S.B.Bodewes
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.

S.Yang
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.

Y. van Sleen
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.

A.M. Smink
Jaar: 2023

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.

A.M. Posthumus
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.

H.Schouw
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. 

C.Campos Pamplona
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.

A.Diepstra
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.

C.Hazenberg
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.

Mr. S. Eskandari
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.

Mr. M. Hu, Bsc
Jaar: 2021

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).

Mr. M. de Borst, MD PhD
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.

Ms. H. Rozema, MSc
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.

Mr. F. Montes de Jesus, MD
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.

Mr. H. Maassen, BSc
Jaar: 2020

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Ms. T. van den Berg, BSc
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.

Ms. W. Kalteren, BSc
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.

Mr. V. van Suylen
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.

Prof.dr. J.A. Lisman
Jaar: 2017

Liver disease is associated with complex changes in the hemostatic system. Although routine indices of hemostasis such as the platelet count and prothrombin time suggest a bleeding tendency, these patients are in fact in hemostatic balance due to a simultaneous decline in pro- and anticoagulant drivers. Whether this rebalanced hemostatic state remains when patients with liver disease become critically ill is unknown and subject of this proposal. Knowledge on the hemostatic status of critically ill patients with liver disease is vital for a rational approach to hemostatic management.

Ms. I. van Zeventer, BSc, BA
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.

Prof.dr. R.P. Coppes
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).

Ms. K. Mattes
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.

Mr. E.L. de Vrij
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.

Dr. M.E. Erasmus – UMCG
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.

Prof. dr. H. van Goor – UMCG
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.

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