Laboratory of Translational Immunology

Utrecht, Netherlands

Laboratory of Translational Immunology

Utrecht, Netherlands

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Admiraal R.,University Utrecht | Admiraal R.,Laboratory of Translational Immunology | Lindemans C.A.,University Utrecht | Van Kesteren C.,University Utrecht | And 7 more authors.
Blood | Year: 2016

Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD41 IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P 5 .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT. © 2016 by The American Society of Hematology.


PubMed | Laboratory of Translational Immunology and Max Delbrück Center for Molecular Medicine
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2016

Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immune response and bacterial translocation through the intestinal mucosal barrier. Previously, we have shown that activation of the bile acid sensor Farnesoid X Receptor (FXR), which belongs to the family of nuclear receptors, improves experimental intestinal inflammation, decreasing expression of pro-inflammatory cytokines and protecting the intestinal barrier. Here, we aimed to investigate the immunological mechanisms that ameliorate colitis when FXR is activated. We analyzed by FACS immune cell populations in mesenteric lymph nodes (MLN) and in the spleen to understand whether FXR activation alters the systemic immune response. We show that FXR activation by obeticholic acid (OCA) has systemic anti-inflammatory effects that include increased levels of plasma IL-10, inhibition of both DSS-colitis associated decrease in splenic dendritic cells (DCs) and increase in Tregs. Impact of OCA on DC relative abundance was seen in spleen but not MLN, possibly related to the increased FXR expression in splenic DCs compared to MLN DCs. Moreover, FXR activation modulates the chemotactic environment in the colonic site of inflammation, as Madcam1 expression is decreased, while Ccl25 is upregulated. Together, our data suggest that OCA treatment elicits an anti-inflammatory immune status including retention of DCs in the spleen, which is associated with decreased colonic inflammation. Pharmacological FXR activation is therefore an attractive new drug target for treatment of IBD.


Kranendonk M.E.G.,University Utrecht | Kranendonk M.E.G.,Molecular Cancer Research | Visseren F.L.J.,University Utrecht | Van Herwaarden J.A.,UMC Utrecht | And 4 more authors.
Obesity | Year: 2014

Objective: Insulin resistance (IR) is a key mechanism in obesity-induced cardiovascular disease. To unravel mechanisms whereby human adipose tissue (AT) contributes to systemic IR, the effect of human AT-extracellular vesicles (EVs) on insulin signaling in liver and muscle cells was determined. Methods: EVs released from human subcutaneous (SAT) and omental AT (OAT)-explants ex vivo were used for stimulation of hepatocytes and myotubes in vitro. Subsequently, insulin-induced Akt phosphorylation and expression of gluconeogenic genes (G6P, PEPCK) was determined. AT-EV adipokine levels were measured by multiplex immunoassay, and AT-EVs were quantified by high-resolution flow cytometry. Results: In hepatocytes, AT-EVs from the majority of patients inhibited insulin-induced Akt phosphorylation, while EVs from some patients stimulated insulin-induced Akt phosphorylation. In myotubes AT-EVs exerted an ambiguous effect on insulin signaling. Hepatic Akt phosphorylation related negatively to G6P-expression by both SAT-EVs (r= -0.60, P=0.01) and OAT-EVs (r= -0.74, P=0.001). MCP-1, IL-6, and MIF concentrations were higher in OAT-EVs compared to SAT-EVs and differently related to lower Akt phosphorylation in hepatocytes. Finally, the number of OAT-EVs correlated positively with liver enzymes indicative for liver dysfunction. Conclusions: Human AT-EVs can stimulate or inhibit insulin signaling in hepatocytes- possibly depending on their adipokine content- and may thereby contribute to systemic IR. © 2014 The Obesity Society.


PubMed | University of Toronto, Laboratory of Translational Immunology, University of Pavia, Leiden University and 3 more.
Type: Journal Article | Journal: Cytotherapy | Year: 2015

Clinical trials aimed at improving results of hematopoietic cell transplantation (HCT) by adjuvant cell-based interventions in children have been limited by small numbers and pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has resulted in a demand for harmonization of disease-specific clinical trials and immune-monitoring. Thus far, most phase I/II trials select different end points evaluated at disparate time points, making inter-study comparisons difficult and, sometimes, impossible. In this review, we discuss the various aspects that are important to consider for harmonizing clinical trial design as well as the critical elements for standardized (immune)-monitoring protocols in cell-based intervention trials in the context of HCT. Comparison data from trials applying harmonized trial design will lead to optimized immunotherapeutic treatment protocols to maximize clinical efficacy while minimizing toxicity.


Geneugelijk K.,Laboratory of Translational Immunology | Spierings E.,Laboratory of Translational Immunology
Cytotherapy | Year: 2015

Hematopoietic stem cell transplantation is currently used as a curative treatment for patients with malignant and non-malignant hematologic diseases. Human leukocyte antigen (HLA) matching is a major determinant for hematopoietic stem cell transplantation outcome. For patients lacking a fully HLA-matched donor, umbilical cord blood (UCB) units are alternative sources of hematopoietic stem cells because UCB transplantation allows a less stringent HLA matching. However, selection of the optimal UCB units remains challenging. The current UCB donor selection strategies are based on both cell dose and HLA matching. This Review focuses on the immunogenetic factors that influence UCB donor selection and highlights the future perspectives in UCB donor search. © 2015 International Society for Cellular Therapy.


Gerritsen B.,University Utrecht | Pandit A.,University Utrecht | Pandit A.,Laboratory of Translational Immunology
Immunology and Cell Biology | Year: 2016

CD8+ T cells have an important role in protection against infections and reinfections of intra-cellular pathogens like viruses. Naive CD8+ T cells circulating in blood or lymphoid tissues can get activated upon stimulation by cognate antigen. The activated T cells undergo rapid proliferation and can expand more than 10 4 -folds comprising largely of effector T cells. Upon antigen clearance, the CD8+ T-cell population contracts due to apoptosis, leaving behind a small population of memory T cells. The timing and mechanisms underlying the differentiation of naive cells into effector cells and memory cells is not yet clear. In this article, we review the recent quantitative studies that support different hypotheses of CD8+ T-cell differentiation. © 2016 Australasian Society for Immunology Inc. All rights reserved.


Hillen M.R.,UMC Utrecht | Hillen M.R.,Laboratory of Translational Immunology | Ververs F.A.,UMC Utrecht | Kruize A.A.,UMC Utrecht | And 2 more authors.
Expert Review of Clinical Immunology | Year: 2014

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that is characterized by mononuclear cell infiltration of exocrine glands. T-cells have been shown to play a central role in tissue destruction and regulation of B-cell activity and the production of autoantibodies typifying pSS. Despite the fact that dendritic cells (DCs) are candidate key players in the activation of T- and B-cells in pSS, their contribution has been under evaluated. This manuscript reviews current insights in DC biology and examines literature on the role of DCs in the immunopathology of primary Sjögren's syndrome, focusing on the interplay between dendritic cells, epithelial cells and T-cells. © 2014 Informa UK, Ltd.


PubMed | Laboratory of Translational Immunology, Erasmus Medical Center and Wilhelmina Childrens Hospital
Type: Journal Article | Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | Year: 2016

Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.


PubMed | Laboratory of Translational Immunology
Type: Journal Article | Journal: Cytotherapy | Year: 2015

Hematopoietic stem cell transplantation is currently used as a curative treatment for patients with malignant and non-malignant hematologic diseases. Human leukocyte antigen (HLA) matching is a major determinant for hematopoietic stem cell transplantation outcome. For patients lacking a fully HLA-matched donor, umbilical cord blood (UCB) units are alternative sources of hematopoietic stem cells because UCB transplantation allows a less stringent HLA matching. However, selection of the optimal UCB units remains challenging. The current UCB donor selection strategies are based on both cell dose and HLA matching. This Review focuses on the immunogenetic factors that influence UCB donor selection and highlights the future perspectives in UCB donor search.


PubMed | Laboratory of Translational Immunology, University Utrecht, Radboud University Nijmegen and Rijnstate Hospital
Type: | Journal: Joint, bone, spine : revue du rhumatisme | Year: 2016

Gout is associated with cardiovascular diseases, and systemic inflammation has a role in this. CXCL8 (interleukin-8) levels were increased in synovial fluid of gout patients, and in serum in gout patients irrespective of their disease activity. We hypothesized that the well-known cardiovascular protective effects of allopurinol could be related to effects of this drug on CXCL8 levels.Patients with a crystal proven gout diagnosis, who newly started allopurinol treatment, were included in this prospective cohort study. After evaluation at baseline for cardiovascular diseases, tophi, uric acid, CRP and CXCL8 serum levels, patients were followed for changes in uric acid and CXCL8 levels. A subgroup analysis was performed in 10 patients with the longest follow-up period and at least 4 assessments of serum uric acid and CXCL8.Sixty patients were included, and patients known with cardiovascular diseases at baseline had significantly higher CXCL8 and uric acid levels (P<0.01). In the whole group, median CXCL8 levels had not decreased after a median (IQR) follow-up of 27 (12-44) weeks (P=0.66). In the subgroup analysis in 9 out of 10 patients, CXCL8 levels showed a slight decrease, sometimes after an initial increase after a median (IQR) follow-up of 51 (45-60) weeks.This pilot study indicates that higher CXCL8 levels were associated cardiovascular diseases in gout patients. Short-term use of allopurinol does not decrease CXCL8 levels in gout patients, but longer use possibly does. Further studies are warranted to establish the potential mechanisms of treatment and effects on CXCL8 levels.

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