Onderzoek
Deze pioniersgedachte ligt ook ten grondslag aan de doelstellingen van het Tekke Huizinga Fonds, een bijdrage leveren aan vernieuwende ideeën of een eerste verkennende uitwerking daarvan binnen de aangegeven onderzoeksgebieden Transplantatie geneeskunde, Regeneratieve geneeskunde en Hematopoëse inclusief Transfusie geneeskunde. De afgelopen jaren zijn een groot aantal projecten toegekend binnen de vastgestelde onderzoeksgebieden. Een overzicht hiervan wordt hieronder weergegeven.
HLA E Genotype as a Determinant of Post Transplant Immunity and Outcomes.
JAAR: 2026
Advances in immunosuppressive therapy have markedly improved outcomes for solid organ transplant recipients. In kidney transplantation, for instance, the incidence of early acute rejection has fallen below 10%, and overall graft survival has steadily increased. Consequently, the major challenges in transplantation are shifting from prevention of early rejection toward mitigation of long-term complications, particularly infections and malignancies. These complications remain a leading cause of morbidity, hospitalizations, reduced quality of life, premature graft loss, and substantial healthcare costs.
Human leukocyte antigen (HLA)‑E may represent a key, yet underappreciated, determinant of these long-term outcomes. Data from both transplant cohorts and the general population suggest that specific HLA‑E genotypes are associated with increased susceptibility to certain viral and bacterial infections and hematological malignancies. Because HLA‑E has only two common alleles, genotyping is straightforward and classifies individuals into three well-defined groups, making it an attractive candidate for clinical implementation as a risk stratification tool.
By integrating HLA‑E genotyping with the detailed clinical outcome data available in the TransplantLines Biobank and Cohort Study, this project will systematically evaluate whether HLA‑E variants are associated with post‑transplant complications, including viral reactivation, rejection, malignancies and graft failure. If HLA‑E genotype proves to be a robust predictor of adverse outcomes, routine HLA‑E typing could become a cost‑effective addition to pre‑transplant evaluation, with significant potential impact on patient care and resource allocation.
Improve pretransplant risk stratification and help explain cases of unexpected or atypical ABMR.
JAAR: 2026
Organ shortage remains a major challenge in kidney transplantation, making it essential to maximize long-term graft survival. Antibody-mediated rejection (ABMR) is one of the leading causes of graft loss and remains difficult to predict prior to transplantation. Current pretransplant rejection risk assessment primarily relies on the detection of donor-specific HLA antibodies and complement-dependent crossmatch assays using lymphocytes as target cells. However, despite advances in HLA typing and antibody detection technologies, ABMR still occurs in clinical practice, suggesting that important pathogenic mechanisms are not captured by existing testing strategies. One widely recognized complement-independent pathway of HLA-mediated cytotoxicity involves antibody-dependent cellular cytotoxicity (ADCC), mediated by natural killer (NK) cells or other Fc receptor–expressing immune cells.
To address this gap, we established an in vitro ADCC assay system that uses NK cells as complement-independent effector cells and a novel immortalized renal microvascular endothelial cell line, which we developed as physiologically relevant target cells. Because the technical setup resembles existing crossmatch platforms, our ADCC assay has the potential to be translated into current diagnostic workflows. With this project we aim at testing this technically optimized assay system with sera of kidney transplant recipients to support this translational step. These sera contain HLA antibodies with different mean fluorescence intensities, but same HLA-specificity for the immortalized renal microvascular endothelial cell line selected. This enables the mean fluorescence intensity to be directly related to the quantitative ADCC signal measured in our in vitro assay.
By capturing mechanisms of antibody-mediated injury that are not assessed in standard diagnostics, this assay may improve pretransplant risk stratification and help explain cases of unexpected or atypical ABMR.
Improving the hepatobiliary viability of human donor livers during normothermic machine perfusion by restoring the gut-liver axis
JAAR: 2026
Normothermic machine perfusion (NMP) of the liver is an advanced technique that allows for a donor liver to be kept viable outside the body by perfusing it with warm, oxygen-rich perfusate. NMP has several advantages, such as better assessment of hepatobiliary function prior to transplantation and lower risk of ischemic injury. While during NMP livers are maintained under near-physiological conditions, they lack physiological interaction with other organs such as the gut, brain and pancreas. With this project, we aim to improve the hepatobiliary viability of human donor livers during NMP by restoring the enterohepatic (gut-liver) feedback regulation. Bile acids play a crucial role in fat absorption from the intestine but also act as hormones that control cholesterol, lipid and glucose metabolism and are therefore important for normal liver function. To investigate whether hepatobiliary viability is improved under NMP conditions, enterohepatic feedback regulation by bile acids will be restored by 1) administration of bile acids, 2) administration of the gut hormone FGF19, which is normally produced in the ileum upon reabsorption of bile acids or, 3) activation of the bile acid receptor farnesoid X receptor (FXR) using natural or synthetic ligands.
Exploring the macrophage landscape in AML as novel therapeutic target
JAAR: 2026
Acute myeloid leukemia (AML) is a disease that is still difficult to treat, with an unfavorable prognosis and average five-year survival rates of 25%. AML is not solely composed of undifferentiated leukemic blasts in the bone marrow, but also of various tumor-associated cells such as stromal cells and innate and adaptive immune cells. In our preliminary studies we have identified that a subgroup of – in particular poor prognosis AML patients – contains a large proportion of so-called tumor supportive M2-type macrophages. For the first time we have begun to functionally study the role of these cells in AML and have shown that they indeed support leukemic growth in vitro and in vivo, and impose drug resistance. The aim of the current project is to characterize the mechanisms by which M2-type macrophages support tumor growth. By linking clonal dynamics to transcriptional programs of leukemic stem cells during macrophage interaction, we hope to identify novel regulators of macrophage-driven tumor support that could be exploited as part of new therapies.
Are inhibitory monocytes drivers of an impaired vaccine response in kidney transplant recipients?
JAAR: 2026
Are inhibitory monocytes drivers of an impaired vaccine response in kidney
transplant recipients? Kidney transplant recipients (KTR) are at increased risk of severe infections because
immunosuppressive medication required to prevent organ rejection weakens immune function. Vaccination is therefore essential to protect this vulnerable population. However, vaccine responses vary considerably between patients. While some KTRs develop adequate protective immunity, others remain poorly protected after vaccination, despite receiving similar immunosuppressive treatment. Understanding the
immunological factors behind this variation is essential for improving vaccine
effectiveness in KTRs. While most research on vaccine responsiveness is focused on adaptive immune cells,
growing evidence suggests that the innate immune system also plays an important role. In our previous research, we identified a population of monocytes with immune-inhibitory characteristics, whose frequency prior to vaccination was higher in KTRs with lower vaccine responses. This suggests that these cells might influence the development of protection following vaccination. Our project will investigate whether these inhibitory monocytes are merely a marker of poor vaccine responsiveness or actively contribute to vaccine failure. By combining deep immunophenotyping with functional in vitro experiments, we aim to uncover how these cells influence vaccine-induced immunity. Ultimately, this research may lead to biomarkers that identify patients at risk of poor vaccine responses and support the development of more personalized vaccination strategies for immunocompromised individuals.
Utilization of furosemide and dapagliflozin to evaluate kidney function during normothermic machine perfusion
JAAR: 2025
Normothermic machine perfusion (NMP) is an ex vivo organ preservation technique that reaches near-physiological conditions by circulating a warm (37°C) solution through the organ, which could allow pre-transplant viability assessment. However, it remains unclear which parameters accurately reflect renal viability during NMP. Furosemide, a loop diuretic stimulating urine output, and dapagliflozin, a drug promoting glucose excretion through the kidneys, could be used to assess the functionality of kidneys during NMP, by assessing the magnitude of response to each drug that the organ can produce. Kidneys will be exposed to two degrees of warm ischemic injury, and subsequently subjected to NMP, during which either furosemide or dapagliflozin will be administered. Urine output and glucose excretion will be the primary outcome measures to quantify the renal response to each drug. We will compare these responses between the groups of warm ischemic injury, hypothesizing that the most injured kidneys will show the least response. With this project, we aim to investigate whether the kidney’s responsiveness to furosemide and dapagliflozin during ex vivo warm perfusion could serve as objective pre-transplant organ assessment biomarkers.
Smelling the signs: Electronic Nose measurements for Early Infection Recognition during stem cell transplantations
JAAR: 2025
Following a stem cell transplantation (SCT), infection management protocols prioritize the immediate administration of broad-spectrum antibiotics whenever a patient develops fever. However, in this patient population, there are numerous non-infectious causes of fever that do not necessitate antibiotic treatment. Emerging evidence suggests that unnecessary antibiotic exposure is associated with adverse clinical outcomes, including increased risk of graft-versus-host disease (GVHD) and transplant-related mortality. This is largely caused by disruption of the gut microbiota. Therefore, early differentiation between infection and inflammation is crucial, this will optimize antimicrobial treatment, improve patient outcomes and reduce length of hospital stay. Electronic noses (eNoses), a non-invasive diagnostic tool that analyses breath profiles, offers a potential solution. The non-invasive, real-time nature of eNose measurements could contribute to a reduction in antibiotic use, ultimately benefiting both patients and the healthcare system.
Introduce long-read sequencing into clinical practice to improve blood matching and reduce antibody risks for SCD and thalassemia patients
JAAR: 2025
Blood transfusions are essential for patients with sickle cell disease (SCD) and thalassemia. However, these patients often develop antibodies against donor blood due to genetic differences in blood group types, especially since most donors in the Netherlands are of Caucasian descent. This can make future transfusions more difficult.
Traditional blood typing methods don’t detect the complex genetic variations common in these patients. Molecular techniques like Single Nucleotide Variant (SNV) detection and targeted next-generation sequencing (NGS) offer better insights but have limitations. SNV only finds known variants, and NGS struggles with large or complex regions due to its short read lengths.
This project aims to introduce long-read sequencing into clinical practice to improve blood matching and reduce antibody risks for SCD and thalassemia patients.
Case control study to explore the role of erythrocyte aberrations in the pathophysiology and treatment response of warm autoimmune hemolytic anemia
JAAR: 2025
Warm autoimmune hemolytic anemia (AIHA) is a potential life-threatening disease characterized by anemia due to immune mediated destruction of erythrocytes. The underlying pathophysiology is heterogeneous and not fully unravelled. It is generally assumed that AIHA is caused by dysregulation of the central and peripheral self- tolerance, resulting in auto-reactive B- and T-lymphocytes. However, several clues suggest that AIHA may also be triggered and maintained by the generation of aberrant erythrocytes that harbour membrane changes or alterations in protein phosphorylation and glycosylation. This would make AIHA a hematopoietic disease. In this case control study it will be explored whether aberrant erythrocytes play a pivotal role in the development and persistence of AIHA, with the ultimate goal to better understand the heterogeneous pathophysiology of AIHA. This, currently missing, information will enable personalized treatment that is focussed on regeneration of normal erythrocyte levels, with a better safety profile and a higher long-term efficacy than the current treatment regimen (steroids).
Mitochondrial transplantation during ex vivo Machine perfusion of donor kidneys
JAAR: 2025
With a critical shortage of donor kidneys, transplant programs often use suboptimal organs prone to ischemia-reperfusion injury (IRI), damage from oxygen deprivation. This injury is largely due to mitochondrial dysfunction. Mitochondrial function of donor kidneys can be targeted during machine perfusion (MP), a preservation modality aimed at enhancing graft viability in the time between donation and transplantation. We hypothesize that supplementing a donor kidney with healthy isolated mitochondria during MP will improve its energy metabolism and alleviate IRI. Transferring isolated respiration-competent mitochondria into diseased organs, known as mitochondrial transplantation, has recently emerged as a novel technique to counteract IRI effects, showing promising results in both cellular and animal models of organ injury. We aim to demonstrate that exogenous mitochondria can be delivered and internalized by kidney cells during perfusion and to evaluate the impact of mitochondrial transplantation on the metabolic function of kidneys using a porcine model.
Continued hypothermic and normothermic machine perfusion without a perfusion solution switch
JAAR: 2024
Liver transplantation is the only treatment for end-stage liver disease, but donor shortages necessitate expanding donor criteria. Sequential hypothermic and normothermic machine perfusion make it possible to asses the viability of high-risk donor livers. However, this protocol suffers from additional cold ischemia time and complexity, limiting its widespread adoption. To address these issues, we propose investigating a modified protocol aiming to streamline the process and increase accessibility for transplantation centers globally.
Our research objectives are to demonstrate the safety and feasibility of an alternative DHOPE approach that eliminates the need for the perfusion fluid exchange. The exchange is deemed necessary because the red blood cells used during warm perfusion can not be used during hypothermic machine perfusion. Expected results include outcomes in safety and feasibility through pre-clinical studies on pig livers and validation with human research livers.
Optimization of donor kidneys with sevoflurane during normothermic machine perfusion
JAAR: 2024
Summary: Ischemia-Reperfusion Injury remains a critically inevitable issue to be addressed in transplant surgeries. Normothermic machine perfusion (NMP) provides an opportunity to add pharmacological substances in order to reduce IRI and enhance repair and improve kidney quality to improve graft outcome and expand the donor pool. Sevoflurane has been shown to interfere with many of the underlying processes in IRI and exerts organ protective capabilities in multiple trials. We set up a model to add sevoflurane to normothermic machine perfusion of the kidney and evaluate the kidney function and cell injury. In this project we aim to validate the protective effect of sevoflurane in the kidney NMP model and we want to elucidate underlying mechanistic pathways. This is of great significance for repairing organs and expanding the donor pool of kidneys.
Our research objectives are to demonstrate the safety and feasibility of an alternative DHOPE approach that eliminates the need for the perfusion fluid exchange. The exchange is deemed necessary because the red blood cells used during warm perfusion can not be used during hypothermic machine perfusion. Expected results include outcomes in safety and feasibility through pre-clinical studies on pig livers and validation with human research livers.
Understanding impaired vaccine responses in immunosuppressed patients: the role of tolerogenic dendritic cells.
JAAR: 2024
In mijn project probeer ik beter te begrijpen waarom de corona vaccinaties minder effectief waren bij niertransplantatiepatiënten. In de RECOVAC studie, die voor een groot deel ook op het UMCG is uitgevoerd, bleek dat niertransplantatiepatiënten verminderde, of soms praktisch geen afweer opbouwden na de eerste corona vaccinatie ronde. Dit bleek in grote mate samen te hangen met het gebruik van afweeronderdrukkende medicatie, zoals mycofenolaatmofetil.
Het doel van mijn studie is het beter begrijpen van de invloed van de afweeronderdrukkende medicaties op belangrijke afweercellen in het bloed, die van essentieel belang zijn in het opstarten van vaccinatieresponsen: dendritische cellen. Dendritische cellen zijn de eerste cellen die reageren op de vaccinatie en zorgen voor de verdere ontwikkeling van de afweerrespons. In mijn studie ga ik onderzoeken in welke mate de afweeronderdrukkende medicatie deze cellen kan veranderen in tolerogene dendritische cellen, die minder goed reageren op vaccinatie. Deze tolerogene dendritische cellen ga ik identificeren en kwantificeren met behulp van spectral flow cytometry, waarbij ik tot in de diepte kan kijken naar welk fenotype deze cellen precies hebben. Dit ga ik meten in samples van de RECOVAC studie, opgeslagen voorafgaand aan vaccinatie, zodat ik de metingen aan dendritische cellen kan relateren aan de “echte” vaccinatierespons in de patiënt.
Met deze studie hoop ik dat er meer duidelijkheid komt over waarom sommige niertransplantatiepatiënten wel en anderen niet een afdoende respons hebben op vaccinatie, om in de toekomst de weg vrij te maken voor meer gepersonaliseerde vaccinatie in deze kwetsbare populatie.
Optimization of donor kidneys with sevoflurane during normothermic machine perfusion
JAAR: 2024
Transplantation of insulin-producing cells is a promising treatment for Type 1 Diabetes (T1D). However, the human body does not provide a transplantation site that supports the long-term functional survival of these cells. Engineering an artificial transplantation site (scaffold) at a surgical accessible site such as under the skin could provide a solution. Creating an optimal microenvironment within such a transplantation device requires a sustainable network of blood vessels, lymphatic vessels, extracellular matrix (ECM), and nerves. We have designed an approach by using the adipose-derived stromal cell (ASC) secretome (= all the soluble proteins and extracellular vesicles released by ASCs). We hypothesize that using the secretome of pre-conditioned ASCs will facilitate the long-term functional survival of insulin-producing cells in a subcutaneous scaffold by providing a sustainable neurovascular network. This ultimately leads to better engraftment and long-term function of insulin-producing cell grafts with fewer donor cells, making transplantation of insulin-producing cells available for a larger group of T1D patients.
Characteristics and development of the bile acid profile before and after liver transplantation.
JAAR: 2024
Before, due to underlying liver disease, and after liver transplantation, it is known that the gut microbiome changes. This change can contribute to a higher mortality rate. Therefore, an altered microbiome composition can be important to predict patient outcomes. Since the gut microbiome is involved in the conversion of primary bile acids into secondary bile acids, a change in the gut microbiome can lead to a change in the bile acid profile or vice versa. Bile acids can influence the gut microbiome through disruption of bacterial membranes, promoting expression of antimicrobial agents via the FXR-receptor, which has the highest expression in the liver and intestine, and through prevention of bacterial overgrowth. Besides, underlying liver diseases leading to cholestasis, such as bile duct diseases and impaired hepatic function, can also lead to a change in bile acid profile and as result in a change in gut microbiome. Therefore, a change in the bile acid profile after liver transplantation might also be important to predict patient outcomes, just like the gut microbiome. Not much is known about the association of the bile acid profile before and after liver transplantation. There is a suspicion that bile acids can contribute to cardiovascular disease (CVD), which is one the leading causes for mortality after transplantation. For this reason, we aim to understand the development of the bile acid profile before and after liver transplantation and to assess the difference in bile acid profile between the liver transplant population and the healthy population. It is hypothesized that there is a difference in the bile acid profile before and after liver transplantation and in comparison with the healthy population. If a change in the bile acid profile is observed, we aim to further investigate the associations between the bile acid profile with the gut microbiome, with all-cause mortality and with cardiovascular parameters/events.
Transplantation of parathyroid gland-derived organoids in rats for regeneration of parathyroid function after surgical induction of hypoparathyroidism
JAAR: 2023
The parathyroid glands are small structures of several millimeters in size that are closely related to the thyroid gland and are responsible for calcium homeostasis in the blood. Surgery in relation to parathyroid and thyroid disease may cause damage to the parathyroid gland resulting in hypoparathyroidism. This requires temporary or permanent treatment with medication that can be challenging to dose. This is where the concept of regenerative medicine might provide a solution in the form of previously cultured parathyroid organoids which produce parathyroid hormone and already mimic a parathyroid gland in-vitro. This project aims to assess and investigate the in-vivo parathyroid hormone producing potential of these parathyroid organoids by transplanting them in rats that have their parathyroid glands surgically removed. This could be a big step towards clinical implementation of the use of parathyroid organoids in the treatment of surgically induced hypoparathyroidism.
Repairing fibrotic discarded human donor kidneys with Galunisertib
JAAR: 2023
One of the biggest hurdles in renal transplantation is the shorter long-term survival of deceased donor kidneys in comparison to living donors. Graft failure is usually a consequence of a gradual decline in kidney function due to increased interstitial fibrosis and tubular atrophy, in which functional units slowly become replaced by scar tissue. Therefore, identifying early onset fibrosis pre-transplant and inhibiting the chronic activation of its signaling cascade would be of great value in the transplant setting. Renal ex vivo normothermic perfusion (NMP) is a technique that provides us with the opportunity to add therapies to an isolated yet functioning organ before transplanting it into the recipient. Our group has previously conducted a trial in which porcine kidneys were treated with an anti-fibrotic agent (Galunisertib) during NMP, and it showed positive results even after 48 hours of administration in a subsequent tissue slice model. Our next step aims to translate these results to a discarded post-mortem human kidneys model.
Improved recognition of cellular rejection in biopsies of transplanted organs
JAAR: 2023
Acute cellular rejection of a transplanted organ is a serious event that can result in graft loss. In most cases, a biopsy of the organ is needed for diagnosis, however this does not always provide a clear answer. There can be many types of immune cells in graft biopsies, and those responsible for rejection are difficult to distinguish from other immune cells with conventional methods. This study aims to visualize the immune cells that cause rejection. We have identified a novel transcription factor called TOX, that is expressed in T cells that have been strongly stimulated by antigen recognition. Immunohistochemistry for this protein in the transplant setting has not been done yet, but our preliminary data indicate that TOX staining specifically highlights rejecting cytotoxic T cells. TOX immunohistochemistry will be applied to kidney explants lost to rejection, kidney biopsies with different forms and severity of rejection and biopsies of the heart, lungs, liver, and small intestine. We expect that TOX immunohistochemistry will improve the recognition of rejection.
The influence of bile salt transporter genetic variants and microbiome alterations on the development of non-anastomotic biliary strictures after a liver transplantation
JAAR: 2022
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Improved recognition of cellular rejection in biopsies of transplanted organs
JAAR: 2022
High-dose chemotherapy followed by autologous stem cell transplantation is an important treatment option for several hematological malignancies, such as acute myeloid leukemia. However, chemotherapy may cause new oncogenic mutations in the stem cells or lead to selection of specific clones which may lead to long-term changes in the stem cells. We aim to study the mutational profile in patients with acute myeloid leukemia at diagnosis, during treatment and after follow-up. This will help us to investigate the longitudinal changes that may lead to relapse of disease or occurrence of a secondary malignancy in these patients. With these findings we hope to improve outcomes for patients receiving this intensive treatment.
Protein detection using CRISPR-Cas: Modular Antibody-Dependent Catalytic Reporter of Faintly-Expressed Targets (MYCROFT).
JAAR: 2022
MYCROFT is a novel diagnostic platform designed to detect discrete protein concentrations associated with allograft dysfunction in the serum and urine of transplant recipients. Specifically, it attunes clustered regularly interspaced short palindromic repeats (CRISPR) and proximity ligation assay (PLA) diagnostics to inform the likelihood of transplant rejection, thereby aiding clinicians in knowing when to perform kidney biopsies. If proven successful, MYCROFT can easily be tweaked for applications beyond the transplant community due to its modular design and detect a broad range of pathological protein signatures—notably, without sacrificing speed, efficiency, or cost-effectiveness.
The effects of hemofiltration in ex vivo lung perfusion using abattoir sheep lungs
Jaar: 2022
Ex Vivo Lung Perfusion (EVLP) has proven to be an excellent technique to increase the scarce supply of donor lungs. With this technique, donor lungs can be assessed and reconditioned before transplantation. To further optimize EVLP and its outcomes, we strive to reduce the damaging effects of ischemia reperfusion injury (IRI). IRI can induce pro-inflammatory cytokines which are a major contributing factor in primary graft dysfunction (PGD). Moreover, PGD has a strong negative correlation with recipient survival. We aim to remove pro-inflammatory cytokines during EVLP with hemofiltration.
Additionally, these hemofilters can remove electrolytes. We will continuously replenish electrolytes and nutrients to maintain a constant osmotic pressure and quality of the perfusion fluid. This is contrary to the current clinical standard in which the perfusion fluid is renewed periodically. For this study, we will use our self-developed abattoir EVLP model, using ovine lungs after circulatory death (DCD).
The impact of iron definiciency on B-lymphocytes in kidney transplantant recipients
Jaar: 2021
Iron is essential for many cellular processes. Emerging data showed that iron deficiency (ID) impairs proliferation and function of B-lymphocytes in mice (Jiang, Nat Commun 2019). Both impaired B-cell function and ID are common in kidney transplant recipients (KTRs). In this project, we will study whether ID also affects B-lymphocyte proliferation and function in humans, and whether iron repletion corrects these abnormalities. This will be addressed in a sub-study from an ongoing randomized controlled trial comparing intravenous iron (iron(III)-carboxymaltose) with placebo in KTRs with ID. Non-iron-deficient KTRs will also be studied as controls. Secondly, we will use RNA sequencing to assess changes in gene expression in B-lymphocytes from iron-sufficient KTRs and in iron-deficient KTRs before and after iron supplementation. Together, these studies will provide key insights in the role of ID in B-cell immunity in KTRs, and pinpoint underlying mechanisms, with the potential to yield clinically relevant outcomes.
The effect of disease modifying treatment on the risk if alloimmunization in transfused patients with myelodysplastic syndromes: database expansion and meta-analysis.
Jaar: 2020
Patients with myelodysplastic syndromes (MDS) often become transfusion dependent during the course of their disease. Different adverse events can occur as a result of (frequent) blood transfusions ranging from iron overload to immunization against blood group antigens. Alloimmunization is an adverse event and results in time-consuming red blood cell (RBC) compatibility testing, increased donor selection pressure on the blood banks, and increased risk of acute hemolytic transfusion reactions in emergency situations (when matching of blood products for patient antibodies is not feasible). Current literature has not yet identified the influence of disease modifying treatment (DMT) on the risk of alloimmunization. It is hypothesized that DMT affects the ability of the immune system to mount an antibody response to non-self blood group antigens.
The impact of iron definiciency on B-lymphocytes in kidney transplantant recipients
Jaar: 2020
One of the most dire complications of lung transplantation is the development PTLD. Currently, pre-emptive treatment may be initiated based on EBV DNA load. A considerable limitation to this approach is the lack of standardized cutoff values, monitoring time points and sampling source. Another possible approach to monitor PTLD is through a diagnostic FDG-PET/CT, however the detection threshold does not allow for accurate detection of early stage disease. Molecular analysis of cell free DNA in plasma is a novel method that allows for the detection of mutations from circulating tumor (ct)DNA. This multidisciplinary study assesses the additional value of ctDNA monitoring in lung transplant patients with the goal of identifying patients at an early stage of developing PTLD who may benefit from (pre-emptive) rituximab treatment.
Oxygenated renal flush-out of porcine kidneys
Jaar: 2020
Development of microthrombi in kidney preservation and transplantation – the new kid on the block?
Jaar: 2019
The occurrence of microthrombi can potentially lead to local perfusion disorders and subsequently to deterioration of kidney graft function. We hypothesize that microthrombi are more frequent than we might expect, due to known activation of haemostatic pathways in deceased donors, the ischemia/reperfusion injury that occurs during the transplant surgery and enhanced kidney function after thrombolytic therapy. The aim of this study is to investigate how often these microthrombi occur, which consequences they bear and whether type of preservation influences their development and hemostatic processes.
Neonatal anemia and red blood cell transfusions
Jaar: 2019
This project addresses the benefits and risks of the RBC transfusion in neonatal anemia in preterm born infants. The lack of knowledge on the balance of potential benefits and risk of RBC transfusion for anemic preterm infants, have led to controversies about the optimal indication for RBC transfusion for this population. Therefore, the overall aim of this research project is to clarify controversial issues regarding neonatal anemia and RBC transfusion. First, we intend to assess the feasibility of using a lower than conventional transfusion Hb-threshold combined with the degree of oxygen saturation of the brain. Second, we intend to increase knowledge of the association between anemia and epo gene expression and on the direct biochemical and functional effects of RBC transfusion in preterm infants regarding organ oxygenation, clinical factors, intestinal hypoxic cell damage, oxidative stress, and neurodevelopment.
Effects of prohemostatic interventions on hemostatic status of patients with liver disease in a clinical setting
Jaar: 2019
Lipidomic and proteomic analysis of potentially transplantable lungs undergoing ex vivo lung perfusion (EVLP)
Jaar: 2018
3DA treatment as a possible enhancer of hematopoietic stem cell function.
Jaar: 2018
Hematopoietic stem cell transplantation is established as a treatment for a broad range of hematological diseases. However, suboptimal engraftment levels and low availability of hematopoietic stem cells (HSCs) limit the use. This highlights the importance of finding ways to maintain and expand the available HSCs and enhance their engraftment potential. In this project we test 3-DEAZAADENOSINE (3DA) as a candidate drug for preventing/blunting senescence. Preliminary in vitro data showed that 3DA treated cord blood CD34+ cells maintained more primitive. The Tekke Huizinga grant enabled us to further investigate whether in vitro 3DA treatment is able to enhance in vivo human HSC capacity.
Resuscitation of discarded donor human hearts on subnormothermic ex-situ machine perfusion with an acellular perfusate
Jaar: 2018
Currently, there is no clinical practice of donation after circulatory death (DCD) heart transplantation in the Netherlands. In addition, certain donation after brain death (DBD) hearts are not transplanted due to the existing strict selection criteria. This study will develop a preservation technique for discarded human donor hearts. It will focus on the effect of subnormothermic acellular machine perfusion on the inflammatory and oxidative status, energy storage capacity, and restoration of function of donor hearts currently deemed unsuitable for transplantation. To study the effect of this preservation technique, we will evaluate these hearts using a normothermic ex-situ heart perfusion machine. The advantage of this machine is its ability to assess the function of the hearts as well as biochemical parameters.
Clinical validation of the analysis of Everolimus, Sirolimus, and Mycophenolate Mofetil in Dried Blood Spots
Jaar: 2017
Is poor stem cell mobilization related to the emergence of clonal haematopoiesis in the bone marrow compartment?
Jaar: 2017
Some patients fail to mobilize sufficient numbers of CD34+ peripheral blood stem cells upon mobilization procedures for autologous hematopoietic cell transplantation. It is now known that clonal haematopoiesis might emerge during ageing and following chemotherapeutic treatment, implying a risk for development of myeloid neoplasms. We aim to study the presence of clonal haematopoiesis in poor mobilizers by a targeted sequencing approach and to relate the mutational profile to clinical outcomes and development of secondary haematological malignancies. Results from this study may contribute to improved and personalized treatment protocols.
Adult stem cells of the human thyroid gland; expansion and functionality
Jaar: 2016
Insufficient levels of thyroid hormone due to cancer treatment related thyroidectomy may lead to fatigue, feeling cold, constipation, and weight increase; whereas high levels may lead to cardiovascular diseases or osteoporosis. In this project we developed a culture protocol for murine and human thyroid stem cell derived tissue resembling organoids. When xeno-transplanted into athyroid mice, these organoids form functional hormone producing thyroid follicles. This opens future therapeutic possibilities for tissue stem cell-based therapies for thyroid cancer patients suffering from hypothyroidism.
This project was a collaboration with Andries Groen, Prof. dr. John Plukker, Dr. Schelto Kruijff (all Surgical Oncology) and Prof. Thera Links (Endocrinology).
Dissecting the epigenetic events that contribute to hematopoietic stem cell expansion
Jaar: 2016
Leukemia stem cells play a crucial role in disease initiation and progression of acute myeloid leukemia (AML). We identified that altered expression of the transcriptional regulators CITED2 and PU.1 impacts the survival and maintenance of both normal- and leukemia stem cells. With support of “Tekke Huizingafonds” we investigated potential molecular mechanisms underlying this observation. Understanding the mechanisms that regulate stem cell self-renewal and survival can help to improve current protocols for hematopoietic stem cell transplantation or highlight opportunities for AML therapy.
Clinical validation of the analysis of Everolimus, Sirolimus, and Mycophenolate Mofetil in Dried Blood Spots
Jaar: 2016
Long term cold storage of human platelets for transfusion is not yet possible due to detrimental effects of low temperature on platelets causing rapid clearance after transfusion. Studies on platelets in hibernating animals do not show these detrimental effects of temperature, despite cycling through extreme temperatures. In this project we assessed the effects of temperature on platelet function in mice mimicking ‘daily hibernation’ and by using intravital microscopy analysis. Studying hibernators and their protective mechanisms against cold may unlock platelet cold storage for non-hibernating mammals.
The hemostatic status of critically ill patients with liver disease
Jaar: 2015
Towards ex vivo normothermic machine perfusion of human donor livers without the requirement for human blood products
Jaar: 2015
Multipotent donor lung therapy with mesenchymal stem cells in an ex vivo lung perfusion model using lungs from brain dead donorrats
Jaar: 2014
Brain death and ischemia cause inflammatory and mitochondrial injury to donor lungs. In our project we stabilized the damaging process by giving stem cells during ex situ perfusion and ventilation of rat donor lungs pre-transplant. Multiple smaller doses were most efficient.
Understanding erythropoiesis from (expanded) hematopoietic stem cells through modulation of CITED2
Jaar: 2014
With this proposal we will investigate the cellular and molecular mechanisms that the transcriptional regulator CITED2 uses in order to expand HSC numbers. We will furthermore gain a deeper understanding how CITED2 increases the overall erythroid output from these cells.
Organ preservation with hydrogensulfide in renal transplantation
Jaar: 2014
Hydrogen sulfide has protective properties during ischemia. It can hypometabolize cells and tissues comparable to cooling down. We currently uss this concept to protect transplant organs in the phases prior to transplantation.
Dissecting the architecture of the normal and leukemic ‘stem cell niche’
Jaar: 2013
In this research proposal, we study the changes in the bone marrow microenvironment of patients after autologous stem cell transplantation. By understanding the changes in the cellular compartments and the molecular pathways involved, we aim to improve future transplantation strategies and post-transplantational care, in order to improve patients’ outcomes.
Efficacy of pro- and antihemostatic drugs in plasma from patients with liver disease
Jaar: 2013
Pilotstudie ‘normotherme machinepreservatie van humane donorlevers’
Jaar: 2012
A prospective cohort piloty study for use of cryolijm-sq in patients with severe COPD
Jaar: 2012
Detection of ischemia/reperfusion injury in human tissue: Anti-aggregatory and anti-inflammatory ectoenzymes in vascular endothelium.
Jaar: 2012
Bone marrow derived endothelial progenitor cell transplantation to ameliorate radiation-induced vascular remodelling in the lung
Jaar: 2011
Exploiting possibilities to improve the long-term engrafment of the hematopoietic stem cell compartment following autologous stem cell transplantation
Jaar: 2010
Transfusion policy in patients with complex changes of hemostatis – a rebalanced hemostatic status in patients with acute liver failure
Jaar: 2010
Transfusion as supportive care, study for improvement of quality of life
Jaar: 2009