Maud Plantinga - Academia.edu (original) (raw)

Papers by Maud Plantinga

Cancers

Dendritic cells (DCs) are professional antigen-presenting cells which instruct both the innate an... more Dendritic cells (DCs) are professional antigen-presenting cells which instruct both the innate and adaptive immune systems. Once mature, they have the capacity to activate and prime naïve T cells for recognition and eradication of pathogens and tumor cells. These characteristics make them excellent candidates for vaccination strategies. Most DC vaccines have been generated from ex vivo culture of monocytes (mo). The use of mo-DCs as vaccines to induce adaptive immunity against cancer has resulted in clinical responses but, overall, treatment success is limited. The application of primary DCs or DCs generated from CD34+ stem cells have been suggested to improve clinical efficacy. Cord blood (CB) is a particularly rich source of CD34+ stem cells for the generation of DCs, but the dynamics and plasticity of the specific DC lineage development are poorly understood. Using flow sorting of DC progenitors from CB cultures and subsequent RNA sequencing, we found that CB-derived DCs (CB-DCs)...

Immunity, Jan 20, 2016

Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1... more Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b(+) dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a perio...

The Journal of allergy and clinical immunology, Jan 9, 2017

Exposure to allergens like house dust mite (HDM) via the skin often precedes allergic inflammatio... more Exposure to allergens like house dust mite (HDM) via the skin often precedes allergic inflammation in the lung. It was proposed that Th2 sensitization via the skin occurs when skin barrier function is disrupted for example by genetic predisposition, mechanical damage or enzymatic activity of allergens. To study how HDM applied to unmanipulated skin leads to Th2 sensitization and to study which antigen presenting cells mediate this process METHODS: HDM was applied epicutaneously by painting HDM on unmanipulated ear skin, or under an occlusive tape. HDM challenge was via the nose. Mouse strains lacking different dendritic cell (DC) populations were used, and 1-DER T cells carrying a transgenic TCR reactive to Der p 1 allergen used as readout for antigen presentation. The Th2-inducing capacity of sorted skin-derived DC subsets was determined by adoptive transfer to naïve mice. Epicutaneous HDM application led to Th2 sensitization and eosinophilic airway inflammation upon intranasal HDM...

Immunity, 2016

Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocy... more Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated ''terminal selectors.'' Using BM chimeras, conditional Irf8 fl/fl mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs. (D) Contribution of donor cells to cell populations along the monocyte development in mixed BM chimeras generated with CD45.1 WT BM and CD45.2 Irf8 À/À BM. Results are presented as the ratio between CD45.1 WT cells and CD45.2 Irf8 À/À cells for each population. (E) Schematic representation of Irf8 fl/fl Lyz2-cre mice. (F and G) Expression of IRF8 in indicated cell populations in Irf8 fl/fl and Irf8 fl/fl Lyz2-cre mice. Irf8 fl/fl mice are represented by dashed lines and Irf8 fl/fl Lyz2-cre mice are represented by filled lines (F). (H) Percentage of IRF8 + Ly6c hi monocytes in BM, spleen, and lung of Irf8 fl/fl mice (filled circles) and Irf8 fl/fl Lyz2-cre mice (open circles). (I) MFI of IRF4 expression in IRF8 + Ly6c hi monocytes (filled circles) and IRF8 À Ly6c hi monocytes in BM, spleen, and lung of Irf8 fl/fl Lyz2-cre mice. (J) Contribution of donor cells to cell populations along the monocyte development in mixed BM chimeras generated with CD45.1 WT BM and CD45.2 Irf8 fl/fl Lyz2cre BM. Results are presented as the ratio between CD45.1 WT cells and CD45.2 Irf8 fl/fl Lyz2-cre cells for each population. (K) Percentage of IRF8 + cells of CD45.1 WT (filled circles) and CD45.2 Irf8 fl/fl Lyz2-cre Ly6c hi monocytes in BM, spleen, and lung of CD45.1 WT: CD45.2 Irf8 fl/fl Lyz2-cre BM chimeras. (A-H and J) Data are representative of at least two independent experiments (n = 6-18 in total per genotype). (I) Data are representative of four mice per group. (K) Data are representative of six mice per group. Error bars indicate mean ± SEM. **p < 0.01, ***p < 0.001, ****p < 0.0001.

Biology of Blood and Marrow Transplantation, 2015

Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into a potent curative tre... more Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into a potent curative treatment option for a variety of malignant and nonmalignant diseases. The occurrence of complications and mortality after allo-HCT is, however, still high and is strongly associated with immune reconstitution (IR). Therefore, detailed information on IR through immunomonitoring is crucial to improve survival chances after HCT. To date, information about the reconstituting immune system after allo-HCT in pediatric patients is mostly derived from routine standard-of-care measurements. More profound knowledge on IR may provide tools to better predict and modulate adverse reactions and, subsequently, improve survival chances. Here, we provide an overview of IR (eg, immune cell subsets and circulating chemokines/cytokines) after allo-HCT in children, taking into account different cell sources and serotherapy, and discuss strategies to enhance immunomonitoring. We conclude that available IR data after allo-HCT contain limited information on immune cell families (mostly only generic T, B, and NK cells), which would improve with more detailed information on reconstituting cell subsets or effector cell functionality at earlier time points (<1 month). In addition, secretome data (eg, multiplex cytokine/chemokine profiles) could add to the understanding of IR mechanisms and cell functionality and may even provide (early) biomarkers for individual disease outcome, such as viral reactivity, graft-versus-host disease, or graft-versus-leukemia. The present data and suggestions for more detailed, standardized, and harmonized immunomonitoring in future (pediatric) allo-HCT studies will pave the path to "precision transplantation:" an individualized HCT approach (including conditioning), based on detailed information on IR and biomarkers, aiming to reduce transplantation related mortality and relapse, and subsequently improve survival chances.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2015

Inflammatory Bowel Disease (IBD) is a multifactorial disorder involving dysregulation of the immu... more 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.

Izuhara/Inflammation and Allergy Drug Design, 2011

OncoImmunology, 2015

The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haemat... more The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced priming of these CTLs using an anti-AML vaccine may result in long-term immunity against AML. Cord blood (CB), as allogeneic HCT source, may provide a unique setting for such post-HCT vaccination, considering its enhanced graft-versus-leukemia (GvL) effects and population of highly responsive na€ ıve T cells. It is our goal to develop a powerful and safe immune therapeutic strategy composed of CB-HCT followed by vaccination with CB CD34 C-derived dendritic cells (DCs) presenting the oncoprotein Wilms Tumor-1 (WT1), which is expressed in AML-blasts in the majority of patients. Here, we describe the optimization of a clinically applicable DC culture protocol. This two-step protocol consisting of an expansion phase followed by the differentiation toward DCs, enables us to generate sufficient cord blood-derived DCs (CBDCs) in the clinical setting. At the end of the culture, the CBDCs exhibit a mature surface phenotype, are able to migrate, express tumor antigen (WT1) after electroporation with mRNA encoding the full-length WT1 protein, and stimulate WT1-specific T cells.

The Impact of Food Bioactives on Health, 2015

Dendritic cells (DCs) are the sentinels of the immune system and play a critical role in stimulat... more Dendritic cells (DCs) are the sentinels of the immune system and play a critical role in stimulating immune responses against pathogens and maintaining immune homeostasis to harmless antigens. They can be found in all lymphoid and most non-lymphoid tissues, including mucosal surfaces, like the lung and the gut, where intricate networks of DCs are situated to sense potential harmful exposures. As such, DCs are among the fi rst cells to come into contact with food bioactives in the gastrointestinal tract and thus are instrumental in shaping the immune system's response to such exposures. Here we provide an overview of DC characteristics, with the emphasis on DCs in the mucosal immune system, and discuss in vitro/ex vivo DC culture settings that can be applied for in vitro testing of (food) compounds.

Clinical and Translational Allergy, 2014

Allergic sensitization is the outcome of a complex interplay between the allergen and the host in... more Allergic sensitization is the outcome of a complex interplay between the allergen and the host in a given environmental context. The first barrier encountered by an allergen on its way to sensitization is the mucosal epithelial layer. Allergic inflammatory diseases are accompanied by increased permeability of the epithelium, which is more susceptible to environmental triggers. Allergens and co-factors from the environment interact with innate immune receptors, such as Toll-like and protease-activated receptors on epithelial cells, stimulating them to produce cytokines that drive T-helper 2-like adaptive immunity in allergy-prone individuals. In this milieu, the next cells interacting with allergens are the dendritic cells lying just underneath the epithelium: plasmacytoid DCs, two types of conventional DCs (CD11b + and CD11b-), and monocyte-derived DCs. It is now becoming clear that CD11b+, cDCs, and moDCs are the inflammatory DCs that instruct naïve T cells to become Th2 cells. The simple paradigm of non-overlapping stable Th1 and Th2 subsets of T-helper cells is now rapidly being replaced by that of a more complex spectrum of different Th cells that together drive or control different aspects of allergic inflammation and display more plasticity in their cytokine profiles. At present, these include Th9, Th17, Th22, and Treg, in addition to Th1 and Th2. The spectrum of co-stimulatory signals coming from DCs determines which subset-characteristics will dominate. When IL-4 and/or IL-13 play a dominant role, B cells switch to IgEproduction, a process that is more effective at young age. IgE-producing plasma cells have been shown to be long-lived, hiding in the bone-marrow or inflammatory tissues where they cannot easily be targeted by therapeutic intervention. Allergic sensitization is a complex interplay between the allergen in its environmental context and the tendency of the host's innate and adaptive immune cells to be skewed towards allergic inflammation. These data and findings were presented at a 2012 international symposium in Prague organized by the Protein Allergenicity Technical

PLoS ONE, 2013

It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA)... more It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T celldependent (TD) or-independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-b or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-b signaling inhibitor or neutralizing anti-TGF-b was added, demonstrating the involvement of RA and TGF-b in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.

Frontiers in Immunology, 2012

Cross-presentation of antigen by dendritic cells (DCs) to CD8 + T cells is a fundamentally import... more Cross-presentation of antigen by dendritic cells (DCs) to CD8 + T cells is a fundamentally important mechanism in the defense against pathogens and tumors. Due to the lack of an appropriate lineage marker, cross-presenting DCs in the mouse are provisionally classified as "Batf3-IRF-8-Id2-dependent DCs" or as "CD8 + DCs" in the spleen, and as "CD103 + CD11b − DCs" in the periphery. We have now generated a mAb to XCR1, a chemokine receptor which is specifically expressed on CD8 + DCs and a subpopulation of double negative DCs in the spleen. Using this antibody, we have determined that only XCR1 + CD8 + (around 80% of CD8 + DCs) and their probable precursors, XCR1 + CD8 − DCs, efficiently take up cellular material and excel in antigen cross-presentation. In lymph nodes (LNs) and peripheral tissues, XCR1 + DCs largely, but not fully, correspond to CD103 + CD11b − DCs. Most importantly, we demonstrate that XCR1 + DCs in the spleen, LNs, and peripheral tissues are dependent on the growth factor Flt3 ligand and are selectively absent in Batf3-deficient animals. These results provide evidence that expression of XCR1 throughout the body defines the Batf3-dependent lineage of DCs with a special capacity to cross-present antigen. XCR1 thus emerges as the first surface marker characterizing a DC lineage in the mouse and potentially also in the human.

PloS one, 2014

Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasc... more Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne's Muscular Dystrophy). Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne's muscular dystrophy. Both in JDM and Duchenne's muscular dystrophy the proportion of FOXP3+ T cells in mu...

The Journal of Immunology, 2011

Chronic obstructive pulmonary disease is mainly triggered by cigarette smoke (CS) and progresses ... more Chronic obstructive pulmonary disease is mainly triggered by cigarette smoke (CS) and progresses even after smoking cessation. CS induces an exaggerated influx of inflammatory cells to the bronchoalveolar space and lung parenchyma, likely resulting from a complex interplay between chemoattractants and their respective receptors. In a murine CS model of chronic obstructive pulmonary disease, we studied the importance of chemokine-like receptor ChemR23 for the induction and resolution of inflammation in CSexposed lungs. Subacute and chronic CS exposure increased protein levels of the ChemR23 ligand and chemoattractant, chemerin, in bronchoalveolar lavage (BAL) fluid of wild-type (WT) mice. Moreover, the proinflammatory chemokines CXCL1, CCL2, and CCL20 were increased in the airways of CS-exposed WT mice, accompanied by a massive accumulation of inflammatory neutrophils and monocytes, CD11b hi CD103 2 and CD11b lo CD103 + dendritic cells (DCs), and CD4 + and CD8 + T cells. The lung parenchyma of WT mice was infiltrated with inflammatory neutrophils, CD11b hi CD103 2 DCs, and activated CD4 + T cells after CS exposure. CS-induced inflammation was severely attenuated in BAL fluid and lungs of ChemR23 knockout mice with regard to the induction of inflammatory chemokines and the recruitment of inflammatory cells. Neutrophils and CD8 + T cells persisted in the airways of WT mice, as did the airway-derived conventional DCs in the mediastinal lymph nodes, for at least 14 d after smoking cessation. In the BAL fluid of CS-exposed ChemR23 knockout mice, there was a remarkable delayed accumulation of T cells 14 d after the final exposure. Our data support a role for ChemR23 in directing innate and adaptive immune cells to CS-exposed lungs.

The Journal of Immunology, 2012

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene act... more The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-kB and its subsequent recruitment onto the IkBa promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.

Journal of Experimental Medicine, 2010

It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). He... more It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). Here, we show that HDM inhalation leads to the TLR4/MyD88-dependent recruitment of IL-4 competent basophils and eosinophils, and of inflammatory DCs to the draining mediastinal nodes. Depletion of basophils only partially reduced Th2 immunity, and depletion of eosinophils had no effect on the Th2 response. Basophils did not take up inhaled antigen, present it to T cells, or express antigen presentation machinery, whereas a population of FceRI+ DCs readily did. Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen.

Immunity, 2013

Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear wh... more Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.