Publications by authors named "Monika Bauer"

28 Publications

  • Page 1 of 1

Cystatin F is a biomarker of prion pathogenesis in mice.

PLoS One 2017 8;12(2):e0171923. Epub 2017 Feb 8.

Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.

Misfolding of the cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) results in progressive, fatal, transmissible neurodegenerative conditions termed prion diseases. Experimental and epidemiological evidence point toward a protracted, clinically silent phase in prion diseases, yet there is no diagnostic test capable of identifying asymptomatic individuals incubating prions. In an effort to identify early biomarkers of prion diseases, we have compared global transcriptional profiles in brains from pre-symptomatic prion-infected mice and controls. We identified Cst7, which encodes cystatin F, as the most strongly upregulated transcript in this model. Early and robust upregulation of Cst7 mRNA levels and of its cognate protein was validated in additional mouse models of prion disease. Surprisingly, we found no significant increase in cystatin F levels in both cerebrospinal fluid or brain parenchyma of patients with Creutzfeldt-Jakob disease compared to Alzheimer's disease or non-demented controls. Our results validate cystatin F as a useful biomarker of early pathogenesis in experimental models of prion disease, and point to unexpected species-specific differences in the transcriptional responses to prion infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171923PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298286PMC
August 2017

Mining the human autoantibody repertoire: isolation of potent IL17A-neutralizing monoclonal antibodies from a patient with thymoma.

MAbs 2014 ;6(6):1608-20

a Valneva Austria GmbH ; Campus Vienna Biocenter 3; Vienna , Austria.

Anti-cytokine autoantibodies have been widely reported to be present in human plasma, both in healthy subjects and in patients with underlying autoimmune conditions, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or thymic epithelial neoplasms. While often asymptomatic, they can cause or facilitate a wide range of diseases including opportunistic infections. The potential therapeutic value of specific neutralizing anti-cytokine autoantibodies has not been thoroughly investigated. Here we used mammalian cell display to isolate IL17A-specific antibodies from a thymoma patient with proven high-titer autoantibodies against the same. We identified 3 distinct clonotypes that efficiently neutralized IL17A in a cell-based in vitro assay. Their potencies were comparable to those of known neutralizing antibodies, including 2, AIN457 (secukinumab) and ixekizumab that are currently in clinical development for the treatment of various inflammatory disorders. These data clearly demonstrate that the human autoantibody repertoire can be mined for antibodies with high therapeutic potential for clinical development.
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http://dx.doi.org/10.4161/mabs.36292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623001PMC
September 2015

Metal fluoride-based transparent nanocomposites with low refractive indices.

Dalton Trans 2013 Apr;42(16):5706-10

Humboldt-Universität zu Berlin, Department of Chemistry, Brook-Taylor-Straße 2, 12489 Berlin, Germany.

The utilisation of magnesium and aluminium fluoride nanoparticles in the preparation of transparent composites leading to materials with superior properties was investigated. Nanoscopic magnesium and aluminium fluoride has been prepared by the fluorolytic sol-gel route from the alkoxides and was surface modified by the reaction with trifluoroacetic acid or perfluorobutyric acid. IR spectroscopic experiments of the xerogels and crystal structure analysis of a trinuclear [Mg3(μ3F)(μ-TFA)6(OCH3)2(py)](3-) cluster unit indicate that the carboxylate group is bound to the particle surface in a monodentate or bidentate bridging fashion. These particles were successfully incorporated into acrylate polymers with up to 40 wt% content to give fully transparent material. Ellipsometry and m-line measurements of thin films show the reduction of the refractive index of composite films with increasing metal fluoride filler content.
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http://dx.doi.org/10.1039/c3dt32652gDOI Listing
April 2013

Low-affinity B cells transport viral particles from the lung to the spleen to initiate antibody responses.

Proc Natl Acad Sci U S A 2012 Dec 20;109(50):20566-71. Epub 2012 Nov 20.

Research Department, Cytos Biotechnology, CH-8952 Zurich-Schlieren, Switzerland.

The lung is an important entry site for pathogens; its exposure to antigens results in systemic as well as local IgA and IgG antibodies. Here we show that intranasal administration of virus-like particles (VLPs) results in splenic B-cell responses with strong local germinal-center formation. Surprisingly, VLPs were not transported from the lung to the spleen in a free form but by B cells. The interaction between VLPs and B cells was initiated in the lung and occurred independently of complement receptor 2 and Fcγ receptors, but was dependent upon B-cell receptors. Thus, B cells passing through the lungs bind VLPs via their B-cell receptors and deliver them to local B cells within the splenic B-cell follicle. This process is fundamentally different from delivery of blood or lymph borne particulate antigens, which are transported into B cell follicles by binding to complement receptors on B cells.
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http://dx.doi.org/10.1073/pnas.1206970109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528531PMC
December 2012

Universal vaccine against influenza virus: linking TLR signaling to anti-viral protection.

Eur J Immunol 2012 Apr;42(4):863-9

Cytos Biotechnology AG, Schlieren-Zürich, Switzerland.

A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7(-/-) mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.
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http://dx.doi.org/10.1002/eji.201041225DOI Listing
April 2012

Cuing consumerism: situational materialism undermines personal and social well-being.

Psychol Sci 2012 May 16;23(5):517-23. Epub 2012 Mar 16.

Northwestern University, Evanston, IL 60208, USA.

Correlational evidence indicates that materialistic individuals experience relatively low levels of well-being. Across four experiments, we found that situational cuing can also trigger materialistic mind-sets, with similarly negative personal and social consequences. Merely viewing desirable consumer goods resulted in increases in materialistic concerns and led to heightened negative affect and reduced social involvement (Experiment 1). Framing a computer task as a "Consumer Reaction Study" led to a stronger automatic bias toward values reflecting self-enhancement, compared with framing the same task as a "Citizen Reaction Study" (Experiment 2). Consumer cues also increased competitiveness (Experiment 3) and selfishness in a water-conservation dilemma (Experiment 4). Thus, the costs of materialism are not localized only in particularly materialistic people, but can also be found in individuals who happen to be exposed to environmental cues that activate consumerism-cues that are commonplace in contemporary society.
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http://dx.doi.org/10.1177/0956797611429579DOI Listing
May 2012

Different binding modes of free and carrier-protein-coupled nicotine in a human monoclonal antibody.

J Mol Biol 2012 Jan 3;415(1):118-27. Epub 2011 Nov 3.

Biomedical Research and Study Center, Ratsupites 1, Riga LV 1067, Latvia.

Nicotine is the principal addictive component of tobacco. Blocking its passage from the lung to the brain with nicotine-specific antibodies is a promising approach for the treatment of smoking addiction. We have determined the crystal structure of nicotine bound to the Fab fragment of a fully human monoclonal antibody (mAb) at 1.85 Å resolution. Nicotine is almost completely (>99%) buried in the interface between the variable domains of heavy and light chains. The high affinity of the mAb is the result of a charge-charge interaction, a hydrogen bond, and several hydrophobic contacts. Additionally, similarly to nicotinic acetylcholine receptors in the brain, two cation-π interactions are present between the pyrrolidine charge and nearby aromatic side chains. The selectivity of the mAb for nicotine versus cotinine, which is the major metabolite of nicotine and differs in only one oxygen atom, is caused by steric constraints in the binding site. The mAb was isolated from B cells of an individual immunized with a nicotine-carrier protein conjugate vaccine. Surprisingly, the nicotine was bound to the Fab fragment in an orientation that was not compatible with binding to the nicotine-carrier protein conjugate. The structure of the Fab fragment in complex with the nicotine-linker derivative that was used for the production of the conjugate vaccine revealed a similar position of the pyridine ring of the nicotine moiety, but the pyrrolidine ring was rotated by about 180°. This allowed the linker part to reach to the Fab surface while high-affinity interactions with the nicotine moiety were maintained.
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http://dx.doi.org/10.1016/j.jmb.2011.10.042DOI Listing
January 2012

Inorganic-organic nanocomposites based on sol-gel derived magnesium fluoride.

Nanoscale 2011 Nov 11;3(11):4774-9. Epub 2011 Oct 11.

Humboldt-Universität zu Berlin, Department of Chemistry, Brook-Taylor-Straße 2, 12489, Berlin, Germany.

Monodispersed magnesium fluoride nanoparticles are utilized for the first time to prepare transparent inorganic-organic nanocomposite materials with improved mechanical properties. The fluorolytic sol-gel synthesis route has been modified for the preparation of monodispersed magnesium fluoride nanoparticles with a size of 2-3 nm. MgF(2) particles are effectively stabilised against agglomeration by phosphonic acids, which strongly bind to the particles and lead to an increased compatibility of the inorganic particles with the organic polymers. This way, highly transparent nanocomposite materials with up to 20 wt% magnesium fluoride in different acrylates are obtained, featuring high dispersion of MgF(2) particles in the polymer matrix and an increased hardness by the factor of 2. The nature of interaction between phosphonic acids and magnesium fluoride is thoroughly investigated by IR and NMR showing a monodentate coordination of phosphonates to the particle's surface.
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http://dx.doi.org/10.1039/c1nr10843cDOI Listing
November 2011

Mechanisms of allergen-specific desensitization.

J Allergy Clin Immunol 2010 Aug 10;126(2):375-83. Epub 2010 Jul 10.

Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.

Background: Allergen-specific desensitization (SIT) is the most effective therapy for allergies. Although allergen-specific antibodies have an important role in the process, mechanisms of IgG-mediated inhibition of allergic reactions are not well defined.

Objective: We investigated mechanisms by which SIT-induced allergen-specific IgGs inhibit allergic reactions.

Methods: We generated mAbs that recognize 3 nonoverlapping epitopes of the major cat allergen Fel d 1. Each of the mAbs was produced as an IgE and different IgG isotype.

Results: IgEs against 2 nonoverlapping epitopes on Fel d 1 are necessary and sufficient to sensitize mast cells for maximal FcepsilonRI signaling and degranulation on exposure to monomeric Fel d 1. IgE antibodies of a third specificity did not further increase mast cell degranulation, indicating that formation of large FcepsilonRI clusters are not required to induce maximal activation of mast cells. A single IgG that was specific for an epitope different from those recognized by the IgEs was a potent inhibitor of Fel d 1-mediated mast cell activation in vitro and in vivo. This inhibition required Fcgamma receptor-IIB. In human beings, IgGs of a single specificity were able to block degranulation of basophils from individuals with cat allergy. The inhibitory potential of these antibodies increased when larger allergen-IgG complexes were formed.

Conclusions: These data reconcile conflicting theories in the literature and might explain the reason IgE levels do not necessarily decrease during therapy, despite clinical efficacy. These findings have important implications for vaccine design.
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http://dx.doi.org/10.1016/j.jaci.2010.05.040DOI Listing
August 2010

Prophylactic and therapeutic activity of fully human monoclonal antibodies directed against influenza A M2 protein.

Virol J 2009 Dec 21;6:224. Epub 2009 Dec 21.

Cytos Biotechnology AG, Wagistrasse 25, CH-8952 Schlieren, Switzerland.

Influenza virus infection is a prevalent disease in humans. Antibodies against hemagglutinin have been shown to prevent infection and hence hemagglutinin is the major constituent of current vaccines. Antibodies directed against the highly conserved extracellular domain of M2 have also been shown to mediate protection against Influenza A infection in various animal models. Active vaccination is generally considered the best approach to combat viral diseases. However, passive immunization is an attractive alternative, particularly in acutely exposed or immune compromized individuals, young children and the elderly. We recently described a novel method for the rapid isolation of natural human antibodies by mammalian cell display. Here we used this approach to isolate human monoclonal antibodies directed against the highly conserved extracellular domain of the Influenza A M2 protein. The identified antibodies bound M2 peptide with high affinities, recognized native cell-surface expressed M2 and protected mice from a lethal influenza virus challenge. Moreover, therapeutic treatment up to 2 days after infection was effective, suggesting that M2-specific monoclonals have a great potential as immunotherapeutic agents against Influenza infection.
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http://dx.doi.org/10.1186/1743-422X-6-224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804611PMC
December 2009

Cutting edge: limited specialization of dendritic cell subsets for MHC class II-associated presentation of viral particles.

J Immunol 2010 Jan 30;184(1):26-9. Epub 2009 Nov 30.

Cytos Biotechnology AG, Zürich-Schlieren, Switzerland.

Dendritic cells (DCs) are the most important APC. It was recently reported that there is a dichotomy for Ag presentation by DC subsets; exogenous Ags reach the MHC class I pathway, but not the MHC class II pathway, in CD8(+) DCs, whereas CD8(-) DCs only process Ags for the MHC class II pathway. In this study, we used virus-like particles (VLPs) to show that CD8(+) and CD8(-) DCs efficiently capture and process VLPs for presentation in association with MHC class II in vivo. In contrast, CD8(+) DCs, but not CD8(-) DCs, cross presented VLP-derived peptides. This pattern was changed in an FcgammaR-dependent fashion in the presence of VLP-specific Abs, because under those conditions both DC subsets failed to efficiently cross present. Thus, the presentation of viral particles to CD4(+) T cells is not restricted to distinct DC subsets, whereas the presentation of viral particles to CD8(+) T cells is limited to CD8(+) DCs.
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http://dx.doi.org/10.4049/jimmunol.0901540DOI Listing
January 2010

Innate signaling regulates cross-priming at the level of DC licensing and not antigen presentation.

Eur J Immunol 2010 Jan;40(1):103-12

Cytos Biotechnology AG, Schlieren, Switzerland.

Innate stimuli, such as TLR ligands, are known to greatly facilitate cross-priming. Currently it is unclear whether innate stimuli enhance cross-priming at the level of cross-presentation or at the level of T-cell priming. In this study, we addressed this question by measuring cross-presentation as well as cross-priming by virus-like particles (VLP) displaying peptide p33 derived of lymphocytic choriomeningitis virus. Innate stimuli were varied by either packaging different TLR ligands into virus-like particles or using mice deficient in two key molecules of TLR-signaling, namely the adaptor molecule MyD88 as well as IFN-alpha/beta receptor. While efficient cross-presentation occurred despite strongly reduced activation of DC in the absence of TLR ligand-mediated signals, T-cell priming was abolished. Thus, innate stimuli regulate cross-priming at the level of DC licensing for T-cell activation and not antigen presentation.
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http://dx.doi.org/10.1002/eji.200939559DOI Listing
January 2010

Displaying Fel d1 on virus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: a novel therapy for cat allergy.

J Exp Med 2009 Aug 10;206(9):1941-55. Epub 2009 Aug 10.

Department of Immunodrugs, Cytos Biotechnology AG, 8952 Schlieren-Zürich, Switzerland.

Allergen-specific desensitization is the only disease-modifying therapy currently available for the treatment of allergies. These therapies require application of allergen over several years and some may induce life-threatening anaphylactic reactions. An ideal vaccine for desensitization should be highly immunogenic and should alleviate allergic symptoms upon few injections while being nonreactogenic. We describe such a vaccine for the treatment of cat allergy, consisting of the major cat allergen Fel d1 coupled to bacteriophage Qbeta-derived virus-like particles (Qbeta-Fel d1). Qbeta-Fel d1 was highly immunogenic, and a single vaccination was sufficient to induce protection against type I allergic reactions. Allergen-specific immunoglobulin G antibodies were shown to be the critical effector molecules and alleviated symptoms by two distinct mechanisms. Although allergen-induced systemic basophil degranulation was inhibited in an FcgammaRIIb-dependent manner, inhibition of local mast cell degranulation in tissues occurred independently of FcgammaRIIb. In addition, treatment with Qbeta-Fel d1 abolished IgE memory responses upon antigen recall. Despite high immunogenicity, the vaccine was essentially nonreactogenic and vaccination induced neither local nor systemic anaphylactic reactions in sensitized mice. Moreover, Qbeta-Fel d1 did not induce degranulation of basophils derived from human volunteers with cat allergies. These data suggest that vaccination with Qbeta-Fel d1 may be a safe and effective treatment for cat allergy.
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http://dx.doi.org/10.1084/jem.20090199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737174PMC
August 2009

Secretory phospholipase A2-IID is an effector molecule of CD4+CD25+ regulatory T cells.

Proc Natl Acad Sci U S A 2009 Jul 29;106(28):11673-8. Epub 2009 Jun 29.

Cytos Biotechnology AG, Wagistrasse 25, CH-8952 Schlieren, Switzerland.

Suppression by natural CD4(+)CD25(+) regulatory T cells (Tregs) is one mechanism by which tolerance is maintained. However, the way in which Tregs mediate suppression is not well understood. Here, we show that secreted phospholipase A2 (sPLA2)-IID is selectively produced by Tregs. sPLA2-IID is a potent mediator of Treg function, because it strongly suppressed proliferation of CD4(+) and CD8(+) T cells in vitro and in vivo in a manner independent of its catalytic activity. Furthermore, sPLA2-IID promoted the differentiation of Tregs, presumably via attenuating signaling through the PI3K/Akt/mammalian target of rapamycin pathway. Importantly, administration of a sPLA2-IID-Fc fusion protein inhibited disease development in murine models of colitis and multiple sclerosis, suggesting that sPLA2-IID's immunosuppressive function might be exploited therapeutically.
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http://dx.doi.org/10.1073/pnas.0812569106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710677PMC
July 2009

Follicular and marginal zone B cells fail to cross-present MHC class I-restricted epitopes derived from viral particles.

J Immunol 2009 May;182(10):6261-6

Cytos Biotechnology AG, Schlieren, Switzerland.

Viruses and virus-like particles (VLPs) are known to be potent inducers of B cell as well as Th cell and CTL responses. It is well established that professional APCs such as dendritic cells (DCs) and macrophages efficiently process viral particles for both MHC class I- and MHC class II-associated presentation, which is essential for induction of CTL and Th cell responses, respectively. Less is known, however, about the ability of B cells to present epitopes derived from viral particles to T cells. Using two different VLPs, in this study we show in vitro as well as in vivo that DCs present VLP-derived peptides in association with MHC class I as well as class II. In contrast, although B cells were able to capture VLPs similarly as DCs and although they efficiently processed VLPs for presentation in association with MHC class II, they failed to process exogenous VLPs for presentation in association with MHC class I. Thus, in contrast to DCs, B cells are not involved in the process of cross-priming. This finding is of physiological importance because B cells with the ability to cross-present Ag to specific CD8(+) T cells may be killed by these cells, preventing the generation of neutralizing Ab responses.
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http://dx.doi.org/10.4049/jimmunol.0804035DOI Listing
May 2009

Isolation of human monoclonal antibodies by mammalian cell display.

Proc Natl Acad Sci U S A 2008 Sep;105(38):14336-41

Cytos Biotechnology AG, Wagistrasse 25, CH-8952 Schlieren, Switzerland.

Due to their low immunogenicity in patients, humanized or fully human mAbs are becoming increasingly important for the treatment of a growing number of diseases, including cancer, infections, and immune disorders. Here, we describe a technology allowing for the rapid isolation of fully human mAbs. In contrast to previously described methods, B cells specific for an antigen of interest are directly isolated from peripheral blood mononuclear cells (PBMC) of human donors. Recombinant, antigen-specific single-chain Fv (scFv) libraries are generated from this pool of B cells and screened by mammalian cell surface display by using a Sindbis virus expression system. This method allows isolating antigen-specific antibodies by a single round of FACS. The variable regions (VRs) of the heavy chains (HCs) and light chains (LCs) are isolated from positive clones and recombinant fully human antibodies produced as whole IgG or Fab fragments. In this manner, several hypermutated high-affinity antibodies binding the Qbeta virus like particle (VLP), a model viral antigen, as well as antibodies specific for nicotine were isolated. All antibodies showed high expression levels in cell culture. The human nicotine-specific mAbs were validated preclinically in a mouse model. Thus, the technology presented here allows for rapid isolation of high-affinity, fully human antibodies with therapeutic potential from human volunteers.
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http://dx.doi.org/10.1073/pnas.0805942105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567231PMC
September 2008

Quantification of circulating endothelial and progenitor cells: comparison of quantitative PCR and four-channel flow cytometry.

BMC Res Notes 2008 Aug 28;1:71. Epub 2008 Aug 28.

Tumor Biology and Angiogenesis Laboratory, Division of Hematology and Oncology, Innrain 66, Innsbruck Medical University, 6020 Innsbruck, Austria.

Background: Circulating endothelial cells (CEC) and endothelial precursor cells (CEP) have been suggested as markers for angiogenesis in cancer. However, CEC/CEP represent a tiny and heterogeneous cell population, rendering a standardized monitoring in peripheral blood difficult. Thus, we investigated whether a PCR-based detection method of CEC/CEP might overcome the limitations of rare-event flow cytometry.

Findings: To test the sensitivity of both assays endothelial colony forming cell clones (ECFC) and cord blood derived CD45- CD34+ progenitor cells were spiked into peripheral blood mononuclear cells (PBMNC) of healthy volunteers. Samples were analyzed for the expression of CD45, CD31, CD34, KDR or CD133 by 4-color flow cytometry and for the expression of CD34, CD133, KDR and CD144 by qPCR. Applying flow cytometry, spiked ECFC and progenitor cells were detectable at frequencies >/= 0.01%, whereas by qPCR a detection limit of 0.001% was achievable. Furthermore, PBMNC from healthy controls (n = 30), patients with locally advanced rectal cancer (n = 20) and metastatic non-small cell lung cancer (NSCLC, n = 25) were analyzed. No increase of CEC/CEP was detectable by flow cytometry. Furthermore, only CD34 and KDR gene expression was significantly elevated in patients with metastatic NSCLC. However, both markers are not specific for endothelial cells.

Conclusion: QPCR is more sensitive, but less specific than 4-channel flow cytometry for the detection of CEC/CEP cell types. However, both methods failed to reliably detect an increase of CEC/CEP in tumor patients. Thus, more specific CEC/CEP markers are needed to validate and improve the detection of these rare cell types by PCR-based assays.
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http://dx.doi.org/10.1186/1756-0500-1-71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546419PMC
August 2008

Nanoparticles target distinct dendritic cell populations according to their size.

Eur J Immunol 2008 May;38(5):1404-13

Department Immunodrugs, Cytos Biotechnology, Schlieren, Switzerland.

The efficiency of a vaccine largely depends on the appropriate targeting of the innate immune system, mainly through prolonged delivery of antigens and immunomodulatory substances to professional antigen-presenting cells in the lymphoid environment. Particulate antigens, such as virus-like particles (VLP) induce potent immune responses. However, little is known about the relative importance of direct drainage of free antigen to lymph nodes (LN) versus cellular transport and the impact of particle size on the process. Here, we show that nanoparticles traffic to the draining LN in a size-dependent manner. Whereas large particles (500-2000 nm) were mostly associated with dendritic cells (DC) from the injection site, small (20-200 nm) nanoparticles and VLP (30 nm) were also found in LN-resident DC and macrophages, suggesting free drainage of these particles to the LN. In vivo imaging studies in mice conditionally depleted of DC confirmed the capacity of small but not large particles to drain freely to the LN and demonstrated that DC are strictly required for transport of large particles from the injection site to the LN. These data provide evidence that particle size determines the mechanism of trafficking to the LN and show that only small nanoparticles can specifically target LN-resident cells.
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http://dx.doi.org/10.1002/eji.200737984DOI Listing
May 2008

Identification of Ly-6K as a novel marker for mouse plasma cells.

Mol Immunol 2008 May 26;45(10):2727-33. Epub 2008 Mar 26.

Cytos Biotechnology AG, Wagistrasse 25, Schlieren, Switzerland.

Plasma cells are the main producers of antibody and key effector cells of the immune system. Despite their importance, analytics of plasma cells still suffers from the limited availability of specific markers. Currently, plasma cell identification relies on the expression of a single marker, CD138/syndecan-1. However, syndecan-1 is widely expressed on various cell types outside the hematopoietic compartment, and furthermore, not expressed on all subsets of plasma cells. To discover novel surface markers, a differential screening followed by signal sequence trap cloning was developed, leading to the identification of mouse Ly-6K (mLy-6K). Expression profiling confirmed that mLy-6K is expressed by plasma cells but not B cells or tissues not containing plasma cells. Expression at the surface of plasma cells isolated from spleen, lymph node, bone marrow, and lamina propria of the small intestine was demonstrated at the protein level using a polyclonal rabbit antibody. This novel plasma cell marker shows promise to help broaden our understanding of plasma cell differentiation and function.
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http://dx.doi.org/10.1016/j.molimm.2008.02.009DOI Listing
May 2008

Alternative splicing of vasohibin-1 generates an inhibitor of endothelial cell proliferation, migration, and capillary tube formation.

Arterioscler Thromb Vasc Biol 2008 Mar 10;28(3):478-84. Epub 2008 Jan 10.

Laboratory of Tumor Biology & Angiogenesis, Division of Hematology and Oncology, Innsbruck Medical University, Innrain 66, A-6020 Innsbruck, Austria.

Objective: In this study, the alternative splicing product of vasohibin 1 (VASH1B) was analyzed in direct comparison to the major isoform (VASH1A) for antiangiogenic effects on endothelial colony forming cells (ECFCs) from peripheral blood and on human umbilical vein endothelial cells (HUVECs).

Methods And Results: Expression studies in primary human endothelial cells revealed that both vasohibin proteins, hVASH1A and hVASH1B, localized in the nucleus and cytoplasm. Adenoviruses carrying the cDNA for VASH1A/B and purified recombinant proteins were used to study the function of both molecules in ECFCs and HUVECs. Recombinant VASH1A protein did not inhibit cell proliferation, tube formation, or vessel growth in vivo in the chick chorioallantoic membrane (CAM) assay, but promoted endothelial cell migration in vitro. The VASH1B protein had an inhibitory effect on cell proliferation, migration, tube formation, and inhibited blood vessel formation in the CAM assay. Adenoviral overexpression of VASH1B, but not of VASH1A, resulted in inhibition of endothelial cell growth, migration, and capillary formation. Interestingly, overexpression of VASH1A and B induced apoptosis in proliferating human fibroblasts, but did not affect cell growth of keratinocytes.

Conclusions: Our data point out that alternative splicing of the VASH1 pre-mRNA transcript generates a potent antiangiogenic protein.
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http://dx.doi.org/10.1161/ATVBAHA.107.160432DOI Listing
March 2008

A virus-like particle-based vaccine selectively targeting soluble TNF-alpha protects from arthritis without inducing reactivation of latent tuberculosis.

J Immunol 2007 Jun;178(11):7450-7

Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.

Neutralization of the proinflammatory cytokine TNF-alpha by mAbs or soluble receptors represents an effective treatment for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, or Crohn's disease. In this study, we describe a novel active immunization approach against TNF-alpha, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Qbeta covalently linked to either the entire soluble TNF-alpha protein (Qbeta-C-TNF(1-156)) or a 20-aa peptide derived from its N terminus (Qbeta-C-TNF(4-23)) yielded specific Abs, which protected from clinical signs of inflammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Qbeta-C-TNF(1-156) showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Qbeta-C-TNF(4-23) were not immunocompromised with respect to infection with these pathogens. This difference was attributed to recognition of both transmembrane and soluble TNF-alpha by Abs elicited by Qbeta-C-TNF(1-156), and a selective recognition of only soluble TNF-alpha by Abs raised by Qbeta-C-TNF(4-23). Thus, by specifically targeting soluble TNF-alpha, Qbeta-C-TNF(4-23) immunization has the potential to become an effective and safe therapy against inflammatory disorders, which might overcome the risk of opportunistic infections associated with the currently available TNF-alpha antagonists.
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http://dx.doi.org/10.4049/jimmunol.178.11.7450DOI Listing
June 2007

[Nursing care of children with a cerebrospinal fluid shunt].

Authors:
Monika Bauer

Kinderkrankenschwester 2002 Apr;21(4):150-4

Kinderklinik München Schwabing, Chirurgische Wach- und Intensivstation, München.

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April 2002

Heterogeneous antibody repertoire of marginal zone B cells specific for virus-like particles.

Microbes Infect 2007 Mar 12;9(3):391-9. Epub 2007 Jan 12.

Cytos Biotechnology AG, Wagistrasse 25, CH-8952 Zurich-Schlieren, Switzerland.

Marginal zone (MZ) B cells differ from follicular (FO) B cells in their functional, phenotypic and localization properties. It is still unclear whether B cells from the MZ compartment also have distinct or biased BCR specificities, recognizing only a limited number of conserved antigenic structures. To address the complexity of the immune response mounted by marginal zone B cells, we compared the antibody repertoire of murine MZ and FO B cells induced by immunization with two different virus-like particles (VLPs). Antibody sequences isolated from sorted VLP-specific MZ and FO B cells were similar in heavy chain V, D and J gene segment usage. Sequence analysis of CDR3 regions of antibodies from MZ and FO B cells also revealed no consistent difference in N nucleotide additions or CDR3 length. In contrast, somatic hypermutations were reduced in CDR regions of antibodies from MZ B cells compared to those from FO B cells. These results indicate that the response of MZ B cells to VLPs is clonotypically heterogeneous and suggest that the MZ B cell compartment is capable of generating variable and diverse antibody responses.
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http://dx.doi.org/10.1016/j.micinf.2006.12.017DOI Listing
March 2007

VSIG4, a B7 family-related protein, is a negative regulator of T cell activation.

J Clin Invest 2006 Oct;116(10):2817-26

Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.

T cell activation by APCs is positively and negatively regulated by members of the B7 family. We have identified a previously unknown function for B7 family-related protein V-set and Ig domain-containing 4 (VSIG4). In vitro experiments using VSIG4-Ig fusion molecules showed that VSIG4 is a strong negative regulator of murine and human T cell proliferation and IL-2 production. Administration to mice of soluble VSIG4-Ig fusion molecules reduced the induction of T cell responses in vivo and inhibited the production of Th cell-dependent IgG responses. Unlike that of B7 family members, surface expression of VSIG4 was restricted to resting tissue macrophages and absent upon activation by LPS or in autoimmune inflammatory foci. The specific expression of VSIG4 on resting macrophages in tissue suggests that this inhibitory ligand may be important for the maintenance of T cell unresponsiveness in healthy tissues.
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http://dx.doi.org/10.1172/JCI25673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578631PMC
October 2006

Dendrimers Based on [1,3,5]-Triazines.

J Polym Sci A Polym Chem 2006 Jun;44(11):3411-3433

Department of Chemistry, Texas A&M University, College Station, Texas 77843.

A comprehensive and chronological account of dendrimers based on [1,3,5]-triazines is provided. Synthetic strategies to install the triazine through cycloaddition, cyclotrimerization, and nucleophilic aromatic substitution of cyanuric chloride are discussed. Motivations and applications of these architectures are surveyed, including the preparation of supra-molecular assemblies in the solution and solid states and their use in medicines, advanced materials, and separations when anchored to solid supports.
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http://dx.doi.org/10.1002/pola.21333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785545PMC
June 2006

Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1.

J Immunol 2006 Feb;176(3):1311-5

Department of Immunology, Institute of Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany.

The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and by T cells. In both humans and mice, KLRG1 identifies Ag-experienced T cells that are impaired in their proliferative capacity but are capable of performing effector functions. In this study, we identified E-cadherin as a ligand for murine KLRG1 by using fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the murine KLRG1 molecule as staining reagents in expression cloning. Ectopic expression of E-cadherin in B16.BL6 target cells did not affect cell-mediated lysis by lymphokine-activated NK cells and by CD8 T cells but inhibited Ag-induced proliferation and induction of cytolytic activity of CD8 T cells. E-cadherin is expressed by normal epithelial cells, Langerhans cells, and keratinocytes and is usually down-regulated on metastatic cancer cells. KLRG1 ligation by E-cadherin in healthy tissue may thus exert an inhibitory effect on primed T cells.
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http://dx.doi.org/10.4049/jimmunol.176.3.1311DOI Listing
February 2006

CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells.

Immunity 2005 Apr;22(4):493-505

Molecular Biomedicine, Department of Environmental Sciences, Swiss Federal Institute of Technology, CH-8092 Zurich, Switzerland.

Dendritic cells (DCs) are key instigators of adaptive immune responses. Using an alphaviral expression cloning technology, we have identified the chemokine CCL19 as a potent inducer of T cell proliferation in a DC-T cell coculture system. Subsequent studies showed that CCL19 enhanced T cell proliferation by inducing maturation of DCs, resulting in upregulation of costimulatory molecules and the production of proinflammatory cytokines. Moreover, CCL19 programmed DCs for the induction of T helper type (Th) 1 rather than Th2 responses. Importantly, only activated DCs that migrated from the periphery to draining lymph nodes, but not resting steady-state DCs residing within lymph nodes, expressed high levels of CCR7 in vivo and responded to CCL19 with the production of proinflammatory cytokines. Migrating DCs isolated from mice genetically deficient in CCL19 and CCL21 (plt/plt) presented an only partially mature phenotype, highlighting the importance of these chemokines for full DC maturation in vivo. Our findings indicate that CCL19 and CCL21 are potent natural adjuvants for terminal activation of DCs and suggest that chemokines not only orchestrate DC migration but also regulate their immunogenic potential for the induction of T cell responses.
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http://dx.doi.org/10.1016/j.immuni.2005.02.010DOI Listing
April 2005