Thomas Soullié

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (16)127.35 Total impact

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    ABSTRACT: Liposomal chemotherapy brings the advantage of minimizing systemic toxicity towards healthy organs and tissues, while has the drawbacks of limited nanoparticle accumulation and low drug bioavailability at targeted tumors. The aim of our study is to apply a clinically available mild hyperthermia (HT) treatment with thermosensitive liposomes (TSL) to tackle both issues A two-step HT approach was combined with systemic administration of doxorubicin (Dox) TSL, in a first step to maximize nanoparticle accumulation in tumors and second step to actively trigger Dox release. The therapeutic activity of the two-step approach was compared to a one-step HT triggering intravascular Dox release from circulating TSL. Whereas the intravascular drug release approach requires fast releasing Dox-TSL (Dox-fTSL), the TSL formulation used in the two-step approach is fine-tuned to prolong Dox retention at physiological temperature in circulation, while releasing their drug content at mild HT at a slower rate (Dox-sTSL). Cytotoxicity assays show that a first-step HT at 41°C for 1hour causes no drug resistance on murine BFS-1 sarcoma, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) towards subsequent exposure to Dox. However, HT sensitizes HUVEC towards Dox at higher concentrations (10-100μM). After 2hours of intratumoral Dox-TSL accumulation, HT at 42°C for 1hour was applied to trigger Dox release from Dox-sTSL. Quantification of intratumoral Dox accumulation revealed that the two-step HT approach increased TSL accumulation and Dox bioavailability reaching levels comparable to the intravascular release approach. The two-step HT in combination with Dox-sTSL delayed tumor growth for 12days compared to PBS group, however, was less effective compared to intravascular Dox release from Dox-fTSL using one-step HT. The two-step approach focuses on interstitial drug release upon mild HT, instead of intravascular drug release. This novel two-step approach represents an attractive alternative for the treatment of large and deep seated tumors, which are difficult to heat precisely and require loco-regional HT of the tumor area and accumulated Dox-sTSL therein to obtain a precise intratumoral drug delivery.
    Journal of Controlled Release 11/2013; · 7.63 Impact Factor
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    ABSTRACT: Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 °C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality.
    Proceedings of the National Academy of Sciences 06/2011; 108(24):9851-6. · 9.81 Impact Factor
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    ABSTRACT: Exercise training attenuates left ventricular (LV) dysfunction after myocardial infarction (MI). It could be speculated that these effects of exercise are mediated by increased endothelial NO synthase (eNOS) activity. In the present study we tested the hypothesis that eNOS plays a critical role in the exercise-induced amelioration of LV dysfunction after MI. MI or sham was induced in eNOS(-/-), eNOS(+/-) and eNOS(+/+) mice. After 8 weeks of voluntary wheel running (approximately 7 km/day in all groups) or sedentary housing, global cardiac function was determined in vivo and (immuno)histochemistry was performed to assess cardiomyocyte size, fibrosis, capillary density and apoptosis in remote myocardium. At baseline eNOS(-/-) mice had higher mean aortic pressure compared to eNOS(+/-) and eNOS(+/+) mice, but had normal global cardiac function. MI resulted in marked LV remodeling, including cardiomyocyte hypertrophy and a reduction in capillary density, increased fibrosis and apoptosis, as well as LV systolic and diastolic dysfunction to the same extent in all genotypes. In eNOS(+/+) MI mice exercise abolished fibrosis and apoptosis in the remote myocardium, attenuated LV systolic dysfunction and ameliorated pulmonary congestion. These beneficial effects were lost in eNOS(+/-) and eNOS(-/-) mice, while LV systolic dysfunction and pulmonary congestion in eNOS(+/-) mice were exacerbated by exercise. In conclusion, the beneficial effects of exercise after MI on LV remodeling and dysfunction depend critically on endogenous eNOS. The observation that the lack of one eNOS allele is sufficient to negate all beneficial effects of exercise, strongly suggests that exercise depends on full eNOS expression.
    Journal of Molecular and Cellular Cardiology 02/2010; 48(6):1041-9. · 5.15 Impact Factor
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    ABSTRACT: The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 microm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but not in the spleen or liver-draining LNs. Dividing T cells returned to the lungs, and a short-lived infiltrate consisting of T cells and DCs formed around trapped Ag. This infiltrate was increased when the Toll-like receptor 4 was stimulated and full DC maturation was induced by CD40 triggering. Under these conditions, OVA-specific cytotoxic T lymphocyte responses, as well as humoral immunity, were induced. The T cell response to embolic Ag was severely reduced in mice depleted of CD11c(hi) cells or Ly6C/G(+) cells but restored upon adoptive transfer of Ly6C(hi) monocytes. We conclude that the lung vascular filter represents a largely unexplored site of immune induction that traps large bloodborne Ags for presentation by monocyte-derived DCs.
    Journal of Experimental Medicine 11/2009; 206(12):2823-35. · 13.21 Impact Factor
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    ABSTRACT: In healthy individuals, humoral immune responses to allergens consist of serum IgA and IgG4, whereas cellular immune responses are controlled by regulatory T (Treg) cells. In search of new compounds that might prevent the onset of allergies by stimulating this type of immune response, we have focused on the mucosal adjuvant, cholera toxin B (CTB), as it induces the formation of Treg cells and production of IgA. Here, we have found that CTB suppresses the potential of dendritic cells to prime for Th2 responses to inhaled allergen. When we administered CTB to the airways of naïve and allergic mice, it strongly suppressed the salient features of asthma, such as airway eosinophilia, Th2 cytokine synthesis, and bronchial hyperreactivity. This beneficial effect was only transferable to other mice by transfer of B but not of T lymphocytes. CTB caused a transforming growth factor-beta-dependent rise in antigen-specific IgA in the airway luminal secretions, which was necessary for its preventive and curative effect, as all effects of CTB were abrogated in mice lacking the luminal IgA transporting polymeric Ig receptor. Not only do these findings show a novel therapeutic avenue for allergy, they also help to explain the complex relationship between IgA levels and risk of developing allergy in humans.
    Mucosal Immunology 05/2009; 2(4):331-9. · 7.54 Impact Factor
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    ABSTRACT: Adoptive transfer of antigen-pulsed dendritic cells (DC) in the airways of mice has been used as a model system for eosinophilic airway inflammation, which allows studying the DC-specific contribution of genes of interest or reagents to induced inflammation by genetically modifying DC or exposure of DC to compounds prior to injection in the airways. Antigen transfer and CD4+ T cell priming by endogenous antigen-presenting cells (APCs) may interfere with the correct interpretation of the data obtained in this model, however. We therefore examined antigen transfer and indirect CD4+ T cell priming by host APCs in this model system. Transfer of antigen between injected DC and host cells appeared to be minimal but could not be totally excluded. However, only direct antigen presentation by injected DC resulted in robust CD4+ T cell priming and eosinophilic airway inflammation. Thus, this adoptive transfer model is well suited to study the role of DC in eosinophilic airway inflammation.
    Journal of Leukocyte Biology 11/2008; 85(1):64-70. · 4.57 Impact Factor
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    ABSTRACT: Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)-resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c(+) monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting "nature's adjuvant," the inflammatory DC through induction of the endogenous danger signal uric acid.
    Journal of Experimental Medicine 05/2008; 205(4):869-82. · 13.21 Impact Factor
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    ABSTRACT: Aims: The study sought to define the long-term angiographic and clinical outcome of a bio-engineered stent, able to sequester endothelial progenitor cells (EPC) to the stent to promote the post-stenting vascular repair response.Methods and results: The HEALING-II was a multicentre, prospective registry, including 63 patients treated with the implantation of a Genous EPC capture stent. Serial quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) analysis was performed at 6 and 18 month. The 18 month composite MACE rate was 7.9%, whereas 6.3% clinically justified target lesion revascularisations were observed. Although patients received one month of clopidogrel, no (sub)acute or late angiographic stent thrombosis occurred. At 6 month follow-up, in-stent late luminal loss was 0.78+/-0.39 mm and percent in-stent volume obstruction was 22.9+/-13.7% (mean+/-sd). Serial angiographic and IVUS analyses were available in 30 event-free patients at post-procedure, 6 months and 18 months. From 6 months to 18 months follow-up, a significant late regression of neointimal hyperplasia was observed on QCA (late luminal loss 0.59+/-0.31, 24.4% reduction or 16.9% by matched serial analysis) and IVUS (percent in-stent volume obstruction 20.3+/-14.3%, 11.4% reduction or 9.6% by matched serial analysis). The relative increase in circulating EPC titers at long-term follow-up correlated with neointimal compaction in individual patients, suggestive of an EPC-mediated vascular repair response.Conclusions: The HEALING II study suggests that the EPC capture stent, aimed to stimulate the coronary vascular repair response, significantly promotes late regression of neointimal hyperplasia up to 18 months after stent implantation.
    EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 12/2007; 3(3):350-8. · 3.17 Impact Factor
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    ABSTRACT: Population studies have suggested that chronic and intense helminth infections, in contrast to acute and mild helminth infections, might suppress allergic airway inflammation. We sought to address the question of how the chronicity and intensity of helminth infections affect allergic airway inflammation in a well-defined experimental model. C57/Bl6 mice were infected with Schistosoma mansoni, followed by sensitization and challenge with ovalbumin (OVA), and different stages and intensities of infection were studied. To this end, mice were analyzed at 8, 12, or 16 weeks, representing the acute, intermediate, or chronic phases of infection, respectively. Lung lavage eosinophilia, peribronchial inflammation, and OVA-induced airway hyperresponsiveness were increased during acute infection but significantly decreased when infection progressed into chronicity. Decreases in lung lavage eosinophilia were parasite density-dependent. Similar levels of OVA-specific IgE were found during all phases of infection, whereas both OVA-specific and parasite-specific T(H)2 cytokine levels were significantly reduced during chronic infection. Inhibition of airway inflammation could be transferred to OVA-sensitized recipient mice by B cells and CD4(+) T cells from spleens of chronically, but not acutely, infected mice. This suppression was IL-10-dependent. During chronic, but not acute, helminth infections, suppressive mechanisms are induced that regulate immune reactions to inhaled allergens. These data confirm human epidemiologic observations in a well-controlled animal model. Characterization of chronic helminth infection-induced regulatory mechanisms will help in the development of future therapeutics to treat or prevent allergic disease.
    Journal of Allergy and Clinical Immunology 11/2007; 120(4):932-40. · 12.05 Impact Factor
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    ABSTRACT: Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D(2) binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3(+) CD4(+) regulatory T cells that suppressed inflammation in an interleukin 10-dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma.
    Journal of Experimental Medicine 03/2007; 204(2):357-67. · 13.21 Impact Factor
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    ABSTRACT: Airway DCs play a crucial role in the pathogenesis of allergic asthma, and interfering with their function could constitute a novel form of therapy. The sphingosine 1-phosphate receptor agonist FTY720 is an oral immunosuppressant that retains lymphocytes in lymph nodes and spleen, thus preventing lymphocyte migration to inflammatory sites. The accompanying lymphopenia could be a serious side effect that would preclude the use of FTY720 as an antiasthmatic drug. Here we show in a murine asthma model that local application of FTY720 via inhalation prior to or during ongoing allergen challenge suppresses Th2-dependent eosinophilic airway inflammation and bronchial hyperresponsiveness without causing lymphopenia and T cell retention in the lymph nodes. Effectiveness of local treatment was achieved by inhibition of the migration of lung DCs to the mediastinal lymph nodes, which in turn inhibited the formation of allergen-specific Th2 cells in lymph nodes. Also, FTY720-treated DCs were intrinsically less potent in activating naive and effector Th2 cells due to a reduced capacity to form stable interactions with T cells and thus to form an immunological synapse. These data support the concept that targeting the function of airway DCs with locally acting drugs is a powerful new strategy in the treatment of asthma.
    Journal of Clinical Investigation 12/2006; 116(11):2935-44. · 12.81 Impact Factor
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    ABSTRACT: Technologies in interventional Cardiology have evolved from balloon to mechanical ablation, atherectomy, stenting, and brachytherapy to current drug eluting interventional strategies. New challenges are to develop techniques that not only prevent restenosis, but also promote vascular and endothelial healing after (balloon) injury. Endothelial healing approaches range from preventing endothelial injury to restoring endothelial function and reendothelialization by pharmacotherapy and cell therapy. These novel healing strategies warrant further exploration as they may represent an alternative to drug-eluting stent approaches.
    Endothelium 01/2006; 13(6):431-9. · 1.65 Impact Factor
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    ABSTRACT: Tolerance is the usual outcome of inhalation of harmless antigen, yet T helper (Th) type 2 cell sensitization to inhaled allergens induced by dendritic cells (DCs) is common in atopic asthma. Here, we show that both myeloid (m) and plasmacytoid (p) DCs take up inhaled antigen in the lung and present it in an immunogenic or tolerogenic form to draining node T cells. Strikingly, depletion of pDCs during inhalation of normally inert antigen led to immunoglobulin E sensitization, airway eosinophilia, goblet cell hyperplasia, and Th2 cell cytokine production, cardinal features of asthma. Furthermore, adoptive transfer of pDCs before sensitization prevented disease in a mouse asthma model. On a functional level, pDCs did not induce T cell division but suppressed the generation of effector T cells induced by mDCs. These studies show that pDCs provide intrinsic protection against inflammatory responses to harmless antigen. Therapies exploiting pDC function might be clinically effective in preventing the development of asthma.
    Journal of Experimental Medicine 08/2004; 200(1):89-98. · 13.21 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.
    American Journal Of Pathology 02/2004; 164(1):263-71. · 4.60 Impact Factor
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    ABSTRACT: PGD(2) is the major mediator released by mast cells during allergic responses, and it acts through two different receptors, the D prostanoid receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown that PGD(2) inhibits the migration of epidermal Langerhans cells to the skin draining lymph nodes (LNs) and affects the subsequent cutaneous inflammatory reaction. However, the role of PGD(2) in the pulmonary immune response remains unclear. Here, we show that the intratracheal instillation of FITC-OVA together with PGD(2) inhibits the migration of FITC(+) lung DC to draining LNs. This process is mimicked by the DP1 agonist BW245C, but not by the DP2 agonist DK-PGD(2). The ligation of DP1 inhibits the migration of FITC-OVA(+) DCs only temporarily, but still inhibits the proliferation of adoptively transferred, OVA-specific, CFSE-labeled, naive T cells in draining LNs. These T cells produced lower amounts of the T cell cytokines IL-4, IL-10, and IFN-gamma compared with T cells from mice that received FITC-OVA alone. Taken together, our data suggest that the activation of DP receptor by PGD(2) may represent a pathway to control airway DC migration and to limit the activation of T cells in the LNs under steady state conditions, possibly contributing to homeostasis in the lung.
    The Journal of Immunology 11/2003; 171(8):3936-40. · 5.52 Impact Factor
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    ABSTRACT: Diagnostic de l'allergie aux médicaments John Libbey Eurotext, Paris © 2005, pp. 21-24 L'asthme allergique est une maladie chronique des voies aériennes caractérisée par une inflammation pulmonaire à éosinophiles, une production de mucus et d'immu-noglobulines de type E (IgE), ainsi que par le développement d'une hyperréactivité bronchique. L'incidence de l'asthme n'a cessé d'augmenter ces vingt dernières années, atteignant des proportions épidémiques [1]. L'hypothèse actuelle est que cette inflammation est contrôlée par des cellules T de type Th2 sécrétant de l'IL-4, IL-5 et IL-13. Les cellules T naïves ont besoin de cellules présentatrices d'antigènes matures [telles que des cellules dendritiques (DCs)] pulsées avec un antigène, pour pouvoir proliférer et acquérir les fonctions effectrices de cellules Th2. Les DCs des voies aériennes sont cruciales pour la sensibilisation aux allergènes conduisant au 03 Hammad et co.qxd 5/16/05 2:47 PM Page 21 développement d'une allergie, mais joueraient également un rôle important dans la phase effectrice de l'asthme allergique. Les cellules dendritiques (DCs) sont présentes dans les poumons et contrôlent la réponse développée vis-à-vis des antigènes inhalés. Dans les voies aériennes, les DCs de type myéloïde sont localisées au-dessus et juste en dessous de la membrane basa-le de l'épithélium bronchique. Certaines macromolécules marquées avec un fluoro-chrome, normalement incapables de traverser les jonctions serrées de la barrière épi-théliale, sont capturées par les DCs des voies aériennes et transportées dans les gan-glions médiastinaux drainants en 12 heures [2, 3]. En l'absence de signaux inflam-matoires, ce processus est continu. Les DCs qui ont capturé l'antigène en périphérie sont dites immatures et sont incapables de stimuler des lymphocytes T [4]. Une fois arrivées dans les zones T des ganglions lymphatiques, les DCs augmentent leur expression de molécules dites de costimulation ainsi que celle du complexe majeur d'histocompatibilité (CMH) de classe II. Ces molécules peuvent alors induire la pro-lifération des cellules T naïves [2, 5]. Malgré une prolifération importante de cellu-les T, en absence d'inflammation, la réponse immunitaire induite est une tolérance qui s'explique par le fait que les antigènes transportés par les DCs en l'absence d'in-flammation n'induisent pas leur maturation complète [6]. En présence de signaux inflammatoires (LPS ou infection virale), l'expansion des cellules T dans les ganglions conduit à la génération de cellules T effectrices et non plus régulatoires [7, 8]. L'inflammation des voies aériennes causée par une infection virale s'accompagne du recrutement de DCs et induit leur complète maturation lors de leur arrivée dans les ganglions lymphatiques [8, 9]. Ces conditions peuvent être reproduites par l'administration de DCs matures de type myéloïde pulsées avec de l'ovalbumine (OVA) dans la trachée de souris [10]. Lorsque la maturation des DCs myéloïdes se fait en l'absence de signaux polarisant, la réponse qui en découle est de type Th2 [11, 12], alors que l'injection intratrachéale de DCs traitées avec du LPS conduit a une réponse Th1 [13].

Publication Stats

1k Citations
127.35 Total Impact Points

Institutions

  • 2003–2011
    • Erasmus MC
      • • Department of Oncological Surgery
      • • Department of Surgery
      Rotterdam, South Holland, Netherlands
  • 2009
    • Ghent University
      Gand, Flanders, Belgium
  • 2008
    • Universitair Ziekenhuis Ghent
      Gand, Flanders, Belgium
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2004
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France