Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma : interim results and correlations with CD4+ T-lymphocyte counts
    Bota, Daniela A. ; Chung, Jinah ; Dandekar, Manisha ; Carrillo, Jose A. ; Kong, Xiao Tang ; Fu, Beverly D. ; Hsu, Frank Pk ; Schönthal, Axel H. ; Hofman, Florence M. ; Chen, Thomas C. ; Zidovetzki, Raphael ; Pretto, Chrystel ; Strik, Ankie ; Schijns, Virgil E.J.C. ; Stathopoulos, Apostolos - \ 2018
    JAMA Oncology 7 (2018)3. - ISSN 2374-2437 - p. CNS22 - CNS22.
    allogeneic - autologous - bevacizumab - CD4+ T lymphocyte - ERC1671 - GBM - GBM vaccine - glioma surgery - immunotherapy

    AIM: ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.

    METHODS: In this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.

    CONCLUSION: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

    Allergen-specific cytokine polarization protects shetland ponies against culicoides obsoletus-induced insect bite hypersensitivity
    Meulenbroeks, C. ; Lugt, J.J. van der; Meide, N.M.A. van der; Willemse, T. ; Rutten, V.P.M.G. ; Zaiss, D.M.W. - \ 2015
    PLoS ONE 10 (2015)4. - ISSN 1932-6203 - 12 p.
    e-bearing cells - mast-cells - british-columbia - friesian horses - skin biopsies - sweet itch - ige - antibodies - tolerance - immunotherapy
    The immunological mechanisms explaining development of an allergy in some individuals and not in others remain incompletely understood. Insect bite hypersensitivity (IBH) is a common, seasonal, IgE-mediated, pruritic skin disorder that affects considerable proportions of horses of different breeds, which is caused by bites of the insect Culicoides obsoletus (C. obsoletus). We investigated the allergen-specific immune status of individual horses that had either been diagnosed to be healthy or to suffer of IBH. Following intradermal allergen injection, skin biopsies were taken of IBH-affected and healthy ponies and cytokine expression was determined by RT-PCR. In addition, allergen-specific antibody titers were measured and cytokine expression of in vitro stimulated, allergen-specific CD4 T-cells was determined. 24 hrs after allergen injection, a significant increase in mRNA expression of the type-2 cytokine IL-4 was observed in the skin of IBH-affected Shetland ponies. In the skin of healthy ponies, however, an increase in IFN¿ mRNA expression was found. Analysis of allergen-specific antibody titers revealed that all animals produced allergen-specific antibodies, and allergen-specific stimulation of CD4 T-cells revealed a significant higher percentage of IFN¿-expressing CD4 T-cells in healthy ponies compared to IBH-affected ponies. These data indicate that horses not affected by IBH, in contrast to the so far established dogma, are not immunologically ignorant but have a Th1-skewed allergen-specific immune response that appears to protect against IBH-associated symptoms. To our knowledge this is the first demonstration of a natural situation, in which an allergen-specific immune skewing is protective in an allergic disorder.
    Discovery of T cell epitopes implementing HLA-peptidomics into a reverse immunology approach
    Hombrink, P. ; Hassan, C. ; Kester, M.G.D. ; Ru, A.H. ; Bergen, C.A.M. ; Nijveen, H. ; Drijfhout, J.W. ; Falkenburg, J.H.F. ; Heemskerk, M.H.M. ; Veelen, P.A. van - \ 2013
    The Journal of Immunology 190 (2013)8. - ISSN 0022-1767 - p. 3869 - 3877.
    minor histocompatibility antigens - versus-host-disease - restricted tissue distribution - identification - peptides - leukemia - gene - immunotherapy - lymphocytes - complexes
    T cell recognition of minor histocompatibility Ags (MiHA) plays an important role in the graft-versus-tumor effect of allogeneic stem cell transplantation. Selective infusion of T cells reactive for hematopoiesis-restricted MiHA presented in the context of HLA class I or II molecules may help to separate the graft-versus-tumor effects from graft-versus-host disease effects after allogeneic stem cell transplantation. Over the years, increasing numbers of MiHA have been identified by forward immunology approaches, and the relevance of these MiHA has been illustrated by correlation with clinical outcome. As the tissue distribution of MiHA affects the clinical outcome of T cell responses against these Ags, it would be beneficial to identify additional predefined MiHA that are exclusively expressed on hematopoietic cells. Therefore, several reverse immunology approaches have been explored for the prediction of MiHA. Thus far, these approaches frequently resulted in the identification of T cells directed against epitopes that are not naturally processed and presented. In this study we established a method for the identification of biologically relevant MiHA, implementing mass spectrometry–based HLA-peptidomics into a reverse immunology approach. For this purpose, HLA class I binding peptides were eluted from transformed B cells, analyzed by mass spectrometry, and matched with a database dedicated to identifying polymorphic peptides. This process resulted in a set of 40 MiHA candidates that were evaluated in multiple selection steps. The identification of LB-NISCH-1A demonstrated the technical feasibility of our approach. On the basis of these results, we present an approach that can be of value for the efficient identification of MiHA or other T cell epitopes.
    Cloning and expression of candidate allergens from Culicoides obsoletus for diagnosis of insect bite hypersensitivity in horses
    Meide, N.M.A. van der; Roders, N. ; Sloet van Oldruitenborgh-Oosterbaan, M.M. ; Schaap, P.J. ; Oers, M.M. van; Leibold, W. ; Savelkoul, H.F.J. ; Tijhaar, E. - \ 2013
    Veterinary Immunology and Immunopathology 153 (2013)3-4. - ISSN 0165-2427 - p. 227 - 239.
    lepidoglyphus-destructor - intradermal challenge - escherichia-coli - skin - identification - extract - ige - immunotherapy - antibodies - responses
    Insect bite hypersensitivity (IBH) is an IgE-mediated (Type I) hypersensitivity reaction induced by allergens from biting midges of the Culicoides spp. The aim of the present study was to identify, clone and express recombinant allergens from C. obsoletus, the main species found feeding on horses in the Netherlands, by sequence homology searches on the C. obsoletus specific RNA database, with previously described allergens from C. nubeculosus and C. sonorensis. BLAST searches with these described allergens resulted in similarity hits with 7 genes coding for C. obsoletus allergens. These allergens were expressed as hexahistidine tagged recombinant proteins in E. coli. Allergens were termed Cul o 1–Cul o 7. A maltase (Cul o 1) plus Cul s 1 (maltase of C. sonorensis) were additionally expressed in insect cells using the baculovirus expression system to compare homologous allergens from different species produced with different expression systems in diagnostic in vitro and in vivo tests. We demonstrate that IBH affected horses in the Netherlands show higher IgE levels to Cul o 1 than to Cul s 1, as determined by an IgE ELISA. Furthermore, we show that Cul o 1 produced in E. coli is at least as suitable for in vitro diagnosis of IBH affected horses as Cul o 1 produced in the baculovirus/insect cell expression system. The resulting proteins were evaluated for their ability to discriminate IBH affected and healthy horses by ELISA and intradermal testing. The frequency of positive test results by ELISA within IBH affected horses ranged from 38% to 67% for the different allergens. When results of IgE-binding to Cul o 1–Cul o 7 were combined the test had a sensitivity of 92% and specificity of 85%. The capability of the allergens to induce Type I hypersensitivity reaction in IBH affected horses was demonstrated by an intradermal test. The results show that E. coli expressed recombinant allergens from C. obsoletus are valuable tools to determine the allergen specific sensitisation profile (component resolved diagnosis) in horses with IBH in countries were C. obsoletus is the most abundant species and may facilitate in the development of future immunotherapy
    Quantile regression for the statistical analysis of immunological data with many non-detects
    Eilers, P.H.C. ; Roder, E. ; Savelkoul, H.F.J. ; Wijk, R.G. van - \ 2012
    BMC Immunology 13 (2012). - ISSN 1471-2172
    Background Immunological parameters are hard to measure. A well-known problem is the occurrence of values below the detection limit, the non-detects. Non-detects are a nuisance, because classical statistical analyses, like ANOVA and regression, cannot be applied. The more advanced statistical techniques currently available for the analysis of datasets with non-detects can only be used if a small percentage of the data are non-detects. Methods and results Quantile regression, a generalization of percentiles to regression models, models the median or higher percentiles and tolerates very high numbers of non-detects. We present a non-technical introduction and illustrate it with an implementation to real data from a clinical trial. We show that by using quantile regression, groups can be compared and that meaningful linear trends can be computed, even if more than half of the data consists of non-detects. Conclusion Quantile regression is a valuable addition to the statistical methods that can be used for the analysis of immunological datasets with non-detects.
    Immunomodulating effects of food compounds : a study using the THP-1 cell line
    Chanput, W. - \ 2012
    Wageningen University. Promotor(en): Harry Wichers; Huub Savelkoul; Jurriaan Mes. - [S.l.] : s.n. - ISBN 9789461734006 - 183
    immuundeficiëntie - immunotherapie - niet-specifieke immunostimulatie - voedingsmiddelen - bèta-glucaan - lipopolysacchariden - immunological deficiency - immunotherapy - nonspecific immunostimulation - foods - beta-glucan - lipopolysaccharides

    THP-1 is a human leukaemia monocytic cell line from the peripheral blood of a 1 year old human male. After exposure to phorbol-12-myristate-13-acetate (PMA), THP-1 cells in monocyte state start to adhere to culture plates and alter their morphology with an indication for differentiation into macrophages. In this thesis, the THP-1 cell line was used in both monocyte and macrophage state. The results obtained during this in vitro study show that THP-1 gene expression can be modulated by specific food compounds such as β-glucans, pectin, polyphenols and fungal immunomodulatory proteins (FIPs) in both activation and resting stage. In activation stage, these cells have been activated by LPS to mimic an inflammatory situation, while in resting stage, PMAdifferentiated THP-1 macrophages without LPS challenged was used. The polarizing ability of the THP-1 cell line into either classically activated M1 or alternatively activated M2 macrophages was examined using stimuli applied in vivo. Based on the expression of M1 and M2 marker genes, THP- 1 macrophages could be successfully polarized into both M1 and M2 stage. Thereby, they can be used as a new macrophage polarizing model to estimate the polarizing/switching ability of test compounds. The integration of results from this thesis with a review of recent publications leads to the conclusion that THP-1 cells present unique characteristics as a model to investigate/estimate immunomodulating effects of food-derived compounds in both activated and resting situations.

    Therapeutic brain cancer targeting by gene therapy and immunomodulation : a translational study
    Stathopoulos, A. - \ 2012
    Wageningen University. Promotor(en): Virgil Schijns; Huub Savelkoul, co-promotor(en): F.A. Hofman. - S.l. : s.n. - ISBN 9789461733634 - 192
    hersenen - hersenkanker - gentherapie - immunotherapie - immunologie - geneeskunde - brain - brain cancer - gene therapy - immunotherapy - immunology - medicine

    The hypothesis pertinent to this thesis is that glioma tumours can be therapeutically targeted by gene and/or immunotherapy in order to eliminate or delay tumour recurrence leading to significant morbidity and mortality. In our gene therapeutic approach, described in Chapter 2, we observed that chronic expression of the C-terminal fusion of IsK with EGFP (enhanced green fluorescent protein) led to cell death of more than 50% of transfected U87-MG human astrocytoma cells as early as 2 days after transfection. Our results are consistent with activation of apoptotic pathways following IsK-mediated increase in K+ efflux. However, we abandoned the gene therapy approach because of the more attractive immunotherapeutic intervention strategies for of brain tumours, which is currently emerging as a highly potential clinical option as reviewed in Chapter 3. Interestingly, as described in Chapter 4, we found a strong therapeutic antitumour efficacy for the innate immune response modifier Resiquimod, even as a stand-alone treatment, eventually leading to immunological memory against secondary tumour challenges. In parallel, we observed that cyclophosphamide treatment, although effective as chemotherapeutic agent, may be deleterious to maintenance of long-term antitumour immune memory. Our data also demonstrates that immunotherapeutic parenteral treatment of established glioma tumours by Resiquimod, as defined in the protocol, significantly improves anti-brain tumour immunity in a way that leads to immune memory, which is superior to cyclophosphamide treatment alone. Our studies have thereby identified a promising novel antitumour immunotherapy which may lead to clinical benefit. In Chapter 5, we describe our finding that, in multiple rat glioma models, a certain composition of antigens derived from syngeneic tumour cells and their lysates when therapeutically co-administered with allogeneic cells and their lysates is able to confer anti-tumour immune responses and tumour regression. For the syngeneic C6 model in SD rats therapeutic injections of allogeneic cells alone were sufficient to trigger tumour regression. This immunization approach may prove useful as a postsurgery adjuvant therapy in future cancer treatment protocols, or even as a stand-alone therapeutic tumour vaccination. In another syngeneic rat glioma model, described in Chapter 6, we found that for regression of CNS-1 glioma tumours in Lewis rats specific innate immune response stimulating substances were required as immunological adjuvants. In our hands BCG and IL-2, the Toll-Like receptor (TLR) 7/8 activator Resiquimod, and the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF), showed potent activity. Finally, as described in Chapter 7, we demonstrate that our prototype therapeutic vaccine, when co-delivered in a specific regimen together with the cytokine GM-CSF as immunological adjuvant, is able to arrest progression of glioma tumour growth, when therapeutically administered following low-dose cyclophosphamide. GM-CSF is an attractive vaccine adjuvant because of its proven immune modulatory effects and low toxicity profile. The safe pharmacological use of GM-CSF in patients is well-established, which makes it feasible for clinical use. The use of GM-CSF has been included in the first clinical studies that have been approved for an Investigational New Drug application (IND) for Single patient use in the U.S..

    Development of systems biology-oriented biomarkers by permuted stepwise regression for the monitoring of seasonal allergic rhinitis treatment effects
    Baars, E.W. ; Nierop, A.F.M. ; Savelkoul, H.F.J. - \ 2012
    Journal of Immunological Methods 378 (2012)1-2. - ISSN 0022-1759 - p. 62 - 71.
    surrogate end-points - regulatory t-cells - gene polymorphisms - cytokine - immunotherapy - definitions - responses - patterns - children - healthy
    Background: The immune system, a complex set of integrated responses, often cannot be explained, predicted, or monitored by examining its separate components as biomarkers. Combining different components may therefore be a suitable approach to develop relevant biomarkers reflecting immune system functioning in an appropriate way. Methods: Here we compute and test pattern variables that should reflect immune system functioning on the systems level. Computation was based on a dataset (from a randomized controlled trial comparing two routes of administration) of allergen-specifically induced expression levels of cytokines IL-1 beta, IL-5, IL-10, IL-12, IL-17, IFN-gamma and TNF-alpha) and symptom severity scores from 22 seasonal allergic rhinitis (SAR) patients measured before and after six weeks of treatment with medicinal products containing Citrus and Cydonia. By means of stepwise regression analyses we explored and tested pattern variables of the immunological data using permuted stepwise regression (PStR) to distinguish optimally between (immunological) baseline and post-baseline data for the whole treatment group (22 patients) and the two separate treatment groups (11 patients in each group). The validity of the stepwise selection method for the computed pattern variables was tested by means of random permutation tests and evaluated with the cross-validated correct rate of classification (CV correct). Results: For the total group a pattern variable was computed with three variables: IL-10 (day 7), TNF-alpha (day 1) and IL-10 (day 1) (CV correct: 091; p
    Allergenicity in food allergy : influence of food processing and immunomodulation by lactic acid bacteria
    Vissers, Y.M. - \ 2011
    Wageningen University. Promotor(en): Harry Wichers; Huub Savelkoul, co-promotor(en): E.N.C. Mills. - [S.l.] : S.n. - ISBN 9789085859161 - 226
    voedselallergieën - voedselverwerking - immunotherapie - aardnoten - melkzuurbacteriën - food allergies - food processing - immunotherapy - groundnuts - lactic acid bacteria

    Allergic diseases such as allergic rhinitis, allergic asthma, atopic eczema and food allergy have become an increasing health problem world-wide, affecting between 20-30% of the total population. Peanut allergy (prevalence ~1%) is a common and persistent food allergy accounting for severe allergic reactions. Peanuts are often consumed after thermal processing (e.g. boiling, roasting) which can alter the protein structure and change its immunoreactivity and allergenicity. In vitro diagnostic testing, however, is generally performed using the native, unprocessed protein and more knowledge on the effect of processing on allergens is necessary to improve these diagnostic procedures. In addition, rationally designed processing could also lead to reduction of the allergen content in certain products and therefore be an effective food technological approach in allergy management. Another approach in allergy management is the use of immunomodulating foods, such as probiotics. There are indications that probiotics, e.g. specific lactic acid bacteria, could be beneficial for many conditions, including different clinical expressions of allergy.
    Chapter 1 gives an overview of several aspects of allergy with a focus on food allergy. Firstly the basic mechanism and the involved immune cells are discussed, after which the prevalence of food allergy in the context of the EuroPrevall project is described. Different food allergens are discussed with an emphasis on the allergens from peanut and different methods are described to assess the potential allergenicity of proteins under widely used processing conditions, including heating and the Maillard reaction. Lastly, different methods to prevent or treat allergies are discussed with a special emphasis on immunomodulation by lactic acid bacteria. This introduction chapter is concluded with the research aim and thesis outline.

    Section 1: Influence of processing on allergenicity of proteins
    In our first study, described in Chapter 2, Ara h 2/6 was purified from raw peanut and heated in solution (boiling) in the presence or absence of glucose. Ara h 2 and 6 were also purified from roasted peanuts for comparison. Structural changes, the capacity to induce cell proliferation and cytokine production, and IgE-binding and IgE cross-linking capacity were evaluated. Although no effect of processing on T-cell reactivity was observed, heat-induced denaturation reduced the IgE-binding and cross-linking capacity. Interestingly, the soluble fraction of the Ara h 2/6 isolated from roasted peanuts retained the conformation and allergenic activity of the native protein.
    In Chapter 3 similar methods were used to assess the effect of heating and glycation on Ara h 1. Heating in solution, irrespective of their level of glycation, resulted in formation of aggregates having reduced IgE-binding and cross-linking capacity, while T-cell reactivity was retained. The soluble fraction of Ara h 1 isolated from roasted peanuts appeared to be highly denatured, formed more globular and smaller aggregates, and showed no evidence of glycation. However, these smaller aggregates retained IgE-binding capacity, unlike the aggregates formed after heating and glycating purified Ara h 1. These results could account for observed differences between boiled and roasted peanuts and suggest that other modifications than the Maillard reaction affect the allergenicity of Ara h 1.
    As peanuts are often consumed after roasting, the wet-thermal processing procedures, employed in the two previous described studies, were related to the effect of thermal treatment and Maillard reaction under low moisture conditions, which is described in Chapter 4. The extensive heating at low moisture resulted in hydrolysis of both Ara h 1 and Ara h 2/6. However, in contrast to Ara h 2/6, soluble Ara h 1 formed large aggregates. Thermally treated Ara h 2/6 had both a lower IgE-binding and degranulation capacity compared to the native form, and the presence of glucose during heating partly counteracted both the decrease in IgE-binding and degranulation capacity. The IgE-binding capacity of Ara h 1 was also decreased; however, the basophil degranulation capacity increased significantly. This demonstrates the importance of including degranulation assays in addition to IgE-binding assays, when assessing allergenic potency of allergens. In addition, we here propose a role for large aggregates in the increased IgE-cross-linking capacity of individual allergens.
    Chapter 5 describes the effect of glycation on the immunoreactivity and basophil degranulation capacity of Cor a 11, the 7S globulin from hazelnut (and thus a homologue of Ara h 1). Three processing methods (heating at low moisture content at 37, 60 and 145°C) resulted in proteins with increasing degrees of glycation. Glycation at 37°C did not influence the specific IgG or IgE binding, while both were decreased after heating at 60°C and 145°C. However, heating at 145°C in the absence or presence of glucose resulting in the formation of aggregated structures, increased the basophil degranulation capacity of Cor a 11 using sera high in Cor a 11 specific IgE, but not when using sera from peanut allergic patients low in Cor a 11 specific IgE. Therefore, this study besides showing the importance of the use of a combination of tests also indicated the importance of using well-characterized sera as a source of IgE.
    In Chapter 6 we focused on the clinical features of all our clinically well-defined peanut allergic patients of which immune cells and sera were used for the previously described studies. In addition, soy allergic patients were included and an extensive IgE profile was determined for all patients. Gly m 4 (Bet v 1 homologue from soy) sensitization was suggested to be an important indicator of severe soy allergy in the soy allergic patients, while in peanut allergic patients sensitization to allergens from soy and pea extract nor Gly m 5 and 6 was found to have a good diagnostic specificity. This is likely due to the presence of clinically non-relevant cross-reactivity between peanut-specific IgE and homologues soy and pea components.

    Section 2: Immunomodulation by Lactobacillus strains
    In the first in vitro study, described in Chapter 7, initially 51 Lactobacillus strains were screened of which 8 were selected and tested for their immunomodulating effects on peripheral blood mononuclear cells (PBMC) of healthy donors. All tested Lactobacillus strains were capable of inducing the production of IL-1β, IL-10, IFN-γ and TNF-α. Clear strain-specific effects were observed with L. plantarum strains showing significantly higher induction capacity of IFN-γ, IL-12 and TNF-α compared with L. acidophilus strains. We therefore concluded that especially L. plantarum strains are promising candidates in IgE-mediated allergy by their stimulation potential of the T-cell response toward a putative Th1 response.
    As healthy subjects, in contrast to allergic individuals, are assumed to finely regulate the Th1/Th2 balance by inducing sufficient Treg cell activity, immunomodulatory effects of six selected Lactobacillus strains were investigated on PBMC of pollen-allergic patients in Chapter 8. All strains could modulate PBMC to induce innate cytokine production and in addition, all strains had the ability to repress IL-13 production. Again a differential effect on IFN-γ and IL-12 induction was observed. In addition, one strain could extensively suppress proliferation induced by anti-CD3/anti-CD28 stimulation. Specific strains that were able to suppress the Th2 cytokine induction and induce Th1 cytokines might be beneficial for allergic patients.
    Effects found in vitro cannot directly be extrapolated to in vivo and therefore, in Chapter 9, we performed an in vivo screening including five Lactobacillus strains. Blood samples were collected before and after a 4-week intervention with probiotics from all 62 birch-pollen-allergic patients included. Four strains caused a decrease in birch-pollen-specific IgE and for one specific strain this coincided with significant decreases in IL-5 and IL-13 and an increase in IL-10 production by anti-CD3/anti-CD28 stimulated PBMC cultures and might therefore have the potential to alleviate seasonal allergy symptoms.
    The last chapter, Chapter 10, gives an overview of the most important results of this thesis and discusses the research limitations and future research perspectives. We hypothesize the role of protein aggregation in allergenicity and we elaborate on the importance of a proper stepwise approach to realize selection of a proper lactic acid strain for in vivo human testing.
    In conclusion, this thesis showed that processing effects can have profound and specific effects on the structure and the allergenicity of relevant allergens. However, to test putative effects on allergenicity, IgE-binding tests only are not sufficient and mediator release assays are important to include, particularly when testing aggregated proteins. These results might have consequences for the proper diagnosis of food allergy in daily practice. Finally, as effects of lactic acid bacteria are strain specific, a proper pre-selection of candidate strains is important to choose the most promising strains for clinical testing. In our in vivo screening, one strain, L. plantarum CBS125632, was found to be promising because of its desired immunomodulatory activity to test in a follow-up trial to reduce symptoms of birch-pollen allergy.

    HSPVdb—the Human Short Peptide Variation Database for improved mass spectrometry-based detection of polymorphic HLA-ligands
    Nijveen, H. ; Kester, M.G.D. ; Hassan, C. ; Viars, A. ; Ru, A.H. ; Jager, M. de; Falkenburg, J.H.F. ; Leunissen, J.A.M. ; Veelen, P.A. van - \ 2011
    Immunogenetics 63 (2011)3. - ISSN 0093-7711 - p. 143 - 153.
    minor histocompatibility antigens - t-cell epitopes - sequence databases - identification - transplantation - immunotherapy - proteomics - molecules - leukemia - design
    T cell epitopes derived from polymorphic proteins or from proteins encoded by alternative reading frames (ARFs) play an important role in (tumor) immunology. Identification of these peptides is successfully performed with mass spectrometry. In a mass spectrometry-based approach, the recorded tandem mass spectra are matched against hypothetical spectra generated from known protein sequence databases. Commonly used protein databases contain a minimal level of redundancy, and thus, are not suitable data sources for searching polymorphic T cell epitopes, either in normal or ARFs. At the same time, however, these databases contain much non-polymorphic sequence information, thereby complicating the matching of recorded and theoretical spectra, and increasing the potential for finding false positives. Therefore, we created a database with peptides from ARFs and peptide variation arising from single nucleotide polymorphisms (SNPs). It is based on the human mRNA sequences from the well-annotated reference sequence (RefSeq) database and associated variation information derived from the Single Nucleotide Polymorphism Database (dbSNP). In this process, we removed all non-polymorphic information. Investigation of the frequency of SNPs in the dbSNP revealed that many SNPs are non-polymorphic “SNPs”. Therefore, we removed those from our dedicated database, and this resulted in a comprehensive high quality database, which we coined the Human Short Peptide Variation Database (HSPVdb). The value of our HSPVdb is shown by identification of the majority of published polymorphic SNP- and/or ARF-derived epitopes from a mass spectrometry-based proteomics workflow, and by a large variety of polymorphic peptides identified as potential T cell epitopes in the HLA-ligandome presented by the Epstein–Barr virus cells
    Targeted PLGA nano- but not microparticles specifically deliver antigen to human dendritic cells via DC-SIGN in vitro
    Cruz, L.J. ; Tacken, P.J. ; Fokkink, R.G. ; Joosten, B. ; Cohen Stuart, M.A. ; Albericio, F. ; Torensma, R. ; Figdor, C.G. - \ 2010
    Journal of Controlled Release 144 (2010)2. - ISSN 0168-3659 - p. 118 - 126.
    nanoparticle vaccines - multilectin receptor - immune-responses - drug-release - vivo - induction - antibody - immunotherapy - enhancement - activation
    Vaccine efficacy is strongly enhanced by antibody-mediated targeting of vaccine components to dendritic cells (DCs), which are professional antigen presenting cells. However, the options to link antigens or immune modulators to a single antibody are limited. Here, we engineered versatile nano- and micrometer-sized slow-release vaccine delivery vehicles that specifically target human DCs to overcome this limitation. The nano- (NPs) and microparticles (MPs), with diameters of approximately 200nm and 2microm, consist of a PLGA core coated with a polyethylene glycol-lipid layer carrying the humanized targeting antibody hD1, which does not interact with complement or Fc receptors and recognizes the human C-type lectin receptor DC-SIGN on DCs. We studied how these particles interact with human DCs and blood cells, as well as the kinetics of PLGA-encapsulated antigen degradation within DCs. Encapsulation of antigen resulted in almost 38% degradation for both NPs and MPs 6days after particle ingestion by DCs, compared to 94% when nonencapsulated, soluble antigen was used. In contrast to the MPs, which were taken up rather nonspecifically, the NPs effectively targeted human DCs. Consequently, targeted delivery only improved antigen presentation of NPs and induced antigen-dependent T cell responses at 10-100 fold lower concentrations than nontargeted NPs
    Immunomodulation by diet : individual differences in sensitivity in layer hens
    Adriaansen-Tennekes, R. - \ 2009
    Wageningen University. Promotor(en): Huub Savelkoul; Bas Kemp, co-promotor(en): Henk Parmentier. - [S.l. : S.n. - ISBN 9789085855064 - 223
    hennen - pluimvee - immunomodulatoren - immunotherapie - pluimveevoeding - lijnen - hens - poultry - immunomodulators - immunotherapy - poultry feeding - lines
    Enhancing relevant immunity of production animals to achieve more
    robust animals is receiving more and more attention. Several epidemics have
    hit production animals recently and with devastating consequences, but enhancing
    diseases resistance increasingly provides new opportunities. Furthermore,
    welfare and health of production animals is becoming a more and
    more consumer driven topic. Several routes are being used to approach the
    possibility of enhancing immunity such as selective breeding, enriched and
    altered housing conditions, vaccination programs, diet supplementation with
    immune stimulating components, and other management procedures. Disease
    susceptibility has been shown to be related to stress reactivity, which in turn
    is related to differences in HPA axis reactivity. Interestingly, independent of
    selection criteria used, the extremes of various selection procedures result in
    a recurrent dichotomy in HPA axis reactivity, either being hyperresponsive
    or hyporesponsive to stress. Animals with a hyperresponsive HPA axis show
    greater environmental sensitivity, while the hyporeactive animals are more
    intrinsically regulated. Often, research on immunomodulation is performed
    with compromised animals and/or exaggerated supplementation of dietary
    components in one generation of animals, but epigenetics by definition seems
    to be the mechanism for mothers to prepare their offspring for the environment
    they will be born into. Enhancing immunity through normal diet in uncompromised
    animals is rarely investigated, let alone over generations. In this
    thesis the aim was to induce immunomodulation through diet in selection lines
    of chicken that have previously been selected on their antibody response to
    sheep red blood cells over two generations of chicken. First, potential HPA
    axis differences were examined in these selection lines to establish their environmental
    sensitivity, whereafter immunomodulation through normal diet
    was investigated in humoral and cellular parameters of immunity. As humoral
    immunocompentence was not easily modulated, an immune trigger was
    used to detect potential differences in humoral reactivity. The selection lines
    showed differential sensitivity to immunomodulation by diet in both generations,
    suggesting that adaptation to environmental factors may be a line-specific
    (genetically based) process, with differential neuroendocrine regulation.
    Most interestingly, the second generation showed effects of the diets in all the
    selection lines, albeit in different manners. It is concluded that normal diet can
    cause immunomodulation, mainly in animals with hyper HPA axis reactivity,
    and that introducing such practices may be more beneficial when mothers are
    treated, as all offspring showed immunomodulation, irrespective of selection line. While genetic background and/or epigenetic processes on neuroendocrine
    and immune regulation of the individual form the framework wherein individual
    immunomodulation by diet can take place, environmental conditions
    determine if the modulation is beneficial or not.
    Therapeutic vaccination against malignant gliomas based on allorecognition and syngeneic tumour antigens: proof of principle in two strains of rat
    Stathopoulos, A. ; Samuelson, C. ; Milbouw, G. ; Hermanne, J.P. ; Schijns, V.E.J.C. ; Chen, T.C. - \ 2008
    Vaccine 26 (2008). - ISSN 0264-410X - p. 1764 - 1772.
    mhc class-i - immune surveillance - cancer-patients - t-cells - glioblastoma - survival - immunotherapy - infection - pathways - melanoma
    In the present study we investigated whether allogeneic glioma cells can be utilized to evoke prophylactic or therapeutic immune-mediated elimination of syngeneic glioma in two rat strains. Fisher 344 and Sprague–Dawley (SD) rats were injected with two syngeneic glioma cell lines, 9L and C6, respectively, resulting in progressive tumor growth. 9L is syngeneic to the Fisher 344 and allogeneic to the SD rats, while C6 cells are syngeneic to SD rats and allogeneic to Fisher 344 rats. Both rat strains were subcutaneously injected with their respective allogeneic tumor cells, which proved unable to grow progressively. The allogeneic cells were either rejected immediately in SD rats or within 25 days in Fisher rats, after limited tumor outgrowth. Both rat strains were subsequently challenged with their respective syngeneic glioma tumor cells and once more 10 days later with a fivefold higher dose. SD rats, even after reinjection with five times the original dosage of C6 cells, remained tumor free for at least 360 days. Similarly, Fisher rats, after initially rejecting allogeneic tumors, failed to develop syngeneic tumors. To determine anti-tumor immunity against established glioma tumors under more demanding therapeutic conditions, rats were first injected subcutaneously with their respective syngeneic tumor and vaccinated once or repeatedly (at 5-day intervals) with a mixture of the allogeneic or xenogeneic cells, with or without a lysate from the same syngeneic tumor, which served as a therapeutic vaccine preparations. The control group received either no treatment or syngeneic instead of allogeneic cells. In both strains of rats, we demonstrated that the therapeutically vaccinated groups were able to significantly reduce tumor growth, while complete rejection of tumors was noted in the SD rats. Immunization with syngeneic tumor cells alone failed to evoke anti-tumor immunity. We conclude that therapeutic immunization with a combination of allogeneic cells and syngeneic lysates induces rejection of malignant gliomas and offers a protective effect against challenge with syngeneic tumor cells. This immunization approach may prove useful as a post-surgery adjuvant therapy in future cancer treatment protocols, or even as a stand-alone therapeutic tumor vaccination.
    Activation of human T cells by a tumor vaccine infected with recombinant Newcastle disease virus producing IL-2
    Janke, M. ; Peeters, B. ; Zhao, H. ; Leeuw, O. ; Moormann, R.J.M. ; Arnold, A. ; Ziouta, Y. ; Fournier, P. ; Schirrmacher, V. - \ 2008
    International Journal of Oncology 33 (2008)4. - ISSN 1019-6439 - p. 823 - 832.
    antitumor vaccination - fusion protein - bone-marrow - therapy - cancer - memory - immunotherapy - parameters - carcinoma
    A new recombinant (rec) Newcastle disease virus (NDV) with incorporated human interleukin 2 (IL-2) as foreign therapeutic gene [rec(IL-2)] will be described. The foreign gene in rec(IL-2) did not affect the main features of NDV replication nor its tumor selectivity. Biologically active IL-2 was produced in high amounts by tumor cells infected with rec(IL-2). Tumor vaccine cells infected by rec(IL-2) stimulated human T cells to exert anti-tumor activity in vitro in a tumor neutralization assay. These effects were significantly increased when compared to vaccine infected by rec(-) virus without IL-2 gene. After incubation with rec(IL-2) infected tumor cells, T cells showed increased expression of the activation marker CD69 and produced increased amounts of IFN gamma when compared to T cells co-incubated with rec(-) infected tumor cells. CD8 T cells incubated with rec(IL-2) infected tumor cells showed upregulation of perform, cell surface exposure of the degranulation marker CD107a and increased anti-tumor cytotoxic activity. Purified T cells from lymph nodes of head and neck squamous cell carcinoma (HNSCC) patients could be stimulated to secrete IFN gamma in an ELISPOT assay upon 40 h of stimulation with rec(IL-2) infected autologous tumor cells [ATV-rec(IL-2)] but not upon stimulation with rec(IL-2) infected allogeneic U937 tumor cells. This suggests direct activation of patient derived tumor antigen-specific memory T cells by ATV-rec(IL-2). In conclusion, the already inherent immunostimulatory properties of NDV could be further augmented by the introduction of the therapeutic gene IL-2. Active specific immunization of patients with ATV-rec(IL-2) should provide the microenvironment at the vaccination site with IL-2 and avoid side effects as seen after systemic IL-2 application.
    Citrus/Cydonia Comp. can restore the immunological balance in seasonal allergic rhinitis-related immunological parameters in vitro
    Baars, E.W. ; Savelkoul, H.F.J. - \ 2008
    Mediators of Inflammation 2008 (2008). - ISSN 0962-9351 - 5 p.
    cells - proliferation - immunotherapy - responses
    In two in vitro studies, we examined the immunological (pathways of the) effects of Citrus/Cydonia comp. from, respectively, a healthy and an allergic donor; peripheral blood mononuclear cells (PBMCs) were isolated out of peripheral blood and analyzed in vitro after polyclonal stimulation of T-cells. The differentiation capacity and the influence with regard to Th1 (IFN-y) and Th2 (IL-5) cells were examined. Citrus/Cydonia comp. has a selective effect on the differentiation of T-cells by producing relatively more IL-10 than IL-12. By that, it also seems to have an effect on the induction of regulatory (IL-10 producing) T-cell subsets. It is in vitro capable of neutralizing (to some extent) the changes, characteristic to allergic rhinitis, with regard to the maturation, differentiation, and activity of the immune system. Thus, Citrus/Cydonia comp. can potentially restore the disturbed immune state of rhinitis patients, which essentially could be sufficient to make allergic symptoms disappear permanently
    A multidisciplinary study of allergy : mouse models, immune modulation and lifestyle
    Jeurink, P.V. - \ 2008
    Wageningen University. Promotor(en): Huub Savelkoul; Gerrit Antonides, co-promotor(en): Johan van Ophem; Harry Wichers. - S.l. : S.n. - ISBN 9789085049616 - 275
    allergieën - immunotherapie - levensstijl - diermodellen - antigenen - t cellen - cytokinen - immuniteitsreactie - immuniteit - immunologie - allergies - immunotherapy - lifestyle - animal models - antigens - t lymphocytes - cytokines - immune response - immunity - immunology
    Allergic diseases affect a substantial part of the global population. Although extensive studies have elucidated the allergic mechanism, no conclusive answer has yet been found that will prevent the onset of an allergic disease. Literature suggests that no single factor like a gene mutation, environmental factor or lifestyle component can be hold accountable for the allergic cascade. Therefore, the main goal of this research project was to use a multidiscipli¬nary approach to allergies, by combining information on the genetic components, lifestyles and in vivo and in vitro assessment of the immune cells involved in allergy.
    The accomplishment of this multidisciplinary goal required knowledge on the genetic factors involved in the immunopathology of allergic diseases, but also immunological and cell biological knowledge. In addition, we investigated the influence of environmental factors on the allergic response which also required knowledge on sociology and economics to assess involved lifestyle factors. Within the multidisciplinary research areas, allergic responses are studied at multiple levels. For example, the genetic differences can be studied by means of mice with different genetic backgrounds (BALB/c, STS/A, C57BL/6) or in knock-out (CD4 or CD8 knock-out) or transgenic (IL-5 transgenic) mice. These differences in the genetic background on their turn have an effect on the expression of the allergic disease characteristics. Examples of the assessed allergic characteristics comprise antigen-presentation by specialized antigen-presenting cells, the presence of T helper 2 cells, the involvement of Th2 produced cytokines like IL-4 and IL-5, and the isotype switching of B cells towards allergen-specific IgE. Alterations of the allergic characteristics were studied by the use of in vitro cultures of human peripheral blood mononuclear cells (PBMC) that display all above mentioned characteristics when they are properly isolated, cryopreserved and cultured. These alterations were elicited by the use of heat-treatment of allergens or the exposure to fungal derived proteins or polysaccharides. Taken together, these different levels within the allergic individual can on their turn be influenced by environmental and nutritional factors. To study this, lifestyle factors have been assessed by the use of a personalized internet-based questionnaire and these data were thereafter linked to allergen-specific immunoglobulin levels. To further stress the importance of multilevel research within a multidisciplinary study, a more detailed description of the separate chapters within this thesis are combined with their major results, and finalized with future perspectives.
    The European LABDEL project and its relevance to the prevention and treatment of allergies
    Daniel, C. ; Repa, A. ; Mercenier, A.M.E. ; Wiedermann, U. ; Wells, J. - \ 2007
    Allergy 62 (2007)11. - ISSN 0105-4538 - p. 1237 - 1242.
    lactic-acid bacteria - birch pollen allergen - bovine beta-lactoglobulin - t-regulatory cells - immune-responses - immunoglobulin-e - murine model - in-vivo - disease - immunotherapy
    In March 2001, the European Commission funded a 3-year project (contract no. QLK3-CT-2000-00340) under the fifth Framework Programme to develop and test prototype products based on the oral delivery of vaccine and therapeutic agents using harmless lactic acid bacteria (LAB). The project, best known under its acronym LABDEL (for LAB delivery) also included research on LAB fermentation and technological innovations aimed at enhancing the efficiency of LAB delivery systems (1). One of the key scientific objectives was to investigate the possibility to prevent or treat a type I allergic disease using mucosal administration of LAB expressing the pollen allergen Bet v 1. The aim of this paper was to describe the background of the project with reference to a limited selection of articles and recent reviews as well as the results and major conclusions arising from this part of the project.
    From phage display to plant expression: Fulfilling prerequisites for chicken oral immunotherapy against coccidiosis
    Wieland, W.H. - \ 2004
    Wageningen University. Promotor(en): Martin Verstegen, co-promotor(en): Arjen Schots; D.V. Orzaéz Calatayud. - Wageningen : S.n. - ISBN 9789085040736 - 132
    kippen - coccidiose - immunotherapie - iga - antilichamen - transgene planten - biotechnologie - immunisatie - immuniteit - immunologie - fowls - coccidiosis - immunotherapy - iga - antibodies - transgenic plants - biotechnology - immunization - immunity - immunology
    The frequency and spectrum of infections with pathogens harbouring resistance to antibiotics and other drugs has dramatically increased over the last years. One of the main causes is the extensive use of antibiotics and other drugs in human and veterinary medicine. Parasites, such as Eimeria causing coccidiosis in chicken and pathogenic bacteria like Salmonellae and Campylobacter are examples of pathogens that acquired resistance. Furthermore, continuous use of drugs in diets of animals kept for human consumption increases the risk of residues in food, that possibly affect human health. These drawbacks of antimicrobial drugs have led to a demand for alternative treatments. In this thesis an alternative approach for prevention of coccidiosis in chicken is described, based on immune intervention by passively administered, plant produced, secretory IgA.As a first step, Eimeria binding IgA fragments were selected using the phage display technique. The phage display system was adapted to be used for the display of chicken Fab fragments. A newly constructed vector, named pChick3, allows straightforward cloning of chicken variable antibody domains in frame with the constant domains of the chicken light chain and the first constant domain of the IgA heavy chain. In a following step, new plant expression vectors were designed and constructed. Ten antibodies, selected from the chicken phage antibody library were then transferred to this vector system and subsequently expressed in planta as full size IgA. Upon expression of the ten selected anti- Eimeria antibodies, differences up to 500-fold in yield were observed. Several factors on translational or protein level could cause the observed differences: e.g. processing, stability, assembly and silencing. Two were tested (silencing, chain compatibility i.e. assembly) and both have an influence on the levels of expression. An explanation may be found in the combination of several factors. These observations lead to the conclusion that an extra in planta selection step is inevitable for successful integration of phage display and plant expression systems. Finally, the structure of the chicken polymeric immunoglobulin receptor was elucidated. In a fashion similar to its mammalian counterpart, this receptor transports IgA to the gut lumen forming secretory IgA. This complex is highly stable, and IgA is protected against degradation by proteases or pH-fluctuation, which makes secretory IgA the most suitable form for passive immunization. Interestingly, the chicken SC comprises only four immunoglobulin-like domains compared to five found in mammals. Thus, an integrated system for both selection and expression of immunoglobulins was developed and with the final achievement of the production of Eimeria -specific secretory IgA in plants, the prerequisites for chicken passive immune therapy were fulfilled.
    Besmettelijke dierziekten: geintegreerd aanpakken
    Hanekamp, W. ; Snoep, J. - \ 1998
    Praktijkonderzoek Rundvee, Schapen en Paarden. Praktijkonderzoek 11 (1998)4. - ISSN 1386-8470 - p. 25 - 29.
    diergeneeskunde - melkvee - melkveehouderij - infectieziekten - vaccinatie - immunisatie - immunotherapie - vaccins - preventieve geneeskunde - ziektepreventie - preventie - diergezondheid - hygiëne - ziekteoverdracht - dieren - zoönosen - veterinary science - dairy cattle - dairy farming - infectious diseases - vaccination - immunization - immunotherapy - vaccines - preventive medicine - disease prevention - prevention - animal health - hygiene - disease transmission - animals - zoonoses
    Omdat het dier de belangrijkste besmettingsbron is, is aankoop van vee een grote risicofactor en dienen mensen die veel in contact komen met dieren bedrijfskleding aan te trekken.
    Immunological aspects of oral vaccination in fish
    Joosten, P.H.M. - \ 1997
    Agricultural University. Promotor(en): W.B. van Muiswinkel; J.H.W.M. Rombout. - S.l. : Joosten - ISBN 9789054856986 - 134
    vissen - diergeneeskunde - vaccinatie - immunisatie - immunotherapie - vaccins - geneesmiddelen - farmacologie - toedieningswijzen - reticulo-endotheliaal systeem - antilichamen - immunoglobulinen - immunologische technieken - elisa - immunochemie - fishes - veterinary science - vaccination - immunization - immunotherapy - vaccines - drugs - pharmacology - application methods - reticuloendothelial system - antibodies - immunoglobulins - immunological techniques - elisa - immunochemistry

    In this thesis immunological consequences of oral vaccination in fish have been described. The efficacy of oral vaccination can be increased by protection of the antigen against degradation in the foregut, in order to reach the hindgut in sufficient quantities for uptake and subsequent activation of the mucosal and systemic immune system. Using a specific monoclonal antibody, in addition to mucosal B cells, a distinct mucosal T cell population was demonstrated, which may play an important role in local immunity. Furthermore, two approaches to protect antigens against digestive degradation are described: bioencapsulation and microencapsulation. For the first approach antigen is encapsulated in living food, and subsequently fed to juvenile carp and seabream. In carp, oral vaccination at 2 and 4 weeks old resulted in immunological tolerance. However, in older carp (8 weeks old) and seabream (8 and 10 weeks old), immunological memory was induced. It can be concluded that oral vaccination with bioencapsulated bacterial antigens is effective for oral vaccination of juvenile fish, when applied at the right age. For microencapsulation an alginate microparticle system was studied, which may be more suitable for vaccination of older fish. The supernatant appeared to be the most immunogenic fraction of a bacterin, which is taken up in the hindgut and evokes best memory formation. This fraction was encapsulated in alginate microparticles and fed to adult carp and trout. Different microparticle preparations, with respect to release time and antigen concentration, were needed for immunological memory formation in each fish species. Therefore, oral vaccination with bacterial antigens in alginate microparticles can be effective. Oral tolerance against protein antigens was demonstrated in animals fed with ferritin or recombinant VHS G protein. However, the immune response to ovalbumin appeared to be carp strain dependent. A carp strain that produced specific antibodies after injection with OVA was selected and repeated feeding of OVA, prior to injection, resulted in increased antibody titres in serum. Oral tolerance induction in fish therefore appeared to depend on the protein and possibly also on genetic factors.

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