Dr. Rob Vandebriel did his MSc at Wageningen University (virology, molecular biology, biochemistry) and his PhD on Transplantation Immunology at the Department of Pathology, Utrecht University Medical Centre. There he became a board certified immunologist. He then moved to the RIVM, first as Postdoc to work on the immune response to Human Papilloma Virus and on an EU project to implement molecular biology in immunotoxicology. Since 1994 he is staff member of the Centre for Health Protection where he has worked on several national and international projects (EU-FP6, FP7, H2020
The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to ... more The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agricult...
For cells, reacting aptly to changes in their environment is of critical importance. The protein ... more For cells, reacting aptly to changes in their environment is of critical importance. The protein Heme oxygenase-1 (HMOX1) plays a critical role as a guard of cellular homeostasis and is considered as a reliable indicator of cellular oxidative stress. A better insight in the regulation of HMOX1 would assist in understanding the physiological role of HMOX1 as well as improving functional interpretation of the gene as a biomarker in toxicogenomics. Remarkably, as many as four transcription factors are known to regulate the HMOX1 gene: HSF1, AP-1, NRF2, and NF-κB. To investigate induction kinetics of these transcription factors, we constructed mathematical simulation models for each of them. We included the topology of the known interactions of molecules involved in the activation of the transcription factors, and the feedback loops resulting in their down-regulation. We evaluate how the molecular circuitries associated with the different transcription factors differ in their kinetics regarding HMOX1 induction, under different scenarios of acute and less acute stress. We also evaluate the combined effect of the four transcription factors on HMOX1 expression and the resulting alleviation of stress. Overall, the results support the assumption of different biological roles for the four transcription factors, with AP-1 being a fast acting general stress response protein at the expense of efficiency, and NRF2 being important for cellular homeostasis in maintaining low levels of oxidative stress.
Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer mem... more Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer membrane. Besides being an endotoxin, LPS also possesses a powerful adjuvant activity. Previously, it has been shown that changes in the chemical composition of the lipid A domain of LPS modulate its biological activity. For example, monophosphoryl lipid A (MPL) has been shown to be a non-toxic immunostimulatory compound. Moreover, several LPS analogs have been shown to antagonise LPS-induced signalling in eukaryotic cells. In the present study, we show that supplementation of a whole-cell pertussis (wP) vaccine with LPS analogs modulates the vaccine-induced immune responses. We show in a mouse-model system that addition of MPL to a wP vaccine increases vaccine efficacy without altering vaccine-induced serum pro-inflammatory cytokine levels. Furthermore, we show that Neisseria meningitidis LpxL2 LPS, an LPS species derived from a N. meningitidis lpxL2 mutant, antagonises wP and LPS-stimulated interleukin-6 (IL-6) production by macrophages in vitro, and that addition of this LPS-derivative to the wP vaccine decreases vaccine-induced serum IL-6 levels and increases vaccine efficacy.
The helper T-cell response to the E7 protein of human papillomavirus type 16 (HPV16) was studied ... more The helper T-cell response to the E7 protein of human papillomavirus type 16 (HPV16) was studied using BALB/c (H-2d) mice. Twenty-two overlapping synthetic peptides spanning the HPV16 E7 protein were split into 6 groups. Mice were sensitized using mixtures of synthetic peptides corresponding to each of the groups. Lymph node cell suspensions were cultured with the corresponding mixture of synthetic peptides that was used for sensitization. Two mixtures induced a proliferative response. Analysis of the individual peptides from these mixtures showed that two (overlapping) peptides induced a proliferative response. This response was mediated by CD4+ cells. The common region of the two peptides was found to be a single epitope, and a minimal epitope was demonstrated (AHYNIVTFCCK). In conclusion, in contrast to others, we demonstrated a helper T-cell response in BALB/c mice. This may be due to the fact that we used synthetic peptides as immunizing agent. The helper T-cell epitopes in HPV16 E7 demonstrated previously are partly overlapping with the (minimal) epitope demonstrated here, underlining the 'public' nature of the epitope.
This review summarizes the literature on mammalian toxicity of ZnO nanoparticles (NPs) published ... more This review summarizes the literature on mammalian toxicity of ZnO nanoparticles (NPs) published between 2009 and 2011. The toxic effects of ZnO NPs are due to the compound's solubility. Whether the increased intracellular [Zn(2+)] is due to the NPs being taken up by cells or to NP dissolution in medium is still unclear. In vivo airway exposure poses an important hazard. Inhalation or instillation of the NPs results in lung inflammation and systemic toxicity. Reactive oxygen species (ROS) generation likely plays an important role in the inflammatory response. The NPs do not, or only to a minimal extent, cross the skin; this also holds for sunburned skin. Intraperitoneal administration induces neurological effects. The NPs show systemic distribution; target organs are liver, spleen, lung, and kidney and, in some cases, the heart. In vitro exposure of BEAS-2B bronchial epithelial cells and A549 alveolar adenocarcinoma cells results in cytotoxicity, increased oxidative stress, increased intracellular [Ca(2+)], decreased mitochondrial membrane potential, and interleukin (IL)-8 production. Decreased contractility of airway smooth muscle cells poses an additional hazard. In contrast to the results for BEAS-2B and A549 cells, in RKO colon carcinoma cells ZnO NPs and not Zn(2+) induce cytotoxicity and mitochondrial dysfunction. Short-term exposure of skin cells results in apoptosis but not in an inflammatory response, while long-term exposure leads to increased ROS generation, decreased mitochondrial activity, and formation of tubular intercellular structures. Macrophages, monocytes, and dendritic cells are affected; exposure results in cytotoxicity, oxidative stress, intracellular Ca(2+) flux, decreased mitochondrial membrane potential, and production of IL-1β and chemokine CXCL9. The NPs are phagocytosed by macrophages and dissolved in lysosomes. In vitro the Comet assay and the cytokinesis-blocked micronucleus assay show genotoxicity, whereas the Ames test does not. This is, however, not confirmed by in vivo genotoxicity assays. Protein binding results in increased stability.
Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer mem... more Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer membrane. Besides being an endotoxin, LPS also possesses a powerful adjuvant activity. Previously, it has been shown that changes in the chemical composition of the lipid A domain of LPS modulate its biological activity. For example, monophosphoryl lipid A (MPL) has been shown to be a non-toxic immunostimulatory compound. Moreover, several LPS analogs have been shown to antagonise LPS-induced signalling in eukaryotic cells. In the present study, we show that supplementation of a whole-cell pertussis (wP) vaccine with LPS analogs modulates the vaccine-induced immune responses. We show in a mouse-model system that addition of MPL to a wP vaccine increases vaccine efficacy without altering vaccine-induced serum pro-inflammatory cytokine levels. Furthermore, we show that Neisseria meningitidis LpxL2 LPS, an LPS species derived from a N. meningitidis lpxL2 mutant, antagonises wP and LPS-stimulated interleukin-6 (IL-6) production by macrophages in vitro, and that addition of this LPS-derivative to the wP vaccine decreases vaccine-induced serum IL-6 levels and increases vaccine efficacy.
Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative b... more Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative bacterium Bordetella pertussis. Although acellular pertussis (aP) vaccines are safe, they are not fully effective and thus require improvement. In contrast to whole-cell pertussis (wP) vaccines, aP vaccines do not contain lipopoly- saccharide (LPS). Monophosphoryl lipid A (MPL) and Neisseria meningitidis LpxL2 LPS have been
The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to ... more The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agricult...
For cells, reacting aptly to changes in their environment is of critical importance. The protein ... more For cells, reacting aptly to changes in their environment is of critical importance. The protein Heme oxygenase-1 (HMOX1) plays a critical role as a guard of cellular homeostasis and is considered as a reliable indicator of cellular oxidative stress. A better insight in the regulation of HMOX1 would assist in understanding the physiological role of HMOX1 as well as improving functional interpretation of the gene as a biomarker in toxicogenomics. Remarkably, as many as four transcription factors are known to regulate the HMOX1 gene: HSF1, AP-1, NRF2, and NF-κB. To investigate induction kinetics of these transcription factors, we constructed mathematical simulation models for each of them. We included the topology of the known interactions of molecules involved in the activation of the transcription factors, and the feedback loops resulting in their down-regulation. We evaluate how the molecular circuitries associated with the different transcription factors differ in their kinetics regarding HMOX1 induction, under different scenarios of acute and less acute stress. We also evaluate the combined effect of the four transcription factors on HMOX1 expression and the resulting alleviation of stress. Overall, the results support the assumption of different biological roles for the four transcription factors, with AP-1 being a fast acting general stress response protein at the expense of efficiency, and NRF2 being important for cellular homeostasis in maintaining low levels of oxidative stress.
Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer mem... more Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer membrane. Besides being an endotoxin, LPS also possesses a powerful adjuvant activity. Previously, it has been shown that changes in the chemical composition of the lipid A domain of LPS modulate its biological activity. For example, monophosphoryl lipid A (MPL) has been shown to be a non-toxic immunostimulatory compound. Moreover, several LPS analogs have been shown to antagonise LPS-induced signalling in eukaryotic cells. In the present study, we show that supplementation of a whole-cell pertussis (wP) vaccine with LPS analogs modulates the vaccine-induced immune responses. We show in a mouse-model system that addition of MPL to a wP vaccine increases vaccine efficacy without altering vaccine-induced serum pro-inflammatory cytokine levels. Furthermore, we show that Neisseria meningitidis LpxL2 LPS, an LPS species derived from a N. meningitidis lpxL2 mutant, antagonises wP and LPS-stimulated interleukin-6 (IL-6) production by macrophages in vitro, and that addition of this LPS-derivative to the wP vaccine decreases vaccine-induced serum IL-6 levels and increases vaccine efficacy.
The helper T-cell response to the E7 protein of human papillomavirus type 16 (HPV16) was studied ... more The helper T-cell response to the E7 protein of human papillomavirus type 16 (HPV16) was studied using BALB/c (H-2d) mice. Twenty-two overlapping synthetic peptides spanning the HPV16 E7 protein were split into 6 groups. Mice were sensitized using mixtures of synthetic peptides corresponding to each of the groups. Lymph node cell suspensions were cultured with the corresponding mixture of synthetic peptides that was used for sensitization. Two mixtures induced a proliferative response. Analysis of the individual peptides from these mixtures showed that two (overlapping) peptides induced a proliferative response. This response was mediated by CD4+ cells. The common region of the two peptides was found to be a single epitope, and a minimal epitope was demonstrated (AHYNIVTFCCK). In conclusion, in contrast to others, we demonstrated a helper T-cell response in BALB/c mice. This may be due to the fact that we used synthetic peptides as immunizing agent. The helper T-cell epitopes in HPV16 E7 demonstrated previously are partly overlapping with the (minimal) epitope demonstrated here, underlining the 'public' nature of the epitope.
This review summarizes the literature on mammalian toxicity of ZnO nanoparticles (NPs) published ... more This review summarizes the literature on mammalian toxicity of ZnO nanoparticles (NPs) published between 2009 and 2011. The toxic effects of ZnO NPs are due to the compound's solubility. Whether the increased intracellular [Zn(2+)] is due to the NPs being taken up by cells or to NP dissolution in medium is still unclear. In vivo airway exposure poses an important hazard. Inhalation or instillation of the NPs results in lung inflammation and systemic toxicity. Reactive oxygen species (ROS) generation likely plays an important role in the inflammatory response. The NPs do not, or only to a minimal extent, cross the skin; this also holds for sunburned skin. Intraperitoneal administration induces neurological effects. The NPs show systemic distribution; target organs are liver, spleen, lung, and kidney and, in some cases, the heart. In vitro exposure of BEAS-2B bronchial epithelial cells and A549 alveolar adenocarcinoma cells results in cytotoxicity, increased oxidative stress, increased intracellular [Ca(2+)], decreased mitochondrial membrane potential, and interleukin (IL)-8 production. Decreased contractility of airway smooth muscle cells poses an additional hazard. In contrast to the results for BEAS-2B and A549 cells, in RKO colon carcinoma cells ZnO NPs and not Zn(2+) induce cytotoxicity and mitochondrial dysfunction. Short-term exposure of skin cells results in apoptosis but not in an inflammatory response, while long-term exposure leads to increased ROS generation, decreased mitochondrial activity, and formation of tubular intercellular structures. Macrophages, monocytes, and dendritic cells are affected; exposure results in cytotoxicity, oxidative stress, intracellular Ca(2+) flux, decreased mitochondrial membrane potential, and production of IL-1β and chemokine CXCL9. The NPs are phagocytosed by macrophages and dissolved in lysosomes. In vitro the Comet assay and the cytokinesis-blocked micronucleus assay show genotoxicity, whereas the Ames test does not. This is, however, not confirmed by in vivo genotoxicity assays. Protein binding results in increased stability.
Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer mem... more Lipopolysaccharide (LPS) is one of the main constituents of the Gram-negative bacterial outer membrane. Besides being an endotoxin, LPS also possesses a powerful adjuvant activity. Previously, it has been shown that changes in the chemical composition of the lipid A domain of LPS modulate its biological activity. For example, monophosphoryl lipid A (MPL) has been shown to be a non-toxic immunostimulatory compound. Moreover, several LPS analogs have been shown to antagonise LPS-induced signalling in eukaryotic cells. In the present study, we show that supplementation of a whole-cell pertussis (wP) vaccine with LPS analogs modulates the vaccine-induced immune responses. We show in a mouse-model system that addition of MPL to a wP vaccine increases vaccine efficacy without altering vaccine-induced serum pro-inflammatory cytokine levels. Furthermore, we show that Neisseria meningitidis LpxL2 LPS, an LPS species derived from a N. meningitidis lpxL2 mutant, antagonises wP and LPS-stimulated interleukin-6 (IL-6) production by macrophages in vitro, and that addition of this LPS-derivative to the wP vaccine decreases vaccine-induced serum IL-6 levels and increases vaccine efficacy.
Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative b... more Pertussis is an infectious disease of the respiratory tract that is caused by the gram-negative bacterium Bordetella pertussis. Although acellular pertussis (aP) vaccines are safe, they are not fully effective and thus require improvement. In contrast to whole-cell pertussis (wP) vaccines, aP vaccines do not contain lipopoly- saccharide (LPS). Monophosphoryl lipid A (MPL) and Neisseria meningitidis LpxL2 LPS have been
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Papers by Rob Vandebriel