Publications by authors named "Willem van Eden"

121 Publications

Goals in Nutrition Science 2020-2025.

Authors:
Josep Bassaganya-Riera Elliot M Berry Ellen E Blaak Barbara Burlingame Johannes le Coutre Willem van Eden Ahmed El-Sohemy J Bruce German Dietrich Knorr Christophe Lacroix Maurizio Muscaritoli David C Nieman Michael Rychlik Andrew Scholey Mauro Serafini

Front Nutr 2020 9;7:606378. Epub 2021 Feb 9.

Functional Food and Metabolic Stress Prevention Laboratory, Faculty of Biosciences and Technologies for Agriculture, Food and Environment, University of Teramo, Teramo, Italy.

Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science - the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability. Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.
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http://dx.doi.org/10.3389/fnut.2020.606378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923694PMC
February 2021

COVID-19 vaccines: the importance of transparency and fact-based education.

Authors:
Adam F Cohen Joop van Gerven Juan Garcia Burgos Anthonius de Boer Ron A M Foucher H Flore Zvi Teitelbaum Willem van Eden Andrew Webb Serge Cremers

Br J Clin Pharmacol 2020 11 14;86(11):2107-2110. Epub 2020 Oct 14.

Department of Pathology & Cell Biology, Division of Laboratory Medicine, Columbia University, New York.

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http://dx.doi.org/10.1111/bcp.14581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576612PMC
November 2020

Macrophage Activation Assays to Evaluate the Immunostimulatory Capacity of in A Multivalent Poultry Vaccine.

Authors:
Robin H G A van den Biggelaar Willem van Eden Victor P M G Rutten Christine A Jansen

Vaccines (Basel) 2020 Nov 10;8(4). Epub 2020 Nov 10.

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584CL Utrecht, The Netherlands.

High-quality vaccines are crucial to prevent infectious disease outbreaks in the poultry industry. In vivo vaccination tests are routinely used to test poultry vaccines for their potency, i.e., their capacity to induce protection against the targeted diseases. A better understanding of how poultry vaccines activate immune cells will facilitate the replacement of in vivo potency tests for in vitro assays. Using the chicken macrophage-like HD11 cell line as a model to evaluate innate immune responses, the current explorative study addresses the immunostimulatory capacity of an inactivated multivalent vaccine for infectious bronchitis, Newcastle disease, egg-drop syndrome, and infectious coryza. The vaccine stimulated HD11 cells to produce nitric oxide and to express pro-inflammatory cytokines , and chemokines and , and the anti-inflammatory cytokine , but only when inactivated , the causative agent of infectious coryza, was present. Lipopolysaccharides from were crucial for the production of nitric oxide and expression of and . The described immune parameters demonstrate the capacity of this multivalent vaccine to activate innate immune cells and may in the future, combined with antigen quantification methods, contribute to vaccine quality testing in vitro, hence the replacement of current in vivo vaccination tests.
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http://dx.doi.org/10.3390/vaccines8040671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712920PMC
November 2020

Hsp70 and NF-kB Mediated Control of Innate Inflammatory Responses in a Canine Macrophage Cell Line.

Authors:
Qingkang Lyu Magdalena Wawrzyniuk Victor P M G Rutten Willem van Eden Alice J A M Sijts Femke Broere

Int J Mol Sci 2020 Sep 4;21(18). Epub 2020 Sep 4.

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.

The pathogenesis of many inflammatory diseases is associated with the uncontrolled activation of nuclear factor kappa B (NF-κB) in macrophages. Previous studies have shown that in various cell types, heat shock protein 70 (Hsp70) plays a crucial role in controlling NF-κB activity. So far, little is known about the role of Hsp70 in canine inflammatory processes. In this study we investigated the potential anti-inflammatory effects of Hsp70 in canine macrophages as well as the mechanisms underlying these effects. To this end, a canine macrophage cell line was stressed with arsenite, a chemical stressor, which upregulated Hsp70 expression as detected by flow cytometry and qPCR. A gene-edited version of this macrophage cell line lacking inducible Hsp70 was generated using CRISPR-Cas9 technology. To determine the effects of Hsp70 on macrophage inflammatory properties, arsenite-stressed wild-type and Hsp70 knockout macrophages were exposed to lipopolysaccharide (LPS), and the expression of the inflammatory cytokines IL-6, IL-1β and tumor necrosis factor-α (TNF-α) and levels of phosphorylated NF-κB were determined by qPCR and Western Blotting, respectively. Our results show that non-toxic concentrations of arsenite induced Hsp70 expression in canine macrophages; Hsp70 upregulation significantly inhibited the LPS-induced expression of the pro-inflammatory mediators TNF-α and IL-6, as well as NF-κB activation in canine macrophages. Furthermore, the gene editing of inducible Hsp70 by CRISPR-Cas9-mediated gene editing neutralized this inhibitory effect of cell stress on NF-κB activation and pro-inflammatory cytokine expression. Collectively, our study reveals that Hsp70 may regulate inflammatory responses through NF-κB activation and cytokine expression in canine macrophages.
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http://dx.doi.org/10.3390/ijms21186464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555705PMC
September 2020

Nitric Oxide Production and Fc Receptor-Mediated Phagocytosis as Functional Readouts of Macrophage Activity upon Stimulation with Inactivated Poultry Vaccines In Vitro.

Authors:
Robin HGA van den Biggelaar Willem van Eden Victor PMG Rutten Christine A Jansen

Vaccines (Basel) 2020 06 22;8(2). Epub 2020 Jun 22.

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584CL Utrecht, The Netherlands.

Vaccine batches must pass routine quality control to confirm that their ability to induce protection against disease is consistent with batches of proven efficacy from development studies. For poultry vaccines, these tests are often performed in laboratory chickens by vaccination-challenge trials or serological assays. The aim of this study was to investigate innate immune responses against inactivated poultry vaccines and identify candidate immune parameters for in vitro quality tests as alternatives for animal-based quality tests. For this purpose, we set up assays to measure nitric oxide production and phagocytosis by the macrophage-like cell line HD11, upon stimulation with inactivated poultry vaccines for infectious bronchitis virus (IBV), Newcastle disease virus (NDV), and egg drop syndrome virus (EDSV). In both assays, macrophages became activated after stimulation with various toll-like receptor agonists. Inactivated poultry vaccines stimulated HD11 cells to produce nitric oxide due to the presence of mineral oil adjuvant. Moreover, inactivated poultry vaccines were found to enhance Fc receptor-mediated phagocytosis due to the presence of allantoic fluid in the vaccine antigen preparations. We showed that inactivated poultry vaccines stimulated nitric oxide production and Fc receptor-mediated phagocytosis by chicken macrophages. Similar to antigen quantification methods, the cell-based assays described here can be used for future assessment of vaccine batch-to-batch consistency. The ability of the assays to determine the immunopotentiating properties of inactivated poultry vaccines provides an additional step in the replacement of current in vivo batch-release quality tests.
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http://dx.doi.org/10.3390/vaccines8020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350413PMC
June 2020

Editorial: New Horizons in Food Science via Agricultural Immunity.

Authors:
Tomonori Nochi Corné M J Pieterse Willem Van Eden

Front Nutr 2020 28;7:19. Epub 2020 Feb 28.

Department of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

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http://dx.doi.org/10.3389/fnut.2020.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093008PMC
February 2020

Transcriptome Analysis of The Inflammatory Responses of Bovine Mammary Epithelial Cells: Exploring Immunomodulatory Target Genes for Bovine Mastitis.

Authors:
Md Aminul Islam Michihiro Takagi Kohtaro Fukuyama Ryoya Komatsu Leonardo Albarracin Tomonori Nochi Yoshihito Suda Wakako Ikeda-Ohtsubo Victor Rutten Willem van Eden Julio Villena Hisashi Aso Haruki Kitazawa

Pathogens 2020 Mar 9;9(3). Epub 2020 Mar 9.

Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.

Bovine mastitis is the inflammatory reaction of the mammary gland and is commonly caused by bacterial infections in high-yielding dairy cows. The detailed investigation of the immunotranscriptomic response of bovine mammary epithelial (BME) cells to pattern recognition receptors (PRRs) activation by microbial-associated molecular patterns (MAMPs) can be of great importance for understanding the innate immune defense mechanisms, and for exploring the immunomodulatory candidate genes. In this work, we investigated the transcriptome modifications of BME cells after the in vitro stimulation with derived lipopolysaccharide (LPS) and heat-killed JE2 and SA003. In addition, the effect of Pam3CSK4 (a synthetic triacylated lipopeptide that activates Toll-like receptor 2 (TLR2)), and the intracellular chemotactic protein cyclophilin A (CyPA), which is secreted by BME cells during mastitis, in the expression changes of selected cytokines and chemokines were evaluated by qPCR. Microarray analysis identified 447, 465 and 520 differentially expressed genes (DEGs) in the BME cells after LPS, JE2 and SA003 stimulation, respectively. A major differential response in the inflammatory gene expression was noticed between the stimulation of LPS and strains. Unlike the strains, LPS stimulation resulted in significant upregulation of , , , and which were confirmed by qPCR analysis. Pam3CSK4 was not able to induce significant changes in the expression of cytokines and chemokines in challenged BME cells. The exogenous CyPA administration was able to upregulate , , and expression in BME cells indicating its ability to promote inflammation. The identification of transcriptional markers of mastitis specific for individual inflammatory factors such as LPS, Pam3CSK4 or CyPA, which can be evaluated in vitro in BME cells, may enable the development of novel diagnostics and/or immunomodulatory treatments, providing new tools for the effective management of mastitis in dairy cows. The results of this work are an advance in this regard.
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http://dx.doi.org/10.3390/pathogens9030200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157600PMC
March 2020

Chicken Bone Marrow-Derived Dendritic Cells Comprise Subsets at Different States of Maturation.

Authors:
Robin H G A van den Biggelaar Ger J A Arkesteijn Victor P M G Rutten Willem van Eden Christine A Jansen

Front Immunol 2020 26;11:141. Epub 2020 Feb 26.

Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

Research in chickens has been fundamental for the discovery of basic aspects of the immune system and has led to an interest in the in-depth characterization of avian immune cell types including dendritic cells (DCs). The generation and expansion of chicken bone marrow-derived DCs (chBMDCs) in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) has provided a way to study chicken DCs, which are only present at limited cell numbers . This method has been employed to study the interactions between chicken DCs and pathogens or vaccines. However, a detailed characterization of the chBMDC culture is still lacking. In the present study, we performed an elaborate phenotypical and functional analysis of the chBMDC culture and addressed its heterogeneity. After 8 days of culture, chBMDCs comprised major histocompatibility complex class II (MHC-II) and MHC-II subsets with different morphologies. Compared with MHC-II chBMDCs, the MHC-II subset showed a more mature phenotype, with higher expressions of CD1.1, CD40, CD80, CCR7, and CD83, and a relatively low opsonophagocytic capacity. Nevertheless, MHC-II chBMDCs did not show an increased capacity to induce T-cell proliferation. Therefore, MHC-II chBMDCs were found to be semi-mature. Interestingly, the presence of the semi-mature MHC-II chBMDC subset reduced when cells were cultured in the presence of IL-4. Finally, prolonged cell culture after fluorescence-activated cell sorting (FACS) converted the semi-mature MHC-II subset back into the immature phenotype of the MHC-II subset, demonstrating plasticity of their maturation state. This detailed characterization explained the heterogeneity of the chBMDC culture by the simultaneous presence of immature and semi-mature chBMDC subsets, in addition to cells without features of antigen-presenting cells. Our findings are instrumental for the interpretation of experiments using the chBMDC culture in past and future research by providing insights into its phenotypically and functionally distinct cell types.
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http://dx.doi.org/10.3389/fimmu.2020.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054383PMC
March 2021

Leucinostatin acts as a co-inducer for heat shock protein 70 in cultured canine retinal pigment epithelial cells.

Authors:
Qingkang Lyu Irene S Ludwig Peter J S Kooten Alice J A M Sijts Victor P M G Rutten Willem van Eden Femke Broere

Cell Stress Chaperones 2020 03 15;25(2):235-243. Epub 2020 Jan 15.

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, Utrecht, The Netherlands.

Dysregulation of retinal pigment epithelium (RPE) cells is the main cause of a variety of ocular diseases. Potentially heat shock proteins, by preventing molecular and cellular damage and modulating inflammatory disease, may exert a protective role in eye disease. In particular, the inducible form of heat shock protein 70 (Hsp70) is widely upregulated in inflamed tissues, and in vivo upregulation of Hsp70 expression by HSP co-inducing compounds has been shown to be a potential therapeutic strategy for inflammatory diseases. In order to gain further understanding of the potential protective effects of Hsp70 in RPE cells, we developed a method for isolation and culture of canine RPE cells. Identity of RPE cells was confirmed by detection of its specific marker, RPE65, in qPCR, flow cytometry, and immunocytochemistry analysis. The ability of RPE cells to express Hsp70 upon experimental induction of cell stress, by arsenite, was analyzed by flow cytometry. Finally, in search of a potential Hsp70 co-inducer, we investigated whether the compound leucinostatin could enhance Hsp70 expression in stressed RPE cells. Canine RPE cells were isolated and cultured successfully. Purity of cells that strongly expressed RPE65 was over 90%. Arsenite-induced stress led to a time- and dose-dependent increase in Hsp70 expression in canine RPE cells in vitro. In addition, leucinostatin, which enhanced heat shock factor-1-induced transcription from the heat shock promoter in DNAJB1-luc-O23 reporter cell line, also enhanced Hsp70 expression in arsenite-stressed RPE cells, in a dose-dependent fashion. These findings demonstrate that leucinostatin can boost Hsp70 expression in canine RPE cells, most likely by activating heat shock factor-1, suggesting that leucinostatin might be applied as a new co-inducer for Hsp70 expression.
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http://dx.doi.org/10.1007/s12192-019-01066-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058576PMC
March 2020

Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis.

Authors:
Rachel Spiering Manon A A Jansen Matthew J Wood Anshorulloh A Fath Oliver Eltherington Amy E Anderson Arthur G Pratt Willem van Eden John D Isaacs Femke Broere Catharien M U Hilkens

J Transl Med 2019 11 14;17(1):375. Epub 2019 Nov 14.

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Background: Autologous tolerogenic dendritic cells (tolDC) are a promising therapeutic strategy for inflammatory arthritis (IA) as they can regulate autoantigen-specific T cell responses. Here, we investigated two outstanding priorities for clinical development: (i) the suitability of using heat-shock proteins (HSP), abundant in inflamed synovia, as surrogate autoantigens to be presented by tolDC and (ii) identification of functional biomarkers that confirm tolDC regulatory activity.

Methods: Cell proliferation dye-labelled human peripheral blood mononuclear cells of IA (rheumatoid arthritis (RA) and psoriatic arthritis (PsA)) patients or healthy donors were cultured with HSP40-, HSP60- and HSP70-derived peptides or recall antigens (e.g. tuberculin purified protein derivative (PPD)) in the presence or absence of tolDC or control DC for 9 days. Functional characteristics of proliferated antigen-specific T-cells were measured using flow cytometry, gene expression profiling and cytokine secretion immunoassays. Repeated measures analysis of variance (ANOVA) with Bonferroni correction for comparisons between multiple groups and paired Student t test for comparisons between two groups were used to determine significance.

Results: All groups showed robust CD4 T-cell responses towards one or more HSP-derived peptide(s) as assessed by a stimulation index > 2 (healthy donors: 78%, RA: 73%, PsA: 90%) and production of the cytokines IFNγ, IL-17A and GM-CSF. Addition of tolDC but not control DC induced a type 1 regulatory (Tr1) phenotype in the antigen-specific CD4 T-cell population, as identified by high expression of LAG3, CD49b and secretion of IL-10. Furthermore, tolDC inhibited bystander natural killer (NK) cell activation in a TGFβ dependent manner.

Conclusions: HSP-specific CD4 T-cells are detectable in the majority of RA and PsA patients and can be converted into Tr1 cells by tolDC. HSP-loaded tolDC may therefore be suitable for directing T regulatory responses to antigens in inflamed synovia of IA patients. Tr1 markers LAG3, CD49b and IL-10 are suitable biomarkers for future tolDC clinical trials.
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http://dx.doi.org/10.1186/s12967-019-2128-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857208PMC
November 2019

Matured Tolerogenic Dendritic Cells Effectively Inhibit Autoantigen Specific CD4 T Cells in a Murine Arthritis Model.

Authors:
Manon A A Jansen Rachel Spiering Irene S Ludwig Willem van Eden Catharien M U Hilkens Femke Broere

Front Immunol 2019 28;10:2068. Epub 2019 Aug 28.

Division of Immunology, Department of Infectious Diseases and Immunology, Faculty Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

Tolerogenic dendritic cells (tolDCs) are a promising treatment modality for diseases caused by a breach in immune tolerance, such as rheumatoid arthritis. Current medication for these diseases is directed toward symptom suppression but no real cure is available yet. TolDC-based therapy aims to restore immune tolerance in an antigen-specific manner. Here we used a mouse model to address two major questions: (i) is a maturation stimulus needed for tolDC function and and is maturation required for functioning in experimental arthritis and (ii) can tolDCs modulate CD4 T cell responses? To answer these questions, we compared matured and immature dexamethasone/vitamin D3-generated tolDCs . Subsequently, we co-transferred these tolDCs with naïve or effector CD4 T cells to study the characteristics of transferred T cells after 3 days with flow cytometry and Luminex multiplex assays. In addition, we tested the suppressive capabilities of tolDCs in an experimental arthritis model. We found that tolDCs cannot only modulate naïve CD4 T cell responses as shown by fewer proliferated and activated CD4 T cells , but also effector CD4 T cells. In addition, Treg (CD4CD25FoxP3) expansions were seen in the proliferating cell population in the presence of tolDCs. Furthermore, we show that administered tolDCs are capable to inhibit arthritis in the proteoglycan-induced arthritis model. However, a maturation stimulus is needed for tolDCs to manifest this tolerizing function in an inflammatory environment. Our data will be instrumental for optimization of future tolDC therapies for autoimmune diseases.
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http://dx.doi.org/10.3389/fimmu.2019.02068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724516PMC
October 2020

Lipidoid-polymer hybrid nanoparticles loaded with TNF siRNA suppress inflammation after intra-articular administration in a murine experimental arthritis model.

Authors:
Manon A A Jansen Lasse H Klausen Kaushik Thanki Jeppe Lyngsø Jan Skov Pedersen Henrik Franzyk Hanne M Nielsen Willem van Eden Mingdong Dong Femke Broere Camilla Foged Xianghui Zeng

Eur J Pharm Biopharm 2019 Sep 11;142:38-48. Epub 2019 Jun 11.

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark. Electronic address:

Rheumatoid arthritis (RA) is a common autoimmune disease, which is characterized by painful chronic inflammation in the joints, and novel safe and efficacious treatments are urgently needed. RNA interference (RNAi) therapy based on small interfering RNA (siRNA) is a promising approach for silencing specific genes involved in inflammation. However, delivery of siRNA to the target site, i.e. the cytosol of immune cells, is a challenge. Here, we designed lipid-polymer hybrid nanoparticles (LPNs) composed of lipidoid and poly(DL-lactic-co-glycolic acid) loaded with a therapeutic cargo siRNA directed against the proinflammatory cytokine tumor necrosis factor (TNF), which plays a key role in the progression of RA. We compared their efficacy and safety with reference lipidoid-based stable nucleic acid lipid particles (SNALPs) in vitro and in vivo. Cryogenic transmission electron microscopy, atomic force microscopy and small-angle X-ray scattering revealed that the mode of loading of siRNA in lamellar structures differs between the two formulations. Thus, siRNA was tightly packed in LPNs, while LPNs displayed lower adhesion than SNALPs. The LPNs mediated a higher TNF silencing effect in vitro than SNALPs in the RAW 264.7 macrophage cell line activated with lipopolysaccharide. For both types of delivery systems, macropinocytosis was involved in cellular uptake. In addition, clathrin-mediated endocytosis contributed to uptake of SNALPs. LPNs loaded with TNF siRNA mediated sequence-specific suppression of inflammation in a murine experimental arthritis model upon intra-articular administration. Hence, the present study demonstrates that LPN-mediated TNF knockdown constitutes a promising approach for arthritis therapy of TNF-mediated chronic inflammatory conditions.
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http://dx.doi.org/10.1016/j.ejpb.2019.06.009DOI Listing
September 2019

Vaccination against autoimmune diseases moves closer to the clinic.

Authors:
Willem van Eden

Hum Vaccin Immunother 2020 22;16(2):228-232. Epub 2019 Apr 22.

Faculty of Veterinary Medicine, Utrecht University, The Netherlands.

Biologicals, e.g. TNF inhibitors, have improved dramatically the efficacy of medical interventions in autoimmune diseases, such as in rheumatoid arthritis (RA). However, although progressive inflammation can be halted in this way, no drug-free remissions or lasting cures are reached. For this to become real, therapies based on induction antigen-specific immune tolerance are sought. This review describes mechanisms of tolerance and the current possibilities for induction of therapeutic tolerance through antigen-specific vaccination approaches. And despite the fact that for various diseases the search for appropriate autoantigens is ongoing, pioneering studies are now already developed that use more broadly inflammation associated antigens. Through their capacity to preferentially induce regulatory T cells, heat shock proteins are an attractive source of such broadly inflammation associated antigens.
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http://dx.doi.org/10.1080/21645515.2019.1593085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062450PMC
April 2019

Heat Shock Proteins Can Be Surrogate Autoantigens for Induction of Antigen Specific Therapeutic Tolerance in Rheumatoid Arthritis.

Authors:
Willem van Eden Manon A A Jansen Irene S Ludwig Paul Leufkens Marlies C van der Goes Jacob M van Laar Femke Broere

Front Immunol 2019 22;10:279. Epub 2019 Feb 22.

Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.

Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis.
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http://dx.doi.org/10.3389/fimmu.2019.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401592PMC
September 2020

Editorial: Stress and Immunity.

Authors:
Yong-Soo Bae Eui-Cheol Shin Yoe-Sik Bae Willem Van Eden

Front Immunol 2019 14;10:245. Epub 2019 Feb 14.

Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.

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http://dx.doi.org/10.3389/fimmu.2019.00245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383636PMC
October 2020

The Well-Developed Mucosal Immune Systems of Birds and Mammals Allow for Similar Approaches of Mucosal Vaccination in Both Types of Animals.

Authors:
Tomonori Nochi Christine A Jansen Masaaki Toyomizu Willem van Eden

Front Nutr 2018 12;5:60. Epub 2018 Jul 12.

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

The mucosal immune system is a compartmentalized part of the immune system that provides local immunity in the mucosa of the respiratory, gastrointestinal, and digestive tracts. It possesses secondary lymphoid tissues, which contain immune cells, such as T, B, and dendritic cells. Once the cells of the mucosal immune system are stimulated by luminal antigens, including microorganisms, they infiltrate into diffuse areas of mucosal tissues (e.g., respiratory mucosa and lamina propria of intestinal villi) and exhibit immune effector functions. Inducing the antigen-specific immune responses in mucosal tissues by mucosal vaccination would be an ideal strategy for not only humans, but also mammals and birds, to protect against infectious diseases occurring in mucosal tissues (e.g., pneumonia and diarrhea). Infectious diseases cause huge economic losses in agriculture, such as livestock and poultry industries. Since most infectious diseases occur in mucosal tissues, vaccines that are capable of inducing immune responses in mucosal tissues are in high need. In this review, we discuss the current understanding of mucosal immunity in mammals and birds, and recent progress in the development of mucosal vaccines.
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http://dx.doi.org/10.3389/fnut.2018.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052093PMC
July 2018

GG-Derived Soluble Mediators Modulate Adaptive Immune Cells.

Authors:
Irene S Ludwig Femke Broere Sarmauli Manurung Tim T Lambers Ruurd van der Zee Willem van Eden

Front Immunol 2018 10;9:1546. Epub 2018 Jul 10.

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.

Probiotics and probiotic-related nutritional interventions have been described to have beneficial effects on immune homeostasis and gut health. In previous studies, GG (LGG) soluble mediators (LSM) have been demonstrated to exert beneficial effects in preclinical models of allergic sensitization, bacterial infection, and intestinal barrier function. In the context of allergic diseases, differentiation of dendritic cells (DCs) and their interactions with T cell populations are crucial for driving tolerogenic responses. In this study, we set out to evaluate whether these LSM can modulate DC maturation and have an impact on prompting protective and/or tolerogenic T cell responses. Monocytes were isolated from PBMC of healthy blood donors and cultured in the presence of GM-CSF, IL-4, and LSM or unconditioned bacterial culture medium control (UCM) during 6 days to induce DC differentiation. Subsequently, these DCs were matured in the presence of TNF-α for 1 day and analyzed for their phenotype and ability to induce autologous T cell activation and differentiation to model recall antigens. After 7 days of co-culture, T cells were analyzed for activation and differentiation by flow cytometry of intracellular cytokines (IFN-γ, IL-2, IL-10, and IL-17A), activation markers (CD25), and Foxp3+ expression. LSM did not alter DC numbers or maturation status. However, these DCs did show improved capacity to induce a T cell response as shown by increased IL-2 and IFN-γ producing T cell populations upon stimulation with recall antigens. These enhanced recall responses coincided with enhanced Foxp3+ expression that was not observed when T cells were cultured in the presence of UCM-treated DCs. By contrast, the number of activated T cells (determined by CD25 expression) was only slightly increased. In conclusion, this study reveals that LSM can influence adaptive immune responses as shown by the modulation of DC functionality. These mechanisms might contribute to previous observed effects in animal models . Altogether, these results suggest that LSM may provide an alternative to live probiotics in case life bacteria may not be used because of health conditions, although further clinical testing is needed.
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http://dx.doi.org/10.3389/fimmu.2018.01546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048560PMC
July 2018

Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design.

Authors:
Anne Marit de Groot Kaushik Thanki Monique Gangloff Emily Falkenberg Xianghui Zeng Djai C J van Bijnen Willem van Eden Henrik Franzyk Hanne M Nielsen Femke Broere Nick J Gay Camilla Foged Alice J A M Sijts

Mol Ther Nucleic Acids 2018 Jun 13;11:159-169. Epub 2018 Feb 13.

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, the Netherlands. Electronic address:

Therapeutics based on small interfering RNA (siRNA) have promising potential as antiviral and anti-inflammatory agents. To deliver siRNA across cell membranes to reach the RNAi pathway in the cytosol of target cells, non-viral nanoparticulate delivery approaches are explored. Recently, we showed that encapsulation of siRNA in lipid-polymer hybrid nanoparticles (LPNs), based on poly(DL-lactic-co-glycolic acid) (PLGA) and cationic lipid-like materials (lipidoids), remarkably enhances intracellular delivery of siRNA as compared to siRNA delivery with LPNs modified with dioleoyltrimethylammoniumpropane (DOTAP) as the lipid component. However, the potential immune modulation by these cationic lipids remains unexplored. By testing lipidoids and DOTAP for innate immune-receptor-activating properties in vitro, we found that neither lipidoids nor DOTAP activate human Toll-like receptor (TLR) 2, 3, 7, and 9. However, in contrast to DOTAP, lipidoids are strong agonists for TLR4 and activate murine antigen-presenting cells in vitro. This agonistic effect was further confirmed in silico using a prediction model based on crystal structures. Also, lipidoids formulated as lipoplexes or as stable nucleic acid lipid particles, which was the reference formulation for siRNA delivery, proved to activate TLR4. However, by combining lipidoids with PLGA into LPNs, TLR4 activation was abrogated. Thus, lipidoid-mediated TLR4 activation during siRNA delivery may be modulated via optimization of the formulation design.
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http://dx.doi.org/10.1016/j.omtn.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992342PMC
June 2018

Immunobiotics for the Bovine Host: Their Interaction with Intestinal Epithelial Cells and Their Effect on Antiviral Immunity.

Authors:
Julio Villena Hisashi Aso Victor P M G Rutten Hideki Takahashi Willem van Eden Haruki Kitazawa

Front Immunol 2018 2;9:326. Epub 2018 Mar 2.

Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.

The scientific community has reported several cases of microbes that exhibit elevated rates of antibiotic resistance in different regions of the planet. Due to this emergence of antimicrobial resistant microorganisms, the use of antibiotics as promoters of livestock animals' growth is being banned in most countries around the world. One of the challenges of agricultural immunology therefore is to find alternatives by modulating the immune system of animals in drug-independent safe food production systems. In this regard, in an effort to supplant antibiotics from bovine feeds, several alternatives were proposed including the use of immunomodulatory probiotics (immunobiotics). The purpose of this review is to provide an update of the status of the modulation of intestinal antiviral innate immunity of the bovine host by immunobiotics, and the beneficial impact of immunobiotics on viral infections, focused on intestinal epithelial cells (IECs). The results of our group, which demonstrate the capacity of immunobiotic strains to beneficially modulate Toll-like receptor 3-triggered immune responses in bovine IECs and improve the resistance to viral infections, are highlighted. This review provides comprehensive information on the innate immune response of bovine IECs against virus, which can be further investigated for the development of strategies aimed to improve defenses in the bovine host.
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http://dx.doi.org/10.3389/fimmu.2018.00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863502PMC
March 2019

Routing dependent immune responses after experimental R848-adjuvated vaccination.

Authors:
Susan van Aalst Manon A A Jansen Irene S Ludwig Ruurd van der Zee Willem van Eden Femke Broere

Vaccine 2018 03;36(11):1405-1413

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands. Electronic address:

Most traditional vaccines are administered via the intramuscular route. Other routes of administration however, can induce equal or improved protective memory responses and might provide practical advantages such as needle-free immunization, dose sparing and induction of tissue-specific (mucosal) immunity. Here we explored the differences in immunological outcome after immunization with model antigens via two promising immunization routes (intradermal and intranasal) with or without the experimental adjuvant and TLR7/8-agonist R848. Because the adaptive immune response is largely determined by the local innate cells at the site of immunization, the effect of R848-adjuvation on local cellular recruitment, antigenic uptake by antigen-presenting cells and the initiation of the adaptive response were analyzed for the two routes of administration. We show a general immune-stimulating effect of R848 irrespective of the route of administration. This includes influx of neutrophils, macrophages and dendritic cells to the respective draining lymph nodes and an increase in antigen-positive antigen-presenting cells which leads for both intradermal and intranasal immunization to a mainly T1 response. Furthermore, both intranasal and intradermal R848-adjuvated immunization induces a local shift in DC subsets; frequencies of CD11bDC increase whereas CD103DC decrease in relative abundance in the draining lymph node. In spite of these similarities, the outcome of immune responses differs for the respective immunization routes in both magnitude and cytokine profile. Via the intradermal route, the induced T-cell response is higher compared to that after intranasal immunization, which corresponds with the local higher uptake of antigen by antigen-presenting cells after intradermal immunization. Furthermore, R848-adjuvation enhances ex vivo IL-10 and IL-17 production after intranasal, but not intradermal, T-cell activation. Quite the opposite, intradermal immunization leads to a decrease in IL-10 production by the vaccine induced T-cells. This knowledge may lead to a more rational development of novel adjuvanted vaccines administered via non-traditional routes.
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http://dx.doi.org/10.1016/j.vaccine.2018.01.077DOI Listing
March 2018

The Immunomodulatory Potential of tolDCs Loaded with Heat Shock Proteins.

Authors:
Willem van Eden Manon A A Jansen A Charlotte Mt de Wolf Irene S Ludwig Paul Leufkens Femke Broere

Front Immunol 2017 30;8:1690. Epub 2017 Nov 30.

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.

Disease suppressive T cell regulation may depend on cognate interactions of regulatory T cells with self-antigens that are abundantly expressed in the inflamed tissues. Heat shock proteins (HSPs) are by their nature upregulated in stressed cells and therefore abundantly present as potential targets for such regulation. HSP immunizations have led to inhibition of experimentally induced inflammatory conditions in various models. However, re-establishment of tolerance in the presence of an ongoing inflammatory process has remained challenging. Since tolerogenic DCs (tolDCs) have the combined capacity of mitigating antigen-specific inflammatory responses and of endowing T cells with regulatory potential, it seems attractive to combine the anti-inflammatory qualities of tolDCs with those of HSPs.
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http://dx.doi.org/10.3389/fimmu.2017.01690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717764PMC
November 2017

The Enigma of Heat Shock Proteins in Immune Tolerance.

Authors:
Willem van Eden Manon A A Jansen Irene Ludwig Peter van Kooten Ruurd van der Zee Femke Broere

Front Immunol 2017 21;8:1599. Epub 2017 Nov 21.

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine (FVM), Utrecht University, Utrecht, Netherlands.

The fundamental problem of autoimmune diseases is the failure of the immune system to downregulate its own potentially dangerous cells, which leads to destruction of tissue expressing the relevant autoantigens. Current immunosuppressive therapies offer relief but fail to restore the basic condition of self-tolerance. They do not induce long-term physiological regulation resulting in medication-free disease remissions. Heat shock proteins (HSPs) have shown to possess the capacity of inducing lasting protective immune responses in models of experimental autoimmune diseases. Especially mycobacterial HSP60 and HSP70 were shown to induce disease inhibitory IL-10-producing regulatory T cells in many different models. This in itself may seem enigmatic, since based on earlier studies, HSPs were also coined sometimes as pro-inflammatory damage-associated molecular patterns. First clinical trials with HSPs in rheumatoid arthritis and type I diabetes have also indicated their potential to restore tolerance in autoimmune diseases. Data obtained from the models have suggested three aspects of HSP as being critical for this tolerance promoting potential: 1. evolutionary conservation, 2. most frequent cytosolic/nuclear MHC class II natural ligand source, and 3. upregulation under (inflammatory) stress. The combination of these three aspects, which are each relatively unique for HSP, may provide an explanation for the enigmatic immune tolerance promoting potential of HSP.
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http://dx.doi.org/10.3389/fimmu.2017.01599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702443PMC
November 2017

Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes.

Authors:
Willem van Eden

Philos Trans R Soc Lond B Biol Sci 2018 Jan;373(1738)

Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584CL Utrecht, The Netherlands

Experimental models of autoimmune diseases have revealed the disease protective role of heat shock proteins (HSPs). Both the administration of exogenous extracellular, mostly recombinant, HSP and the experimental co-induction of endogenous intracellular HSP in models have been shown to lead to production of disease protective regulatory T cells (Tregs). Similar to HSP taken up from extracellular bodily fluids, due to stress-related autophagy upregulated HSP also from intracellular sources is a major provider for the major histocompatibility class II (MHCII) ligandome; therefore, both extracellular and intracellular HSP can be prominent targets of Treg. The development of therapeutic peptide vaccines for the restoration of immune tolerance in inflammatory diseases is an area of intensive research. In this area, HSPs are a target for tolerance-inducing T-cell therapy, because of their wide expression in inflamed tissues. In humans, in whom the actual disease trigger is frequently unknown, HSP peptides offer chances for tolerance-promoting interventions through induction of HSP-specific Treg. Recently, we have shown the ability of a bacterial HSP70-derived peptide, HSP70-B29, to induce HSP-specific Tregs that suppressed arthritis by cross-recognition of their mammalian HSP70 homologues, abundantly present in the MHCII ligandome of stressed mouse and human antigen-presenting cells in inflamed tissues.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
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http://dx.doi.org/10.1098/rstb.2016.0531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717531PMC
January 2018

An Unexpected Major Role for Proteasome-Catalyzed Peptide Splicing in Generation of T Cell Epitopes: Is There Relevance for Vaccine Development?

Authors:
Anouk C M Platteel Juliane Liepe Willem van Eden Michele Mishto Alice J A M Sijts

Front Immunol 2017 3;8:1441. Epub 2017 Nov 3.

Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.

Efficient and safe induction of CD8 T cell responses is a desired characteristic of vaccines against intracellular pathogens. To achieve this, a new generation of safe vaccines is being developed accommodating single, dominant antigens of pathogens of interest. In particular, the selection of such antigens is challenging, since due to HLA polymorphism the ligand specificities and immunodominance hierarchies of pathogen-specific CD8 T cell responses differ throughout the human population. A recently discovered mechanism of proteasome-mediated CD8 T cell epitope generation, i.e., by proteasome-catalyzed peptide splicing (PCPS), expands the pool of peptides and antigens, presented by MHC class I HLA molecules. On the cell surface, one-third of the presented self-peptides are generated by PCPS, which coincides with one-fourth in terms of abundance. Spliced epitopes are targeted by CD8 T cell responses during infection and, like non-spliced epitopes, can be identified within antigen sequences using a novel strategy. The existence of spliced epitopes, by enlarging the pool of peptides available for presentation by different HLA variants, opens new opportunities for immunotherapies and vaccine design.
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http://dx.doi.org/10.3389/fimmu.2017.01441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675849PMC
November 2017

T Cell-Mediated Chronic Inflammatory Diseases Are Candidates for Therapeutic Tolerance Induction with Heat Shock Proteins.

Authors:
Ariana Barbera Betancourt Qingkang Lyu Femke Broere Alice Sijts Victor P M G Rutten Willem van Eden

Front Immunol 2017 26;8:1408. Epub 2017 Oct 26.

Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.

Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA) and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs) have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs). Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides) are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation.
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http://dx.doi.org/10.3389/fimmu.2017.01408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662553PMC
October 2017

Targeting of tolerogenic dendritic cells towards heat-shock proteins: a novel therapeutic strategy for autoimmune diseases?

Authors:
Manon A A Jansen Rachel Spiering Femke Broere Jacob M van Laar John D Isaacs Willem van Eden Catharien M U Hilkens

Immunology 2018 01 18;153(1):51-59. Epub 2017 Sep 18.

Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Tolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens.
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http://dx.doi.org/10.1111/imm.12811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721256PMC
January 2018

Regulatory T cell frequencies and phenotypes following anti-viral vaccination.

Authors:
A Charlotte M T de Wolf Susan van Aalst Irene S Ludwig Caroline L Bodinham David J Lewis Ruurd van der Zee Willem van Eden Femke Broere

PLoS One 2017 28;12(6):e0179942. Epub 2017 Jun 28.

Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands.

Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays investigated, but the impact of vaccination on Treg homeostasis is still largely unknown. This may be a relevant safety aspect, since loss of tolerance through reduced Treg may trigger autoimmunity. In exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59®, an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg) and activated (aTreg) subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization. Vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes. Vaccination with the hepatitis B vaccine led to slightly increased frequencies of both rTreg and aTreg subpopulations and a decrease in expression of functionality marker CD39 on aTreg. The live attenuated vaccine resulted in a decrease in rTreg frequency, and an increase in expression of activation marker CD25 on both subpopulations, possibly indicating a conversion from resting to migratory aTreg due to vaccine virus replication. To study the more local effects of vaccination on Treg in lymphoid organs, we immunized mice and analyzed the CD4+ Treg frequency and phenotype in draining lymph nodes and spleen. Vaccination resulted in a transient local decrease in Treg frequency in lymph nodes, followed by a systemic Treg increase in the spleen. Taken together, we showed that vaccination with vaccines with an already established safe profile have only minimal impact on frequencies and characteristics of Treg over time. These findings may serve as a bench-mark of inter-individual variation of Treg frequencies and phenotypes following vaccination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489208PMC
September 2017

Bystander activation of irrelevant CD4+ T cells following antigen-specific vaccination occurs in the presence and absence of adjuvant.

Authors:
Susan van Aalst Irene S Ludwig Ruurd van der Zee Willem van Eden Femke Broere

PLoS One 2017 10;12(5):e0177365. Epub 2017 May 10.

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.

Autoimmune and other chronic inflammatory diseases (AID) are prevalent diseases which can severely impact the quality of life of those that suffer from the disease. In most cases, the etiology of these conditions have remained unclear. Immune responses that take place e.g. during natural infection or after vaccination are often linked with the development or exacerbation of AID. It is highly debated if vaccines induce or aggravate AID and in particular adjuvants are mentioned as potential cause. Since vaccines are given on a large scale to healthy individuals but also to elderly and immunocompromised individuals, more research is warranted. Non-specific induction of naïve or memory autoreactive T cells via bystander activation is one of the proposed mechanisms of how vaccination might be involved in AID. During bystander activation, T cells unrelated to the antigen presented can be activated without (strong) T cell receptor (TCR) ligation, but via signals derived from the ongoing response directed against the vaccine-antigen or adjuvant at hand. In this study we have set up a TCR transgenic T cell transfer mouse model by which we were able to measure local bystander activation of transferred and labeled CD4+ T cells. Intramuscular injection with the highly immunogenic Complete Freund's Adjuvant (CFA) led to local in vivo proliferation and activation of intravenously transferred CD4+ T cells in the iliac lymph node. This local bystander activation was also observed after CFA prime and Incomplete Freund's Adjuvant (IFA) boost injection. Furthermore, we showed that an antigen specific response is sufficient for the induction of a bystander activation response and the general, immune stimulating effect of CFA or IFA does not appear to increase this effect. In other words, no evidence was obtained that adjuvation of antigen specific responses is essential for bystander activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425230PMC
September 2017

Dynamics of APC recruitment at the site of injection following injection of vaccine adjuvants.

Authors:
Susan van Aalst Irene Stephanie Ludwig Peter Johannes Sylvester van Kooten Ruurd van der Zee Willem van Eden Femke Broere

Vaccine 2017 03 17;35(12):1622-1629. Epub 2017 Feb 17.

Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands. Electronic address:

Vaccines often contain adjuvants to strengthen the response to the vaccine antigen. However, their modes of action at the site of injection (SOI) are poorly understood. Therefore, we assessed the local effects of adjuvant on the innate immune system in mice. We investigated the safe, widely used adjuvants MF59 and aluminum hydroxide (alum), as well as trehalose-6,6'-dibehenate (TDB), Complete Freund's Adjuvant (CFA) and the Toll-Like-Receptor-ligands lipopolysaccharide (LPS) and Pam3CysSerLys4 (PamCSK). We assessed muscle immune cell infiltration after adjuvant injection and observed 16h post immunization (hpi) an increased influx with CFA, MF59 and TDB, but not with alum, LPS or PamCSK. An elevated influx with the latter three became visible only 72hpi. Contribution of granulocytes, macrophages and dendritic cells to the influx differed per adjuvant and in time. Adjuvants generally induced a local pro-inflammatory micro-milieu that was transient except for CFA and TDB. The gene expression of CXCL-1, CCL-2 and CCL-5, involved in recruitment of immune cells, varied per adjuvant and corresponded grossly with the observed influx of granulocytes and monocytes/macrophages. Muscles injected with CFA or MF59 (when co-injected with peptide) resulted in APC ex vivo capable to induce proliferation of peptide-specific T-cells. By adding in vitro an excess of peptide to the APC/T cell co-cultures, we observed an adjuvant-enhanced co-stimulation or antigen presentation by APC after CFA- but not MF59-injection. After TDB-injection this effect was observed only at 72hpi, but not 24hpi. Thus the cellular influx profile and the local cytokine and chemokine micro-milieu in the muscle were strongly influenced by the type of adjuvant. Additionally, the capacity of muscle APC to load and present antigen was affected by the adjuvant. These findings may assist the development of novel adjuvanted vaccines in a more rational manner.
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http://dx.doi.org/10.1016/j.vaccine.2017.02.005DOI Listing
March 2017

Heat shock proteins and their immunomodulatory role in inflammatory arthritis.

Authors:
Julia Spierings Willem van Eden

Rheumatology (Oxford) 2017 02 13;56(2):198-208. Epub 2016 Jul 13.

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands

Autoimmune diseases, including inflammatory arthritis, are characterized by a loss of self-tolerance, leading to an excessive immune responses and subsequent ongoing inflammation. Current therapies are focused on dampening this inflammation, but a permanent state of tolerance is seldom achieved. Therefore, novel therapies that restore and maintain tolerance are needed. Tregs could be a potential target to achieve permanent immunotolerance. Activation of Tregs can be accomplished when they recognize and bind their specific antigens. HSPs are proteins present in all cells and are upregulated during inflammation. These proteins are immunogenic and can be recognized by Tregs. Several studies in animal models and in human clinical trials have shown the immunoregulatory effects of HSPs and their protective effects in inflammatory arthritis. In this review, an overview is presented of the immunomodulatory effects of several members of the HSP family in general and in inflammatory arthritis. These effects can be attributed to the activation of Tregs through cellular interactions within the immune system. The effect of HSP-specific therapies in patients with inflammatory arthritis should be explored further, especially with regard to long-term efficacy and safety and their use in combination with current therapeutic approaches.
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http://dx.doi.org/10.1093/rheumatology/kew266DOI Listing
February 2017