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W J Pichler

Publications and source records attributed to W J Pichler.

At least 19 recordsLinked to original sources
PubMed2002

[Chronic idiopathic urticaria: effectiveness of fexofenadine. A double-blind, placebo controlled study with 21 patients].

Chronic urticaria defined as repeated or daily eruptions of wheals within a week over a period of at least 1 1/2 months is a frustrating problem not only for the patient but also for the physician. Since a cause will seldom be identified, therapy is symptomatic. In this study the effect of fexofenadine the active metabolite of terfenadine on pruritus, wheal formation and subjective feedbacks has been investigated in 21 patients with chronic urticaria. The study was double-blind, placebo-controlled designed. Following a 1-week washout period all study subjects received fexofenadine 180 mg OD for 3 weeks; thereafter the subjects were randomized for another 3 weeks in a placebo and fexofenadine arm. This study showed that fexofenadine had a beneficial effect on urticaria, particularly pruritus, and the patient-reported symptoms. Reports on side effects were non characteristic and not different between fexofenadine and placebo. Prolongation of QTc intervals or other cardiac side effects have not been observed. Fexofenadine 180 mg is a new antihistamine that is effective in the treatment of chronic urticaria and that has a profile of side effects similar to placebo.

Adult↗
PubMed2002

Boletus edulis: a digestion-resistant allergen may be relevant for food allergy.

BACKGROUND: Fungal components can cause allergic symptoms either through inhalation, ingestion or contact. Whereas respiratory allergy is thought to be induced by spores, allergic reactions following ingestion are attributed to other parts of the mushroom. Reports of food-related allergic reactions due to the edible mushroom Boletus edulis have occasionally been reported. OBJECTIVE: The aim of the study was to investigate whether separate allergens may be detected in alimentary allergy to Boletus edulis. METHODS: Sera of two subjects, one with recurrent anaphylaxis and the other with a predominantly oral allergy syndrome following ingestion of Boletus edulis, have been analysed by a time-course digestion assay using simulated gastric fluid and by SDS-PAGE immunoblotting. Sera of four Boletus edulis skin prick test-negative subjects and all without clinical symptoms to ingested Boletus edulis served as controls. RESULTS: In lyophilized Boletus edulis extract, at least four water-soluble proteins were detected, the most reactive at 55 kDa and at 80 kDa. Following the time-course digestion assay, IgE binding was found to a 75-kDa protein, but only if the sera of the subject with recurrent anaphylaxis was used. CONCLUSION: The data indicate that Boletus edulis can cause an IgE-mediated food allergy due to a digestion-stabile protein at 75 kDa. No IgE immune response to this protein was detected in the serum of a subject with respiratory allergy and oral allergy syndrome to Boletus edulis nor in control sera.

Adult↗
PubMed2001

Predictive drug allergy testing: an alternative viewpoint.

T- and B-cells recognise drugs when bound as haptens to carrier molecules. Recent studies suggest that drugs might also bind in a non-covalent form to MHC-peptide complexes and T cell receptors, and are thereby able to stimulate T cells. This has, however, only been shown for drug-specific T cell clones. Functional analysis revealed that drug-reactive T cells secrete high amounts of IL-5 and are cytotoxic. Cytotoxicity is mediated by drug-specific CD4(+) and CD8(+) cells and, as revealed by the immunohistochemical analysis of drug-induced exanthems, might be involved in the killing of keratinocytes thus explaining the drug-induced exanthem. Further work is needed to clarify the type and exact location of the rather labile drug binding to MHC and T cell receptors, and to evaluate what drug allergies might be caused by such an unusual presentation and immune stimulation. This new model as well as findings from the analysis of clinical drug allergies may have major implications on how to test and predict the allergenic potential of drugs. A change and expansion of currently performed test procedures is required to predict the allergenic potential of drugs.

Animal Testing Alternatives↗
PubMed2001

A comparative study of the expression of cytotoxic proteins in allergic contact dermatitis and psoriasis: spongiotic skin lesions in allergic contact dermatitis are highly infiltrated by T cells expressing perforin and granzyme B.

Recent reports indicate that cytotoxic T cells are critically involved in contact hypersensitivity reactions in animals. In this study we sought to investigate the in vivo expression of cytotoxic granule proteins in the elicitation phase of allergic contact dermatitis in humans. Skin biopsy specimens were obtained from patients with allergic contact dermatitis (n = 8) and psoriasis (n = 6) and from controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by in situ hybridization and immunohistochemistry. In contrast to normal skin and psoriasis, a significant enhancement of perforin and granzyme B gene expression and immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells, which were located in the dense perivascular infiltrate as well as at sites of marked spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. In conclusion, our data suggest that T-cell-mediated mechanisms involving cytotoxic granule proteins may elicit epidermal cell injury in vivo and thereby strongly contribute to the development of allergic contact dermatitis in humans.

Adult↗
PubMed2001

Peptide vaccines against hepatitis B virus: from animal model to human studies.

An estimated 400 million people are chronically infected with the hepatitis B virus (HBV). Chronic viral hepatitis infection incurs serious sequelae such as liver cirrhosis and hepatocellular carcinoma. Prevention and treatment, thus, represent an important target for public health. Preventive vaccines using HBsAg alone or combined with other antigens allow for the generation of neutralizing antibodies which effectively prevent infection in immunocompetent individuals. Cell-mediated immunological mechanisms are thought to be crucial in determining viral persistence or viral elimination. Therapeutic approaches aiming to shift cellular immunity towards viral elimination have been on the research agenda for many years. This paper summarizes pre-clinical and clinical results obtained with the use of immunogenic peptides formulated as vaccines to selectively boost cellular immune responses. Such vaccines are capable of generating cellular immune responses in animal models as well as in humans and represent an important step towards the development of a therapeutic vaccine against chronic hepatitis.

Animals↗
PubMed2001

Perspectives: towards a peptide-based vaccine against hepatitis C virus.

Hepatitis C virus (HCV) is a widespread infectious disease in humans with the negative implication of becoming chronic in most persons. Patients infected with HCV are at risk of liver cirrhosis or hepatocellular carcinoma at later stages. In contrast to hepatitis A and hepatitis B, there is no immunization yet available, neither prophylactic nor therapeutic. Thus, there is an urgent need to develop a safe, protective vaccine against this fatal disease. Developing countries are even more at risk for HCV. There are currently a number of scientific approaches aimed towards solving this problem. Taking both risks and costs of immunization into consideration, a peptide-based vaccine may be a reasonable prophylactic protection. Also, it might be of therapeutic use in already infected patients by increasing a specific CTL response against HCV. In our lab, we are focusing on immunopotentiating reconstituted influenza virosomes (IRIVs) as carriers for immunogenic HLA-A2-restricted core epitopes to induce peptide-specific cytotoxic T lymphocytes (CTLs). The IRIVs are similar to liposomes, but in addition contain influenza-derived hemagglutinin and neuraminidase on their outer surface which makes them fusogenic, thus, permitting antigen delivery to host cells. So far, virosomes have been successfully used for vaccine development and as a result a virosomal vaccine against both influenza virus (Inflexal) BERNA) and hepatitis A virus (HAV) (Epaxal) BERNA) already exist on the market. This paper focuses on the importance of development of a successful vaccine against HCV and, more specifically, we discuss the use, advantages and disadvantages of a peptide-based vaccine. A brief report of our latest findings will be included.

HLA-A2 Antigen↗
PubMed2001

[Specific and nonspecific (anti-IgE) immunotherapy of allergic diseases].

Specific immunotherapy comprises a special form of allergy treatment which consists of stepwise increasing doses of the allergen, given subcutaneously or orally with the aim to reprogram the specific immunity (from allergy to tolerance). This requires some experience and an exact allergological workup, since the main mistake in the treatment of this specific immunotherapy is the selection of unsuitable patients. The effectivity of specific immunotherapy is well documented for bee and wasp venom allergy, pollinosis and more and more also for asthma bronchiale. A type of unspecific passive immunotherapy is the injection of anti-IgE antibodies. However they block only soluble IgE and are not able to remove mast cell bound IgE. Thus, the allergic reactivity persists. Clinical studies have shown some efficacy in asthma as well as in pollinosis. However, at present it is unclear, whether this drug, which has to be given every two to four weeks in relatively high concentrations, is effective in patients with polysensitization (i.e. patients suffering from mite, fungal and pollen allergy) or is effective in patients which have manifestations of their allergy in different organs.

Adult↗
PubMed2001

Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity.

Twenty-seven patients with allergy to house-dust mite and the clinical symptoms of perennial rhinitis and/or mild asthma were treated with specific immunotherapy (SIT) with standardized extracts of house-dust mite for 3 years. The success of therapy was evaluated in yearly intervals by 1) subjective rhinitis and asthma scores. 2) allergen-specific skin and conjunctival tests. 3) nonspecific bronchial hyperreactivity to methacholine. 4) medication scores of rhinitis and asthma. SIT induced a significant improvement of all parameters already after 1 year, with further improvement in the follow-up measurements at 2 and 3 years. We found a constant improvement of the rhinitis and asthma symptom scores, a reduced reactivity in the skin prick and conjunctival provocation tests, and a constantly increasing reduction of bronchial hyperreactivity to methacholine. Concomitantly, the use of medication (topical corticosteroids, beta2-mimetics, and antihistamines) was reduced. Our data support the concept that SIT with standardized extracts of house-dust mite results in an improvement of allergen-specific parameters in patients with perennial rhinitis and intermittent asthma. This beneficial effect of SIT on allergen-specific immune parameters seems to induce also a diminution of nonspecific bronchial hyperreactivity and enables reduction of symptomatic treatment.

Adult↗
PubMed2001

Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells.

1. Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NHOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). SMX-NO covalently modifies self proteins which in turn might be recognized as neo-antigens by T-cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX-NHOH and/or SMX. 2. To study the reactivity of T-cells to SMX metabolites and their respective role in the generation of drug-specific T-cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX-NHOH and SMX-NO. Furthermore, we monitored the proliferative response of drug-specific T-cell clones in the presence or absence of GSH. 3. We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX-specific response but enhanced the proliferation to SMX-metabolites. The response of SMX-NO-specific T-cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX-specific T-cell clones gained reactivity through the conversion of SMX-NO to the parent drug by GSH. While GSH had no effect on the initial activation of T-cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug-specific T-cells to non-reactive drug metabolites. 4. Our data support the concept that in allergic individuals T-cells recognize the non-covalently bound parent drug rather than APC covalently modified by SMX-NO.

Adult↗
PubMed2001

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo.

Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by flow cytometry using a specific anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. CD4+ or CD8+ depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-gamma, but not IL-4. Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.

Adjuvants, Immunologic↗
PubMed2001

Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis.

BACKGROUND: Infiltration of the skin by pathogenic T cells is regarded as a key factor in the development of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. OBJECTIVES: To investigate whether T cells containing cytotoxic proteins may contribute to the generation of skin inflammation in these skin diseases. METHODS: Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD (n = 8) and psoriasis (n = 6), and from non-atopic controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by immunohistochemistry. RESULTS: A significant enhancement of perforin and granzyme B expression was observed in lesional AD skin as compared with normal skin, non-lesional AD skin and psoriasis. Expression of these cytotoxic proteins was also increased in psoriasis as compared with normal skin and non-lesional psoriatic skin. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells located in the perivascular infiltrate. In AD increased numbers of positive cells were also observed focally at sites of spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. CONCLUSIONS: Our data suggest that cytotoxic CD4+ and CD8+ T cells containing perforin and granzyme B may play an integral part in eliciting cutaneous inflammation in AD.

Adolescent↗
PubMed2001

T cell involvement in cutaneous drug eruptions.

BACKGROUND: The most frequent side-effects of drug therapy are skin eruptions. Their pathomechanism is rather unclear. OBJECTIVE: In this prospective study we investigated the T cell activation and drug specificity in different forms of drug-induced exanthemas from 22 patients. METHODS: During acute drug allergy, liver parameters and T cell subset activation in the circulation (up-regulation of CD25 and HLA-DR) were evaluated and skin biopsies of the acute lesion performed. After recovery, the causative drug was identified by lymphocyte transformation (LTT) and scratch-patch tests. RESULTS: Seventeen of 22 (17/22) patients had maculo-papular exanthema, 4/22 bullous exanthema and 1/22 urticaria. The causative drugs were mainly antibiotics, anti-epileptics and anti-hypertensives. Up-regulation of HLA-DR on circulating CD4(+) and/or CD8(+) T cells was detected in 17 patients, being most marked in patients with bullous reactions or hepatic involvement. The LTT was positive in 14/21 analysed and the patch test in 7/15. All patients showed lymphocytic infiltration in the skin biopsy of the acute lesion. Generally CD4(+) T cells dominated; a higher percentage of circulating CD8(+) T cells was found in patients with bullous skin reactions or hepatic involvement. CONCLUSION: Our data demonstrate activation and drug specificity of T cells in drug-induced skin eruptions. A predominant CD8(+) T cell activation leads to more severe (bullous) skin symptoms or liver involvement, while predominant activation of CD4(+) cells elicits mainly maculo-papular reactions.

Administration, Cutaneous↗
PubMed2001

Degeneracy and additional alloreactivity of drug-specific human alpha beta(+) T cell clones.

It has been well established that T cells can recognize small mol. wt compounds such as drugs. Results from previous studies revealing a high heterogeneity and cross-reactivity of drug-specific T cell clones (TCC) in individual patients prompted us to analyze the degeneracy of drug-reactive TCR in detail. Hence, we analyzed the MHC restriction pattern of a panel of 100 drug-specific TCC isolated from different drug-allergic donors. We found that 28 of the tested clones showed an MHC allele-unrestricted drug recognition. Most of these clones were at the same time highly drug specific, i.e. they could only be stimulated by the original drug and not by any drug derivatives. In contrast, TCC with the ability to interact with different drug derivatives displayed a clearly MHC allele-restricted drug recognition. Therefore, we concluded that the TCR of these clones is mainly interacting with side chains of the appropriate drug molecules and hence able to tolerate alterations in the MHC molecule. Moreover, we tested all clones for additional alloreactivity and found that 27 clones could be stimulated by a self-MHC--peptide--drug complex as well as by a non-self-MHC--peptide complex. This cross-reactivity with allogeneic MHC molecules was substantially higher in drug-specific TCC compared to tetanus toxoid-specific clones from the same donors. This suggests that from the point of view of drug-specific TCR, non-self-MHC--peptide complexes have a higher incidence to mimic the 'original' self-MHC--peptide-drug complex and this may occur for TCR recognizing self-MHC--pathogen-derived peptide complexes. Finally, the biological functions of bispecific TCC were not influenced by the nature of the stimulating ligand. Both drug as well as allogeneic stimulation led to similar reaction patterns in the analyzed TCC.

Clone Cells↗
PubMed2001

Drug allergy.

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Drug Hypersensitivity↗
PubMed2001

Immunohistology of drug-induced exanthema: clues to pathogenesis.

Hypersensitivity reactions to drugs can cause a variety of different skin disorders, the most frequent being maculopapular eruptions. In recent years increasing evidence has indicated the important involvement of T cells in this drug reaction. Histopathological changes typically show a dominant T-cell infiltration together with vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and CD8+ T cells, which contain perforin and granzyme B, in close proximity to keratinocytes showing signs of cell destruction. Expression of Fas ligand is barely detectable, which suggests that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. In addition, drug-specific T cells may orchestrate the inflammatory skin reaction through the release and induction of various cytokines (i.e. IL-5, IL-6, TNF-alpha, IFN-gamma) and chemokines (i.e. regulated on activation, normal T-cell expressed and secreted; eotaxin). These mediators contribute to the generation of eosinophilia, which may amplify the underlying immune response through the release of further proinflammatory mediators in drug-induced maculopapular exanthema.

CD4-Positive T-Lymphocytes↗
PubMed2001

T-cell involvement in drug-induced acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption most often provoked by drugs, by acute infections with enteroviruses, or by mercury. It is characterized by acute, extensive formation of nonfollicular sterile pustules on erythematous background, fever, and peripheral blood leukocytosis. We present clinical and immunological data on four patients with this disease, which is caused by different drugs. An involvement of T cells could be implied by positive skin patch tests and lymphocyte transformation tests. Immunohistochemistry revealed a massive cell infiltrate consisting of neutrophils in pustules and T cells in the dermis and epidermis. Expression of the potent neutrophil-attracting chemokine IL-8 was elevated in keratinocytes and infiltrating mononuclear cells. Drug-specific T cells were generated from the blood and skin of three patients, and phenotypic characterization showed a heterogeneous distribution of CD4/CD8 phenotype and of T-cell receptor Vbeta-expression. Analysis of cytokine/chemokine profiles revealed that IL-8 is produced significantly more by drug-specific T cells from patients with AGEP compared with drug-specific T cells from patients that had non-AGEP exanthemas. In conclusion, our data demonstrate the involvement of drug-specific T cells in the pathomechanism of this rather rare and peculiar form of drug allergy. In addition, they indicate that even in some neutrophil-rich inflammatory responses specific T cells are engaged and might orchestrate the immune reaction.

Acute Disease↗
PubMed2001

T-cell reactions to drugs in distinct clinical manifestations of drug allergy.

BACKGROUND: Recent data indicate that T cells play a major role in different forms of drug allergies. OBJECTIVE: To show that T-cell reactions are involved in various forms of adverse reactions to different kinds of drugs, and that lymphocyte transformation and skin tests may be positive in patients who had distinct clinical manifestations of drug allergies. METHODS: We collected data of 44 patients with a highly suggestive history for adverse drug reaction who had on subsequent investigations a positive lymphocyte transforrmation test. In 41/44 patients (93%) skin tests with the suspected drugs were performed and in some cases drug-specific IgE-antibodies were determined. All patients were HLA typed. RESULTS: Clinical manifestations of the drug allergy were heterogeneous, comprising maculopapular and bullous exanthema, erythema exsudativum multiforme, vasculitis, serum sickness, urticaria, as well as involvement of internal organs. Maculopapular exanthemas formed the largest group (54%), followed by reactions more indicative of immediate hypersensitivity (28%), such as urticaria/angioedema. In most cases (63%), beta-lactam antibiotics were found to have caused the allergic reaction. Skin tests for immediate reactions were positive in 6/40 patients (15%) tested, those for late reactions in 24/38 patients (63%) tested. CONCLUSIONS: Our data provide evidence that drug-specific T cells can be detected in distinct clinical manifestations of drug allergy. A combined approach using a detailed case history, lymphocyte transformation tests, skin tests (immediate and delayed type) appears to be helpful to identifying the incriminated drug.

Adolescent↗