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Kindergeneeskunde, wetenschapsstage immunologie en reumatologie

Ben je student geneeskunde in het UMC Utrecht? En zoek je een wetenschapsstage kindergeneeskunde op het gebied van Immunologie en reumatologie? Bekijk ons aanbod

Antiviral immunotherapy

Development of Adjuvant Antiviral Immunotherapy using Dentritic Cell vaccinations

Stem cell transplantation (SCT) is a last resort treatment in several diseases including malignancies, inborn errors of metabolism, immune deficiencies and bone marrow failure syndromes, such as seen in pediatric patients. SCT is a high-risk procedure, partially caused by a lag-period of immunodeficiency during which the immune system regenerates from infused stem cell precursors. During this period, patients have an increased risk of developing viral reactivations, mostly caused by herpes viruses.

Although cord blood (CB) transplantation has several advantages in comparison to related or unrelated donors (e.g. availability, HLA-matching), recipients experience increased risk for developing viral reactivations, which is caused by the presence of naïve but not virus-specific effector/memory T-cells in the SCT graft. As a consequence, these patients face a mortality rate that approaches 40%. Antiviral drugs have shown not to be effective enough, so new antiviral therapies are warranted. It is our aim to develop a new approach to prevent viral activations after SCT, and thereby decrease cases of SCT-related mortality.

Doel

In our project we aim at developing a “vaccine” by culturing dendritic cells (DCs) from a small fraction of the donor blood and stimulate these DCs in vitro to prime naïve T-cells after reinfusion into the recipient. We propose that this approach will yield rapid T-cell mediated immune protection to prevent viral reactivations and lower the mortality in pediatric bone marrow transplantation recipients.

Contactpersoon

Thijs Flinsenberg (MSc.)

T.W.H.Flinsenberg@umcutrecht.nl

Cerebral perfusion

Cerebral perfusion during neonatal cardiac surgery: Can we improve outcome?

Neonates with a congenital heart defect (CHD) are often in need of cardiac surgery. In complicated heart defects, cardiopulmonary bypass (CPB) is usually used, as well as deep hypothermic circulatory arrest (DHCA). Two unevitable mechanisms in this procedure are thought to primarily induce a systemic inflammatory response. These are the ischemic-reperfusion injury and the contact of blood with foreign material. An imbalance in both the innate and adaptive immune system is thought to be the cause of the inflammatory response which can occur after the operation. If this response is unregulated, it can ultimately lead to multi-organ failure, in the same way as sepsis does.

Furthermore, as the term suggests, DHCA deprives organs of perfusion. The brain is especially vulnerable to this ischemic injury, which puts neonates undergoing these operations at high risk of neurodevelopmental disorders. Therefore, currently selective antegrade cerebral perfusion (ACP) is used during these complex operations which may contribute to less brain injury.

Doel

The objective is comparing DHCA to ACP during neonatal cardiac surgery, we will investigate the activation of the immune system perioperatively. Furthermore, we will look into endothelial activation and organ injury, especially that of the brain.

Hypothese

We hypothesise that neonates operated with the use of ACP will have less systemic inflammation, less endothelial activation, less organ damage and better neurodevelopment.

Thirty neonates undergoing aortic arch reconstruction, will undergo surgery using either DHCA (n=15) or ACP (n=15). We will compare the inflammatory process by serum cytokine analyses and focus on T-cell function by phenotyping and functional cellular assays. We will investigate the endothelial activation and cerebral, myocardial, intestinal, hepatic and renal damage by assessing serum markers and function. Neurodevelopment will be assessed by long-term follow-up of the patients.

Duur stage

  • 6-9 maanden

Contactpersoon

 

Diabetes

Immunomodulation and cytokine profiling in type 1 diabetes

Type 1 diabetes is an autoimmune disease characterized by the selective destruction of the insulin-producing beta cells in the pancreas. A key role in this process is played by T cells.
After clinical onset of the disease a substantial part of the patients experience a honeymoon period, in which there is a very low insulin requirement and good metabolic control. This honeymoon period does not develop in all patients and can be of variable duration.

The initial trigger, leading to the immunological cascade ultimately ending in the clinical onset of type 1 diabetes is not known. Heat Shock Protein 60 (HSP60) is naturally expressed upon stress and therefore present at sites of inflammation. Also, a immunoregulatory role for HSP60 has been reported in various diseases, among which type 1 diabetes.

HSP60 peptides can be are recognized in recently onset type 1 diabetes patients and may be used therapeutically to induce a more tolerogenic environment, ameliorating the progression of the disease.

Doel

We set out to establish a cohort of newly diagnosed type 1 diabetes patients, which will be followed over time to evaluate T cell functions and recognition of specific HSP peptides.

The cohort will also be used for cytokine profiling. A possible relation between progression of the disease, metabolic control and cytokine profiles will be investigated.

We will try to determine whether a honeymoon phase is correlated with recognition of HSP peptides and with a specific protective cytokine profile.

Duur stage

  • 6-9 maanden

Contactpersoon

Eurofever

Treatment of hereditary inflammatory diseases, a European survey

Hereditary autoinflammatory diseases are a group of rare genetic disorders of the innate immune system.
Examples are familial Mediterranean fever, TNF-receptor associated periodic and the hyper IgD periodic fever syndrome.

For most of these disorders therapy is difficult. Since numbers are small, randomized controlled trials are lacking.
Prospective trials will require International cooperation.

As a preparation we will investigate current therapeutic experience in a EU sponsored survey. Thus we hope to determine the most promising therapies for further investigation. In addition we will develop outcome measures for these trials.

Methode

The student will gather clinical data in the Netherlands and will perform a web based consensus procedure to develop a compound outcome measure for future trials.

Mogelijk als combistage?

  • Ja

Contactpersoon

Dr. J. Frenkel

Genetica en immuundeficiënties

Next Generation Sequencing voor Primaire Immuundeficienties

Primaire Immuundeficienties zijn een groep ziektes van de afweer die leiden tot een sterk verhoogde vatbaarheid voor infecties. Inmiddels zijn er meer dan 170 genetische defecten bekend die kunnen leiden tot een immuundeficiëntie.

Een groot probleem bij immuundeficienties is het tijdig stellen van de juiste diagnose. Daarvoor is beschrijvende en funtionele diagnostiek voorhanden, maar in een groot deel van de gevallen leiden die niet tot een exacte (genetische) diagnose.

Dit onderzoek zal een van de nieuwste technieken uit de genetica (Next Generation Sequencing, NGS) gaan toepassen om bij patiënten met een afweerstoornis snel tot de juiste diagnose te komen.

Hypothese

Het toepassen van Next Generation Sequencing bij patiënten met een afweerstoornis zal in de meerderheid van de patiënten leiden tot een belangrijke verkorting van de diagnostische fase.

Methode

Een grote groep (N=150) patiënten is reeds bekend op de polikliniek pediatrische immunologie. Deze patiënten hebben allen al een uitgebreide beschrijvende evaluatie ondergaan, maar er is nog geen verklarende genetische diagnose.

In deze fase van het onderzoek zal bij hen NGS toegepast worden. Vervolgens worden de resultaten hiervan vergeleken met de reeds bekende gegevens. Bij een gedeelte van de patiënten zal vervolgens aanvullende laboratorium diagnostiek plaatsvinden.

Wie zijn wij?

Dit project is een samenwerking tussen de kinderimmunologie (dr. Joris van Montfrans, dr. Marianne Boes) en de afdeling medische genetica (dr. Marielle van Gijn). Het immunologische werk zal daarom plaatsvinden bij de pediatrische immunologie; het genetisch onderzoek bij de medische genetica.

Wie zoeken wij?

Een enthousiaste geneeskunde/SUMMA student voor een onderzoeksstage waarbij klinisch en deels laboratorium onderzoek gecombineerd worden.
Wat houdt het werk in?

  • Inventarisatie van patiënten die voor dit onderzoek in aanmerking komen
  • Organiseren van DNA samples van deze patiënten
  • Meedraaien in interpretatie van gegevens en aanvullende diagnostiek waar nodig.
  • Meehelpen aan documentatie van onderzoeksgegevens.

Wanneer?

Start: tussen juli 2011 en januari 2012
Duur: minimaal 4 maanden fulltime; bij voorkeur 6 maanden of langer

Contactpersoon

Dr. Joris van Montfrans, kinderarts immunoloog

Gericht genonderzoek en aangeboren ontstekingsziekten

Inleiding

Aangeboren ontstekingsziekten (periodieke koortssyndromen) zijn stoornissen in de controle van het aangeboren (“innate”) immuunsysteem. Deze ziektebeelden zijn vaak genetisch bepaald. Er zijn inmiddels 13 genen bekend die dergelijke ziekten kunnen veroorzaken. Echter, bij 80% van de onderzochte patiënten kunnen wij in geen van deze genen een pathogene mutatie vinden. De huidige benadering is dat op grond van het klinisch beeld één of enkele genen worden geanalyseerd.

Inmiddels kunnen we met behulp van de nieuwste high throughput sequencing-methoden honderden genen simultaan testen. Niet alleen de bekende genen maar ook genen waarvan vermoed wordt dat ze betrokken zijn bij de beheersing van ontstekingsreacties. Wij beginnen nu bij patiënten nieuwe gen-afwijkingen te vinden. De vraag is zijn dit pathogene mutaties of toevallige polymorfismen.

Methode

De student controleert de juistheid de reeds systematisch verzamelde klinische gegevens, voert deze in een ACCESS database in en correleert de data met uitkomsten van genetisch onderzoek.

Waar genetische afwijkingen zijn gevonden verricht de student uitgebreid literatuuronderzoek en maakt een plan voor functioneel celbiologisch onderzoek ter confirmatie van de afwijking.

Het doel is de resultaten van deze analyse te publiceren met de deelnemende student als coauteur .
Er zijn reeds enkele mutaties die klaarliggen om verder te worden uitgewerkt.

Mogelijk als combistage?

  • Ja

Contactpersoon

Dr. J. Frenkel

Immune system

Mechanisms that underlie antigen processing- and transport pathways in antigen presenting cells of the immune system

Our research effort focuses on the mechanisms that underlie antigen processing- and transport pathways in antigen presenting cells of the immune system. Elucidation of these mechanisms should yield insight in the development of potent immune defense to microorganisms and to the maintenance of immune tolerance. It is our intention to extend basic research findings into improvements in patient care.

We are intrigued by the ability of antigen presenting cells and amongst those especially dendritic cells, to activate quiescent naïve T lymphocytes, which is essential to host defense against infectious disease. At least as important, antigen-presenting cells have a major role in the maintenance of immune tolerance to prevent the development of autoimmune disease. Immature dendritic cells continuously sample their surrounding tissues via pinocytosis and receptor-mediated endocytosis. The encounter of antigens under stimulatory conditions triggers sentinel-type dendritic cells in the mucosae of the lungs and intestinal tract or the skin to migrate to lymph nodes. Stimulation of dendritic cells is most readily attained via ligation of pattern recognition receptors specific for conserved moieties expressed by pathogens, which facilitates the expression of the chemokine receptors (i.e. CCR7) to allow for directed homing to regional lymph nodes. During transit to lymphoid tissues, sampled antigen is processed and displayed as antigen-derived peptide/MHC complexes, essentially providing an antigenic snapshot for inspection by patrolling naïve T lymphocytes in lymph nodes. Other members of the dendritic cell family reside constitutively in lymphoid tissues, and present antigens acquired via afferent lymphatic vessels and the blood, either in free from or transported via migratory cells, for induction of adaptive immune responses to antigens from peripheral sites.

The processes outlined above are generalized and are moreover likely to differ under healthy compared to pathological conditions. Elucidation of the mechanisms that underlie dendritic cell migration, and their processing and presentation of antigenic moieties, should facilitate the development of new therapies to improve the lives of individuals suffering from inherited and acquired immune deviations. We focus our studies on presentation of endosome-derived antigen, which includes the presentation via products of the Class II and Class I MHC locus (in the process of cross-presentation), and lipid presentation in the form of lipid/CD1 complexes.

Methode

Our preferred approach lies in novel mouse models, which we combine with experiments using materials from healthy and patient donors. Mouse strains we generated include fluorescent knock-in mice, knock-out mice and transgenic mice. We currently focus our research effort on the mechanisms involved with lipid antigen selection for presentation in thymus and peripheral tissues, for support of invariant NKT cell development and function. We study the tolerance mechanisms in liver and skin using newly developed mouse models, in which T cell responses specific to tissue-expressed antigen are investigated. We moreover study the role of early immune stimulation in lung tissue during infection with respiratory syncytial virus. We develop new tools to extend our work on endosomal processing of antigens for (cross-) presentation via Class I MHC and Class II MHC, with emphasis on receptor-mediated uptake and phagosomal maturation.

Duur stage

  • 6-9 maanden

Contactpersoon

Immuno-education

Immuno-education in the neonatal period: Prevention of allergic disease?

Immunebalance is disturbed and immunological tolerance is lacking in inflammatory diseases like allergy. Previous studies have suggested that immune maturation in early life in children who later develop allergy is different from (high risk) children who will become a tolerant state. In utero and directly after birth a tolerant environment is necessary to avoid premature birth and a chronic state of hyperinflammation post-natally. However, the capacity to fully mobilize the adaptive immune system needs to be retained in case of infections.

Gradually the immune system is developing a mature immune system. When this process fails a neonate is at risk for allergy. This project focuses on the development of the immune system and factors influencing this highly flexible maturation process.

The plasticity of the immune system of neonates involves many innate driven immuneregulatory processes. A better understanding of these processes in early life will raise opportunities for the development of preventive therapies for children at risk for allergic disease.

Doel

The first part of this project concentrates on a better understanding of normal maturation processes. Healthy neonates and neonates at high risk for atopy are followed in time from birth. Focus is on interaction and regulation between the innate and adaptive immune system over time.

The second part of this project aims at induction of immune tolerance in (cow’s milk) allergy by prebiotics (as potential immunomodulatory carbohydrates). This is a randomised placebo-controlled trial with a follow-up period of 2 years. Children will be clinically evaluated for allergy each year. Immunologic effects of prebiotics will also be investigated by in vitro experiments.

Duur stage

  • 6-9 maanden

Contactpersoon

 

Immunodeficiency and infections in the immunocompromised host

In the Netherlands, the clinical department of paediatric immunology and infectious diseases cares for the largest group of patients with primary immunodeficiency disease in the Netherlands.. For a large part these are patients with humoral immunodeficiency and treated with gammaglobulin infusions.

Doel

Although for many patients (80%) with primary immunodeficiency with monogenetic background, the genetic defect is known, tha largets group treated with ganaglobulins concern common variable immunodeficiency patients with unknown and most likely polygenetic defects. We recently started a large study in 70 paediatric patients with CVID and obtained funding for a database, study of B-cell and T-cell defects in these patients, and genetic studies next to clinical features. One PhD student is currently working on this subject (A vd Ven) funded by the pharmaceutical company Baxter. Apart from patients treated with gammaglobulins, the department gets referred patients who need stem cell transplantation for primary immunodeficiency. Utrecht is one of the two Dutch centres who perform stem cell transplantation in children for immunodeficiency, haematological malignancy as well for other indications like inborn errors of metabolism and auto-immunity/inflammation.

Wie zijn wij?

In recent years, cord blood transplantation has steadily increased. Due to the temporary but severe immunodeficiency which lasts several weeks during SCT procedures, (reactivation of) infections cause major complications, morbidity and mortality. At present one of our PhD students (A. de Pagter, MD-PhD grant) is involved in reactivation studies of (persistent) viruses like CMV and EBV and the role of HHV6 reactivation together with Dr D. van Baerle, Laboratory of immunology and Dr R Schuurman (Virology laboratory) and Dr JJ Boelens. Antiviral defence (Prof Dr B Prakken) and immune reconstitution (Dr A Bloem, K. Tesselaar, J Borghhans) are also studied. Interactions and toxicity by he numerous immunosuppressive and antiviral medications in SCT patients are studied together with the UMCU pharmacy (Prof Dr A vd Velden) by a PhD student I. Bartelink. For these PKPD studies, Sanders obtained TI Pharma funding together with Prof Dr M Danhof (LUMC, Sylvius Institute) and the pharmacist Dr C. Knibbe ( Antonius Ziekenhuis Nieuwegein).

Duur stage

  • minimaal 6 maanden

Contactpersoon

Induced pluripotent stem cells

Induced pluripotent stem cells, a model for hereditary immune diseases

Hereditary immune defects are rare, but devastating genetic diseases, affecting primarily young patients. An example is the severe inflammatory disease, mevalonate kinase deficiency. Targeted therapy is lacking due to the rarity of the disease, the absence of animal models and the ethical limitations on studying tissues from young children. Induced pluripotent stem cells offer the possibility to generate the relevant cells and tissues from affected individuals. Our group studies the affected cells in mevalonate kinase deficiency, primarily monocytes and macrophages in order to identify potential treatment for these patients.

Methode

The student will acquire stem cell culture skills as well as basic immunological methods. Moreover, the student will acquire skills in processing experimental data for publication. Students may join Dr. Frenkel on out-patient clinics caring for affected patients.

Contactpersoon

Dr. J. Frenkel

Inflammatie bij kinderen met obesitas

Vetcellen (adipocyten) zijn altijd beschouwd als simpele ‘vetopslag’ cellen. De laatste jaren wordt steeds duidelijker dat vetcellen ook immunologische functies hebben. Ze brengen Toll-like receptoren (TLRs) tot expressie en scheiden verscheidene immunologisch actieve stoffen (adipokines) uit. Bij obesitas neemt de secretie van pro-inflammatoire adipokines toe, met low-grade systemische inflammatie en een sterk verhoogd risico op hart- en vaatziekten als gevolg.

Doel

Wij hebben het afgelopen jaar een cohort obese en nonobese kinderen geïncludeerd voor de AIMOB studie (Adipokines and Inflammatory Markers in Childhood Obesity), en willen nu onderzoeken of bij obese kinderen al sprake is van een low-grade systemische inflammatie. Daarvoor is de immuuncel functie van deze kinderen uitgebreid in kaart gebracht, en worden 25 circulerende adipokines gemeten. Met behulp van alle beschikbare gegevens kan de inflammatoire status van obese kinderen uitgebreid in kaart worden gebracht.

Taakomschrijving: Klinisch onderzoek / analyse onderzoeksgegevens

De inflammatoire status van de obese en nonobese kinderen is uitgebreid in kaart gebracht. Taak van de student is deze data samenvoegen en analyseren. Daarnaast is er de mogelijkheid om op het laboratorium mee te kijken en eventueel mee te helpen met de metingen.

Netjes werken en interesse in statistiek is een pre!

Duur stage

  • 3-6 maanden

Wat bieden wij?

  • Enthousiaste begeleiding, leuke combinatie van klinisch onderzoek en kennismaken met lab-onderzoek / fundamenteel onderzoek
  • Gedreven, gezellig en enthousiast team.

Contactpersoon

Henk Schipper, arts-onderzoeker

Osteoporose

Osteoporose bij kinderen met chronisch prednisongebruik

Voor het onderstaande project zoeken wij korte termijn een enthousiaste student, met belangstelling voor de kindergeneeskunde en/of de nucleaire geneeskunde.

Hoewel langdurig gebruik van prednison bij heel veel aandoeningen wordt voorgeschreven, hebben wij onvoldoende zicht op de incidentie van steroid-geinduceerde osteoporose in de populatie kinderen die wij behandelen.

Doel

In deze studie willen we dit probleem in kaart brengen aan de hand van een bestaande data-base van uitkomsten van DEXA-scans. Vervolgens worden de gegevens van de DEXA-scans gekoppeld aan de klinische data (duur en dosis prednison, wervelinzakkingen en/of fracturen) en wordt gekeken naar de preventieve maatregelen die werden genomen.

Aan de hand van deze data en een uitvoerige literatuurstudie is het onze bedoeling een landelijk protocol te ontwikkelen voor de preventie van steroid-geïnduceerde osteoporose bij kinderen.

Contactpersoon

Drs. A. van Dijk, algemeen kinderarts en projectcoördinator

Probiotics

Improving the use of probiotics in immune mediated diseases

Recent intervention studies with probiotic bacteria in immune mediated diseases have provided different and sometimes contradictory results. This is probably due to poor strain selection. We hypothesize that each immune mediated disease to be influenced needs a strain with specific characteristics, fit for the specific immunological background of the disease.

Doel

In this project, we characterize the immune modulationg capacities of several probiotic strains. PBMC isolated from healty volunteers are cocultured with several strains. Subsequently, mRNA of transcription factors T-bet, GATA3, RORyT and FOXP3 is isolated to quantify the induction of Th1, Th2, Th17 and Treg cells.

The bacteria most potent to induce a T helper subset will be used for further analysis of the induced subsets. For this purpose we FACS analyse the cells for specific cytokines, and use proliferation assays to see if the subsets are induced from naive cells or from expanding memory cells.

Methode

Our special focus is on the induction of regulatory T cells, as these cells appear to be the master regulators of immune homeostasis. The suppressive capacities of Tregs induced by bacteria is characterized with suppression assays. The effect of bacteria on existing Tregs will also be tested.

When immunologically different bacteria are selected, we will test if PBMC from children with immune mediated diseases as atopic dermatitis, colitis ulcerosa and juvenile arthritis can be ‘skewed’ in a Th1, Th2 or Th17 direction by bacteria. Of course, the induction of Tregs and their suppressive capacity will again be a focus of interest.

With the results of this project, we can improve strain selection and the use of probiotics in immune mediated diseases.

Duur stage

  • 6-9 maanden

Contactpersoon

T cells

Can functional regulatory T cells (Treg) be induced in peripheral blood from humans and used for therapy in immune disorders?

CD4+ Treg can suppress activation of other T cells and therefore they are important for immune regulation. Treg express the transcription factor FOXP3. People with a defect in FOXP3 suffer from a severe disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). Furthermore it is shown in several animal models but also in humans that the presence of Treg can influence the course of autoimmune disease.

Doel

Our research focuses on how to manipulate Treg. The reason is that Treg are potential targets to decrease for instance autoimmunity.

Heat Shock Protein 60 (HSP60) is naturally expressed upon stress and therefore present at sites of inflammation. In our group we found that the T cell reactivity to HSP60 correlates with disease remission in Juvenile Idiopathic Arthritis1. Therefore we hypothesized that HSP60 can induce Treg.

We found indeed that we can induce FOXP3 expressing Treg from CD4+ non-Treg in vitro with HSP602.

Methode

Currently we are investigating the mechanism of HSP60 mediated Treg induction.

Furthermore if we want to use induced Treg to modulate disease, it is essential to show at least that it is possible to isolate functional Treg that will do their job in vivo. In literature there are very contradictory results regarding functionality of human induced Treg.

Therefore we are also looking more into the functionality of FOXP3 expressing human induced Treg.

Duur stage

  • 6-9 maanden

Contactpersoon

 

Vaccination strategies

Focus on optimal vaccination strategies against respiratory tract infections, number and timing of vaccinations, effects on nasopharyngeal flora, immunology, transmission of pathogens and herd-immunity and prevention of invasive bacterial disease

All microbial causes of respiratory tract infections originate from the upper respiratory tract. Asymptomatic nasopharyngeal colonization with bacteria is common, with high carriage rates of S. pneumoniae, H. influenzae, M. catarrhalis and S. aureus in infants and children that decline with age and maturing of immunity. Respiratory viral infections like influenza and RSV often precede direct spread of these bacteria from the nasopharynx to otherwise sterile body sites leading to infections of the lungs, nasal sinuses and the middle ear cavity. Furthermore, these commonly colonizing bacteria can also invade the bloodstream and cause serious systemic disease, with mortality rates up to 20% for sepsis and meningitis, despite the availability of antibiotics and intensive care facilities. Particular risk groups for severe (bacterial and viral) respiratory tract infections are infants, elderly and immunocompromised patients.

Doel

The microbial flora of the upper respiratory tract forms a highly diversified ecological system, containing more than 400 bacterial species and intermittently hosting a wide range of different viruses, constantly interacting with each other and with the mucosal immune system. The balance of this complex ecological system is pivotal in preventing respiratory tract and systemic infections to occur. The new conjugate pneumococcal vaccines reduce carriage with the pneumococcal serotypes included in the vaccine but increase carriage with other serotypes, and other bacterial species such as H. influenzae and S. aureus (replacement). While the introduction of the 7-valent conjugate pneumococcal vaccine in the United States has had a dramatic effect on the incidence of vaccine-specific pneumococcal infections, it is also associated with a marked increase in infections with penicillin-resistant serotype 19A pneumococcus, that is not included in the vaccine.

Currently, Sanders and her group are conducting several unique large field studies of reduced number of the currently licensed 7-valent pneumococcal conjugate vaccine in infants with the primary question what these reduced schedules will mean for carriage reduction of pathogens in the upper respiratory tract and herd-immunity. Other focus of interest is what vaccination will mean for replacement in the nasopharyngeal niche by non-vaccine pneumococcal serotypes and other species Haemophilus influenzae, Moraxella catarrhalis and S. aureus. Also, the immunology and long term immunological memory after vaccinations are studied.

Methode

For prediction of effects on nasopharyngeal flora and herd immunity, (household) transmission models are developed to predict effects of vaccinations with reduced doses numbers.

The mentioned studies are financed by the Ministry of Health and performed by Sanders and her group. The studies are in collaboration with governmental agencies like the Netherlands Vaccine Institute (Dr L van Alphen, Dr G van de Dobbelsteen) and RIVM/CIb (Dr G Berbers).

Resultaten

In addition, new studies have started for ongoing surveillance of effects of implementation of the 7-valent pneumococcal vaccine in the national infant vaccination program on nasopharyngeal carriage of both the target group of infants as well as household members. They have shown that significant shifts occur both in the nasopharynx of vaccinees as well as adult contacts. Shifts in nasopharyngeal carriage are early predictors for potentially new emerging pathogens (like new pneumococcal serotypes) in invasive disease as well as respiratory disease. Sanders and her group have also an active role in national surveillance of invasive bacterial disease and connections between (shift in) nasopharyngeal colonization, together with Dr. A van de Ende, Netherlands Reference laboratory for Bacterial Meningitis)

Another important issue, that of long-term immunity after eradication of bacteria; less circulation of potential pathogens may lead to waning immunity in the population and might make populations more vulnerable instead of protected. To this aim, induction of pneumococcal antibodies and B-cell memory after different vaccination schedules are studied together with the NVI (Dr G vd Dobbelsteen)

Additional studies on this subject are meningococcal C immunology studies, together with the group of Dr G Berber, Dr F van de Klis, RIVM. Recently, we showed in a large population cohort that specific immunity for Meningococcal C bacteria has declined in non-vaccinees after the meningococcal C conjugate vaccination in 2002 of all 1-18 year old children and adolescents.

Apart from infants and children who have the highest risk for bacterial respiratory and invasive disease like meningitis and sepsis, elderly are a vulnerable groups for pneumonia. Sanders and her group participate in a study large study in 85.000 elderly on prevention of pneumonia by a recently developed 13-valent pneumococcal conjugate vaccines (CAPITA, PI Prof M. Bonten), financed by the pharmaceutical industry. Sanders and her group focus on effects on nasopharyngeal carriage of the 13-valent vaccine in elderly, immunology and adverse events in a subset of 2.000 elderly, followed for 2 years with collection of nasopharynx samples, blood and questionnaires.

Duur stage

  • Minimaal 6 maanden

Contactpersoon

 

Antimicrobiële resistentie

Inhoud

Antimicrobiële resistentie (AMR) is wereldwijd een snel toenemend probleem met progressief therapie falen. Uitbraken van infecties met multiresistente micro-organismen komen steeds vaker voor. Verminderen van antibioticagebruik en het ontwikkelen van nieuwe antibiotica zullen bijdragen aan een oplossing. Echter, in de afgelopen 20 jaar zijn nauwelijks nieuwe antibiotica op de markt gekomen. Beter inzicht in het reservoir van AMR bij de mens en de verspreiding hiervan is belangrijk om effectieve maatregelen te treffen in de nabije toekomst. In de ZEBRA studie kijken we naar de korte en lange termijn prevalentie van AMR genen in de darmen van neonaten die in hun eerste levensweek zijn behandeld met breed-spectrum antibiotica en naar de invloed van antibiotica op het darmmicrobioom.

Wat wij bieden

Je zult onderdeel uitmaken van de onderzoeksgroep Infection & Immunity van het Wilhelmina Kinderziekenhuis. Wij bieden een uitdagende wetenschappelijke stage op een medisch gebied dat zich snel aan het ontwikkelen is. De duur van de stage is 14-24 weken.

Wie wij zoeken

Wij zoeken een student die het theoretisch kader van de ZEBRA studie duidelijk kan beschrijven en een systematisch overzicht kan maken van de verschillende verspreidingswegen van AMR. Proactiviteit, zorgvuldigheid en sterke communicatie zijn voor ons belangrijke eigenschappen. Interesse in kindergeneeskunde, infectieziekten en immunologie maken de stage voor jou relevanter.

Contact

Bij interesse kun je contact opnemen met:

Marta Reyman, arts-onderzoeker ZEBRA studie

mreyman@spaarneziekenhuis.nl

De hoofdbegeleider is M.A. van Houten, kinderarts Spaarne Gasthuis Hoofddorp.

Harnessing invariant Natural Killer T cells for immunoprotection

Background

Childhood survival of chronic disease steadily increased over the last decades. Unfortunately, prolonged survival comes at a price. Many survivors struggle with atherosclerotic cardiovascular disease later in life. As to the mechanisms underlying the enhanced atherosclerosis, over the last few years the concept emerged that systemic inflammation plays a primordial role in atherogenesis. One of the cellular players involved are invariant Natural Killer T (iNKT) cells. In response to endogenous lipids such as oxidized-LDL derivatives, iNKT cells propagate systemic inflammation and atherogenesis. The role of iNKT cells in children with cardiovascular risk is unexplored up to now, but high circulating iNKT cell numbers and enhanced antigen-responsiveness in childhood suggest that the relevance of iNKT cells for atherogenesis is even higher in children than adults.

Aims

Both immunological research internships (biomedical/SUMMA students: 9 months) and clinical research internships (SUMMA/medical students: 6-9 months) are available.
1) Fundamental research project:
- Unravelling the role of iNKT cell-lipid interactions in the atherosclerotic plaque.
- Explore therapeutic options to manipulate iNKT cell function in vivo.
2) Clinical research project:
Establish the role of circulating iNKT cells in systemic inflammation and atherogenesis in children at risk.

Methods

1) Fundamental research: iNKT cell phenotype and function is studied ex vivo on patient materials, making use of multi-colour flow cytometry, quantitative PCR, multiplex immunoassays, cloning/CRISPR and other state-of-the-art molecular techniques.
2) Clinical research: starting in September 2016, several groups of children with chronic disease will undergo cardiovascular MRI to assess their vascular phenotype and function.

Duration internship

6-9 months

Contact

1) Dr. H.S. Schipper (pediatric registrar, postdoctoral research fellow pediatric immunology/cardiology)

h.s.schipper-3@umcutrecht.nl

2) Drs. F. Ververs (arts-onderzoeker)

f.a.ververs@umcutrecht.nl

CDC-studie

Cardiovascular disease in children with chronic inflammation

Achtergrond

De overleving van chronisch zieke kinderen is enorm verbeterd. Helaas krijgen veel van deze kinderen op jonge leeftijd atherosclerose. Hierbij kan chronische inflammatie, voeding, insuline resistentie, dyslipidemie en hypertensie een rol spelen. Om de ernst van de atherosclerose in kaart te brengen wordt middels een intima-media dikte meting en cardiovasculaire MRI de vaatwand van 40 kinderen met een hypoplastische aortaboog, 40 kinderen met jeugdreuma, 40 kinderen met cystic fibrosis, 40 kinderen met obesitas en 40 kinderen met een ASD (controle groep) in kaart gebracht. Daarnaast wordt middels ex vivo immunoassays de
systemische inflammatie in kaart gebracht, om relevante inflammatoire parameters te identificeren.

Invulling van de stage

  1. Je maakt onderdeel uit van een gedreven en enthousiast onderzoeksteam, waarbij kennis gemaakt kan worden met zowel fundamenteel/laboratorium onderzoek als alle fases van klinisch onderzoek.
  2. Praktische uitvoering van de klinische studie: meedraaien in het studieteam, patienten includeren, data invoeren en analyseren.
  3. Subvraag onderzoeken: elke student zal binnen het onderzoeksproject zelfstandig een subvraag onderzoeken, data analyseren, en presenteren.

Wie zoeken wij?

Wij zoeken gemotiveerde geneeskunde of SUMMA studenten voor een onderzoeksstage van tenminste 3 maanden, liefst langer. Vanaf 1 juni 2017 hebben we nog vacatures, dus kom kennismaken! Een hoge mate van zelfstandigheid is vereist. Ook wordt van de student verwacht dat hij of zij onder begeleiding een Engelstalig wetenschappelijk verslag of artikel kan schrijven.

Contactpersonen

1. Dr. H.S. Schipper (kinderarts in opleiding, postdoctoral research fellow kinderimmunologie/cardiologie)

h.s.schipper-3@umcutrecht.nl

2. Drs. F. Ververs (arts-onderzoeker)
f.a.ververs@umcutrecht.nl