pollen-allergic patients suffer from an oral allergy syndrome (OAS) to fruits and/or nuts, especially to apple (1-3). This pollen fruit syndrome is based on a molecular similarity of their major allergens (all PR-10) leading to clinical cross-reactivity. One of the best studied examples is the cross-reactivity between Bet v 1 in birch pollen and Mal d 1 in apple (4). PR-10 proteins are rapidly released during the chewing process, but rather labile and quickly destroyed by digestive enzymes in the oral cavity. A large proportion of patients with OAS avoid or only eat processed fruits, which contain only negligible amounts of PR-10 proteins. As fresh fruits are considered important for well-balanced diet (5), many of these patients seek help in getting rid of these mostly harmless, but annoying symptoms. There is beneficial effect of birchpollen-specific subcutaneous immunotherapy on OAS to apple, with excellent improvement in some (1, 6-9), but limited effect in other studies (10-15). However, successful birch-pollen-specific sublingual immunotherapy only improved respiratory symptoms but showed no consistent effect on OAS (12, 14-16). In this study, we investigated whether it is possible to induce local oral tolerance in these patients by daily oral intake of increasing amounts of apple allergens. Furthermore, we analyzed the systemic immune response by several in vivo and in vitro markers.
Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to w... more Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an
There is a long tradition of attempts to derive the Libyco-Berber script from the Phoenician one ... more There is a long tradition of attempts to derive the Libyco-Berber script from the Phoenician one (Halévy 1874, Meinhof 1931, Bates 1914, Prasse 1972, Chaker 1984, Iliffe 1997, Pichler 2007), comparatively few colleagues favoured the Punic thesis (Février 1959, O' ...
Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimula... more Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimulations are not antigen-driven, but due to non-covalent drug-protein binding. The drugs may bind to immune receptors like HLA or TCR which elicits a strong T cell reaction (p-i concept), the binding may enhance the affinity of antibodies (enhanced affinity model), or drug binding may occur on soluble proteins which imitate a true antigen (fake antigen model). These novel models of DH could have a major impact on how to perform risk assessments in drug development. Herein, we discuss the difficulties of detecting such non-covalent, labile and reversible, but immunologically relevant drug-protein interactions early on in drug development. The enormous diversity of the immune system, varying interactions, and heterogeneous functional consequences make it to a challenging task. We propose that a realistic approach to detect clinically relevant non-covalent drug interactions for a new drug coul...
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Extensive formation of nonfollicular sterile pustules on erythematous background combined with fe... more Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease , showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells , differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4-and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis , to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease , in particular for the formation of vesicles. The data reveal that drug-specific CD4 ؉ as well as CD8 ؉ T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.
Drug side eVects are common. They are usually classified as type A reactions if they are related ... more Drug side eVects are common. They are usually classified as type A reactions if they are related to the pharmacological activity of the drug, and type B reactions if unrelated to the pharmacological activity. Immune mediated side eVects are type B reactions and account for about one seventh of all drug related side eVects. Their frequency is, however, highly dependent on the type of drug. Some drugs are notorious for their allergic side eVects—for example, some antibiotics and antiepileptics— while other drugs are seldom related to allergies. The diagnosis of drug allergy is diYcult for various reasons. Firstly, the clinical manifestations of drug allergies are very heterogeneous. Drug allergic reactions imitate diseases, causing symptoms similar to infectious, autoimmune, or superantigen triggered diseases. If no skin symptoms are present, drug induced allergic reactions such as hepatitis or interstitial lung diseases are likely to be underdiagnosed. Moreover, viral infections such...
Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well establ... more Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are (a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. (b) Some noncovalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-protein adducts. Such drug-protein complexes represent so-called "fake antigens," as they are unable to induce immunity, but may react with and cross-link preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. (c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE-mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.
Swiss Medical Forum ‒ Schweizerisches Medizin-Forum, 2008
Herzlichen Dank, dass Sie sich Zeit genommen haben, in den Schlaglichtern des SMF Ihre Ansicht zu... more Herzlichen Dank, dass Sie sich Zeit genommen haben, in den Schlaglichtern des SMF Ihre Ansicht zu Sicherheit von Medikamenten darzustellen. Sie beklagen, dass die Zulassungsbehörden wie z.B. die FDA aufgrund von politischem Druck die Sicherheitsfrage von Medikamenten so interpretieren, dass eine Nulltoleranz-Politik entwickelt und die Nutzen-Nebenwirkungsabwägung den Ärzten entzogen werden. Dies führt dazu, dass wirksame Medikamente wegen potentieller Gefahren in einer Subgruppe nicht mehr zugelassen und als Folge davon bald gar nicht mehr entwickelt werden.
Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including s... more Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10 −9) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10 −9) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
International Journal of Basic and Clinical Pharmacology, 2016
This patient had a two-month history of four clinical manifestations of drug hypersensitivity rea... more This patient had a two-month history of four clinical manifestations of drug hypersensitivity reactions (DHR): maculo papular eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN). The eliciting drugs were rifampicin, possibly gabapentin, levofloxacin, meropenam and/or colistin. Thus, the patient might develop a multiple drug hypersensitivity syndrome. The TEN-like lesion appeared after stopping drugs for two days. A different manifestation of DHR in dependence of drug use suggests that the distinct manifestations of DHRs are due to the stimulation of T cells with distinct functions. The simultaneous appearance of AGEP and DRESS symptoms might be due to the simultaneous stimulation of two (or more) different T cell subsets, which are functionally dominant. Lastly, the appearance and further propagation of symptoms after therapy-stop is a common but somewhat neglected problem in DHR, which raises questions regarding the cause of persisting T cell activation.
Current opinion in allergy and clinical immunology, 2010
Vychází díky edukačnímu grantu firmy Medical Tribune CZ, s. r. o., má výhradní právo na překlady ... more Vychází díky edukačnímu grantu firmy Medical Tribune CZ, s. r. o., má výhradní právo na překlady a publikaci článků z časopisu Current Opinion in Allergy and Clinical Immunology a Current Opinion in Pulmonary Medicine. Pořizování kopií jakéhokoli článku nebo jeho části a jejich šíření v jakékoli formě bez předchozího souhlasu nakladatelství Lippincott Williams & Wilkins a Medical Tribune CZ, s. r. o. je zakázáno. Redakce neodpovídá za obsah uveřejněné reklamy.
The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usually explained with the... more 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...
More than 70% of birch-pollen-allergic patients suffer from an oral allergy syndrome (OAS) to fru... more More than 70% of birch-pollen-allergic patients suffer from an oral allergy syndrome (OAS) to fruits and/or nuts, especially to apple (1-3). This pollen fruit syndrome is based on a molecular similarity of their major allergens (all PR-10) leading to clinical cross-reactivity. One of the best studied examples is the cross-reactivity between Bet v 1 in birch pollen and Mal d 1 in apple (4). PR-10 proteins are rapidly released during the chewing process, but rather labile and quickly destroyed by digestive enzymes in the oral cavity. A large proportion of patients with OAS avoid or only eat processed fruits, which contain only negligible amounts of PR-10 proteins. As fresh fruits are considered important for well-balanced diet (5), many of these patients seek help in getting rid of these mostly harmless, but annoying symptoms. There is beneficial effect of birchpollen-specific subcutaneous immunotherapy on OAS to apple, with excellent improvement in some (1, 6-9), but limited effect in other studies (10-15). However, successful birch-pollen-specific sublingual immunotherapy only improved respiratory symptoms but showed no consistent effect on OAS (12, 14-16). In this study, we investigated whether it is possible to induce local oral tolerance in these patients by daily oral intake of increasing amounts of apple allergens. Furthermore, we analyzed the systemic immune response by several in vivo and in vitro markers.
Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to w... more Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an
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