Center for Pathophysiology


Center for Pathophysiology

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Prusa A.-R.,Intensive Care and Neuropaediatry | Wiedermann U.,Center for Pathophysiology | Kasper D.C.,Medical University of Vienna | Hayde M.,Intensive Care and Neuropaediatry | And 3 more authors.
Neonatology | Year: 2011

Objective: In consideration of comprehensive and well-established vaccination programmes in industrialized countries, it is expected that immunity against tetanus among expectant mothers and their offspring is complete. Our study evaluated seroprotection against tetanus among newborns in Austria, who may gain passive immunity by transplacental transfer of maternal tetanus antibody. Methods: Cord blood samples from 99 deliveries were analyzed for antibody concentration against tetanus toxoid by standardized ELISA. Results: 85/99 (85.8%) individuals presented with levels of tetanus immunity having a protective antibody concentration ≥0.1 IU/ml. 9/99 (9.1%) samples showed low seropositivity, while in 5/99 (5.1%) samples no tetanus antibodies could be detected. The median antibody concentration was 0.95 IU/ml. Conclusions: Our data provide evidence for a lack of adequate tetanus immunity in 14.2% of newborns delivered in an Austrian University Hospital. This investigation is emphasizing the importance of stringent regimens concerning prenatal vaccination care, even in countries with generalized immunization programs. If indicated, maternal immunization during pregnancy should be initiated for protection of newborns. Copyright © 2011 S. Karger AG, Basel.

Patsch J.M.,Center for Pathophysiology | Patsch J.M.,Medical University of Vienna | Kohler T.,B cube AG | Berzlanovich A.,Medical University of Vienna | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2011

Male idiopathic osteoporosis (MIO) is a metabolic bone disease that is characterized by low bone mass, microstructural alterations, and increased fracture risk in otherwise healthy men. Although the detailed pathophysiology of MIO has yet to be clarified, evidence increasingly suggests an osteoblastic defect as the underlying cause. In this study we tested the hypothesis that the expression profile of certain osteoblastic or osteoblast-related genes (ie, WNT10B, RUNX2, Osterix, Osteocalcin, SOST, RANKL, and OPG) is different in iliac crest biopsies of MIO patients when compared with healthy controls. Furthermore, we investigated the relation of local gene expression characteristics with histomorphometric, microstructural, and clinical features. Following written informed consent and diligent clinical patient characterization, iliac crest biopsies were performed in nine men. While RNA extraction, reverse-transcription, and real-time polymerase chain reactions (PCRs) were performed on one biopsy, a second biopsy of each patient was submitted for histomorphometry and micro-computed tomography (μCT). Age-matched bone samples from forensic autopsies served as controls. MIO patients displayed significantly reduced WNT10B, RUNX2, RANKL, and SOST expression. Performing μCT for the first time in MIO biopsies, we found significant decreases in trabecular number and connectivity density. Trabecular separation was increased significantly, but trabecular thickness was similar in both groups. Histomorphometry revealed decreased BV/TV and osteoid volume and fewer osteoclasts in MIO. By providing evidence for reduced local WNT10B, RUNX2, and RANKL gene expression and histomorphometric low turnover, our data support the osteoblast dysfunction model discussed for MIO. Further, MIO seems to lead to a different microstructural pathology than age-related bone loss. Copyright © 2011 American Society for Bone and Mineral Research.

Casset A.,Center for Pathophysiology | Mari A.,Center for Molecular Allergology | Purohit A.,University of Strasbourg | Resch Y.,Center for Pathophysiology | And 10 more authors.
International Archives of Allergy and Immunology | Year: 2012

Background: Diagnosis and immunotherapy of house-dust mite (HDM) allergy is still based on natural allergen extracts. The aim of this study was to analyze commercially available Dermatophagoides pteronyssinus extracts from different manufacturers regarding allergen composition and content and whether variations may affect their allergenic activity. Methods: Antibodies specific for several D. pteronyssinus allergens (Der p 1, 2, 5, 7, 10 and 21) were used to analyze extracts from 10 different manufacturers by immunoblotting. Sandwich ELISAs were used to quantify Der p 1 and Der p 2 in the extracts. Mite-allergic patients (n = 45) were skin-tested with the extracts and tested for immunoglobulin E (IgE) reactivity to a panel of 10 mite allergens (Der p 1, 2, 4, 5, 7, 8, 10, 14, 20 and 21) by dot blot. Results: Only Der p 1 and Der p 2 were detected in all extracts but their concentrations and ratios showed high variability (Der p 1: 6.0-40.8 μg ml-1; Der p 2: 1.7-45.0 μg ml-1). At least 1 out of 4 allergens (i.e. Der p 5, 7, 10 and 21) was not detected in 8 of the studied extracts. Mite-allergic subjects showed different IgE reactivity profiles to the individual mite allergens, the extracts showed different allergenic activity in skin-prick tests and false-negative results. Conclusions: Commercially available D. pteronyssinus extracts lack important allergens, show great variability regarding allergen composition and content and some gave false-negative diagnostic test results in certain patients. Copyright © 2012 S. Karger AG, Basel.

Hamilton G.,Ludwig Boltzmann Cluster of Translational Oncology | Hamilton G.,Medical University of Vienna | Klameth L.,Ludwig Boltzmann Cluster of Translational Oncology | Klameth L.,Center for Pathophysiology | And 2 more authors.
Molecules | Year: 2014

Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)- methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10- hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to the chemosensitive SCLC26A cell line. Whereas the CDK4/6 inhibitor PD0332991 proved less effective to chemosensitize SCLC cells to CPT analogs, the CDK inhibitors CDK4I, roscovitine and olomoucine gave comparable chemosensitization effects in combination with 9AC, SN38, rubitecan and to a lesser extent with TPT and CPT109, not directly related with topoisomerase mRNA expression. In conclusion, smallchemical modifications of the parent CPT structure result in differing cytotoxicities and chemomodulatory effects in combination with CDKIs of the resulting analogs. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Mechtcheriakova D.,Center for Pathophysiology | Svoboda M.,Center for Pathophysiology | Meshcheryakova A.,Center for Pathophysiology | Jensen-Jarolim E.,Center for Pathophysiology | Jensen-Jarolim E.,Medical University of Vienna
Cancer Immunology, Immunotherapy | Year: 2012

Activation-induced cytidine deaminase (AID) is critically involved in class switch recombination and somatic hypermutation of Ig loci resulting in diversification of antibodies repertoire and production of high-affinity antibodies and as such represents a physiological tool to introduce DNA alterations. These processes take place within germinal centers of secondary lymphoid organs. Under physiological conditions, AID is expressed predominantly in activated B lymphocytes. Because of the mutagenic and recombinogenic potential of AID, its expression and activity is tightly regulated on different levels to minimize the risk of unwanted DNA damage. However, chronic inflammation and, probably, combination of other not-yet-identified factors are able to create a microenvironment sufficient for triggering an aberrant AID expression in B cells and, importantly, in non-B-cell background. Under these circumstances, AID may target also non-Ig genes, including cancer-related genes as oncogenes, tumor suppressor genes, and genomic stability genes, and modulate both genetic and epigenetic information. Despite ongoing progress, the complete understanding of fundamental aspects is still lacking as (1) what are the crucial factors triggering an aberrant AID expression/ activity including the impact of Th2-driven inflammation and (2) to what extent may aberrant AID in human non-B cells lead to abnormal cell state associated with an increased rate of genomic alterations as point mutations, small insertions or deletions, and/or recurrent chromosomal translocations during solid tumor development and progression. © The Author(s) 2012.

Linhart B.,Center for Pathophysiology | Valenta R.,Center for Pathophysiology | Valenta R.,Medical University of Vienna
Current Opinion in Immunology | Year: 2012

Vaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based on immunoglobulin E production against harmless environmental antigens, i.e., allergens. Nevertheless, vaccination with allergens, termed allergen-specific immunotherapy is the only disease-modifying therapy of allergy with long-lasting effects. New forms of allergy diagnosis and allergy vaccines based on recombinant allergen-derivatives, peptides and allergen genes have emerged through molecular allergen characterization. The molecular allergy vaccines allow sophisticated targeting of the immune system and may eliminate side effects which so far have limited the use of traditional allergen extract-based vaccines. Successful clinical trials performed with the new vaccines indicate that broad allergy vaccination is on the horizon and may help to control the allergy pandemic. © 2012 Elsevier Ltd.

Valenta R.,Christian Doppler Laboratory | Valenta R.,Center for Pathophysiology | Linhart B.,Center for Pathophysiology | Swoboda I.,Christian Doppler Laboratory | Niederberger V.,Medical University of Vienna
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies. © 2011 John Wiley & Sons A/S.

Lair D.,French Institute of Health and Medical Research | Lair D.,University of Nantes | Vrtala S.,Center for pathophysiology | Magnan A.,French Institute of Health and Medical Research | Magnan A.,University of Nantes
Revue Francaise d'Allergologie | Year: 2013

Asthma is mainly a chronic inflammatory allergic disease. One of the key treatments for this condition, allergen-specific immunotherapy (AIT), consists of desensitizing the allergic patient to the specific allergen to which he/she is sensitized. AIT is based on the administration of allergenic extracts produced by different methods. At present, such extracts still have unequal composition and efficiency. The use of molecular biology techniques has led to the availability of a panel of recombinant allergens in large quantities and with excellent purity. However, AIT is still not entirely safe, and a number of research teams are developing different strategies to improve it, such as new therapeutic approaches (e.g., DNA vaccination, cell therapy, etc.), the use of different routes of administration, and the preparation of allergens with immunogenicity but without allergenicity. © 2013 Elsevier Masson SAS.

PubMed | Medical University of Vienna and Center for Pathophysiology
Type: Journal Article | Journal: The Journal of allergy and clinical immunology | Year: 2016

In the past, the development of more effective, safe, convenient, broadly applicable, and easy to manufacture vaccines for allergen-specific immunotherapy (AIT) has been limited by the poor quality of natural allergen extracts. Progress made in the field of molecular allergen characterization has now made it possible to produce defined vaccines for AIT and eventually for preventive allergy vaccination based on recombinant DNA technology and synthetic peptide chemistry. Here we review the characteristics of recombinant and synthetic allergy vaccines that have reached clinical evaluation and discuss how molecular vaccine approaches can make AIT more safe and effective and thus more convenient. Furthermore, we discuss how new technologies can facilitate the reproducible manufacturing of vaccines of pharmaceutical grade for inhalant, food, and venom allergens. Allergy vaccines in clinical trials based on recombinant allergens, recombinant allergen derivatives, and synthetic peptides allow us to target selectively different immune mechanisms, and certain of those show features that might make them applicable not only for therapeutic but also for prophylactic vaccination.

PubMed | Friedrich - Alexander - University, Erlangen - Nuremberg, Medical University of Vienna and Center for Pathophysiology
Type: Journal Article | Journal: The Journal of allergy and clinical immunology | Year: 2015

Celiac disease (CD) is an inflammatory disease of the small intestine caused by an immunologic hypersensitivity reaction to dietary wheat gluten.We sought to clone, express, and perform IgA epitope mapping of a CD-specific wheat antigen and to study its usefulness for identifying patients with CD and monitoring adherence to a gluten-free diet.A synthetic gene coding for -gliadin 1 (GG1) was expressed in Escherichia coli. Recombinant -gliadin 1 (rGG1) was purified and characterized biochemically, structurally, and immunologically by using sera from patients with CD and control subjects. Overlapping GG1 peptides were synthesized for IgA and IgG epitope mapping. GG1 and peptide-specific antibodies were raised for tracing GG1 in cereals and dietary wheat products and to study its resistance to digestion.rGG1 was expressed and purified. rGG1-based IgA ELISAs performed in populations of patients with CD and control subjects showed a specificity of 92.9%, which was higher than that of gliadin extract (e). Furthermore, it allowed monitoring of adherence to a gluten-free diet in patients. A 26-amino-acid peptide from the proline-glutamine-rich repetitive N-terminal region was identified as the immunodominant IgA epitope. GG1-related antigens were found in rye, barley, and spelt but not in oat, rice, or maize. GG1 was detected in dietary wheat products after baking, and in particular, the major IgA epitope-containing region was resistant against digestion.rGG1 and its epitope might be useful for identifying patients with CD, monitoring treatment, and studying the pathomechanisms of CD and development of preventive and therapeutic strategies.

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