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Givi M.E.,University Utrecht | Peck M.J.,Philip Morris International | Boon L.,Bioceros | Mortaz E.,University Utrecht | Mortaz E.,Shahid Beheshti University of Medical Sciences
European Journal of Pharmacology | Year: 2013

Chronic Obstructive Pulmonary Disease (COPD) is an important lung and airway disease which affects the lives of around 200 million people worldwide. The pathological hallmark of COPD is emphysema and bronchiolitis and is based on the inflammatory response of the innate and adaptive immune system to the inhalation of toxic particles and gases. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells (DC). The potential role of DCs as mediators of inflammation in the airways of smokers and COPD patients is poorly understood. The current study investigated the role of DC subsets in an animal model of cigarette smoke-induced lung emphysema through the expansion or depletion of DC subsets. Expansion of both myeloid DC (mDC) and plasmacytoid DC (pDC) by Flt3L treatment induced a decline in macrophage numbers and increased the levels of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) in the bronchoalveolar lavage (BAL) fluid of smoke-exposed animals. The increase in the mean linear intercept (Lm) following Flt3L treatment was decreased by pDC depletion. In conclusion, pharmacological modulation of DC subsets may have an effect on the development of airway responses and emphysema as indicated by the decline in macrophage numbers and the increase in FGF and VEGF levels in the bronchoalveolar lavage fluid. Moreover, the depletion of pDCs decreased the Lm which might suggest a role for pDC in the pathogenesis of lung emphysema. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.

De Bruin A.M.,Academical Medical Center | Libregts S.F.,Academical Medical Center | Libregts S.F.,Sanquin Research and Landsteiner Laboratory | Valkhof M.,Erasmus Medical Center | And 4 more authors.
Blood | Year: 2012

Steady-state hematopoiesis is altered on infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. In the present study, we demonstrate that the pro-inflammatory cytokine IFNγ is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays, we show that IFNγ induces the differentiation of monocytes over neutrophils at the level of myeloid progenitors. Infection with lymphocytic choriomeningitis virus induces monopoiesis in wild-type mice, but causes increased neutrophil production in IFNγ -/- mice. We demonstrate that IFNγ enhances the expression of the monopoiesis-inducing transcription factors IRF8 and PU.1 in myeloid progenitor cells, whereas it reduces G-CSF-driven neutrophil differentiation via a SOCS3- dependent inhibition of STAT3 phosphorylation. These results establish a critical role for IFNγ in directing monocyte versus neutrophil development during immune activation. © 2012 by The American Society of Hematology.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 7.88M | Year: 2013

Atherosclerosis and its most disabling sequelae, coronary artery disease (CAD) and stroke, are leading causes of death in Europe. Until now, preventive and therapeutic interventions for these diseases aim at ameliorating the effects of established cardiovascular risk factors. More recently, results of genome-wide association (GWA) studies added to our perception of mechanisms leading to atherosclerosis. At present, over 40 CAD and several genomic risk loci have been identified, the majority through efforts led by the applicants. Some genes at these loci work through known risk factors such as lipids and, in fact, are already established or evolving treatment targets. However, this is not true for the majority of risk variants, which implies that key pathways leading to atherosclerosis are yet to be exploited for therapeutic intervention. This EU network (CVgenes@target), which brings together an equal number of SME- and academic partners, will utilize genomic variants affecting atherosclerosis risk for identification of both underlying genes and affected pathways in order to identify, characterize, and validate novel therapeutically relevant targets for prevention and treatment of CAD and stroke. In programme 1 we will investigate molecular mechanisms at the genomic loci in order to further unravel causal genes, in programme 2 we will explore in vitro and in vivo whether the pathways disturbed by causal genes are suitable for therapeutic intervention, and in programme 3 we will establish assays and initiate high throughput screens to tackle therapeutically attractive targets. Our resources including large OMICs and state-of-the-art bioinformatics platforms as well as multiple, already established in vitro and in vivo models support the feasibility of the approach. In fact, two genomic risk loci (ADAMTS7 (CAD); HDAC9 (stroke and CAD)), both identified in GWA studies under direction of the applicants, already revealed attractive targets for therapeutic intervention.

Maes W.,Laboratory for Thrombosis Research | Verschuere T.,Catholic University of Leuven | Van Hoylandt A.,Catholic University of Leuven | Boon L.,Bioceros | Van Gool S.,Catholic University of Leuven
Clinical and Developmental Immunology | Year: 2013

The recruitment and activation of regulatory T cells (Tregs) in the micro-environment of malignant brain tumors has detrimental effects on antitumoral immune responses. Hence, local elimination of Tregs within the tumor micro-environment represents a highly valuable tool from both a fundamental and clinical perspective. In the syngeneic experimental GL261 murine glioma model, Tregs were prophylactically eliminated through treatment with PC61, an anti-CD25 mAb. This resulted in specific elimination of CD4+CD25hiFoxp3+ Treg within brain-infiltrating lymphocytes and complete protection against subsequent orthotopic GL261 tumor challenge. Interestingly, PC61-treated mice also showed a pronounced infiltration of CD11b+ myeloid cells in the brain. Phenotypically, these cells could not be considered as Gr-1+ myeloid-derived suppressor cells (MDSC) but were identified as F4/80+ macrophages and granulocytes. © 2013 Wim Maes et al.

Kamburova E.G.,Radboud University Nijmegen | Koenen H.J.P.M.,Radboud University Nijmegen | Boon L.,Bioceros | Hilbrands L.B.,Radboud University Nijmegen | Joosten I.,Radboud University Nijmegen
American Journal of Transplantation | Year: 2012

Rituximab is a chimeric anti-CD20 monoclonal antibody (mAb) used in B-cell malignancies, various autoimmune disorders and organ transplantation. Although administration of a single dose of rituximab results in full B-cell depletion in peripheral blood, there remains a residual B-cell population in secondary lymphoid organs. These nondepleted B cells might be altered by exposure to rituximab with subsequent immunomodulatory effects. Therefore, we analyzed in vitro the effects of rituximab on proliferation, activation and differentiation of CD19 + B cells by means of carboxyfluorescein succinimidyl ester (CFSE)-based multiparameter flow cytometry. Rituximab inhibited the proliferation of CD27 - naïve, but not of CD27 + memory B cells. Interestingly, upon stimulation with anti-CD40 mAb and interleukin-21 in the presence of rituximab there was an enrichment of B cells that underwent only one or two cell divisions and displayed an activated naïve phenotype (CD27 -IgD +CD38 -/+). The potency of prestimulated B cells to induce T-cell proliferation was increased by exposure of the B cells to rituximab. Of note, after stimulation with rituximab-treated B cells, proliferated T cells displayed a more Th2-like phenotype. Overall, these results demonstrate that rituximab can affect human B-cell phenotype and function, resulting in an altered outcome of B-T cell interaction. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

De Bruin A.M.,University of Amsterdam | Buitenhuis M.,Erasmus Medical Center | Van Der Sluijs K.F.,University of Amsterdam | Van Gisbergen K.P.J.M.,University of Amsterdam | And 2 more authors.
Blood | Year: 2010

To explore whether and how T cells can affect myelopoiesis, we investigated myeloid differentiation in a model for T cell-mediated immune activation. We found that CD70-transgenic (CD70TG) mice, which have elevated numbers of interferon-γ (IFN-γ)-producing effector T cells in the periphery and bone marrow, are almost devoid of eosinophilic granulocytes. Induction of allergic airway inflammation in these mice failed to induce eosinophilia as well as airway hyper-responsiveness. CD70TG mice also have strongly reduced numbers of eosinophil lineage-committed progenitors, whereas granulocyte/macrophage progenitors from these mice are unable to generate eosinophils in vitro.We found that granulocyte/macrophage progenitors express IFN-γR1 and that IFN-γ is sufficient to inhibit eosinophil differentiation of both murine and human progenitor cells in vitro. We demonstrate that inhibition of eosinophil development in CD70TG mice is IFN-γ-dependent and that T cell-derived IFN-γ is sufficient to inhibit eosinophil formation in vivo. Finally, we found that IFN-γ produced on anti-CD40 treatment and during viral infection can also suppress eosinophil formation in wild-type mice. These data demonstrate that IFN-γ inhibits the differentiation of myeloid progenitors to eosinophils, indicating that the adaptive immune system plays an important role in orchestrating the formation of the appropriate type of myeloid cells during immune activation. © 2010 by The American Society of Hematology.

Ramirez-Ortiz Z.G.,University of Massachusetts Medical School | Lee C.K.,University of Massachusetts Medical School | Wang J.P.,University of Massachusetts Medical School | Boon L.,Bioceros | And 2 more authors.
Cell Host and Microbe | Year: 2011

While plasmacytoid dendritic cells (pDCs), a natural type I interferon (IFN)-producing cell type, are regarded as critical for innate immunity to viruses, their role in defense against fungal infections remains unknown. We examined the interactions of pDCs with hyphae of the invasive human fungal pathogen Aspergillus fumigatus. Human pDCs spread over hyphae and inhibited their growth. Antifungal activity was retained in pDC lysates, did not require direct fungal contact, and was partially reversed by zinc. Incubation with hyphae resulted in pDC cytotoxicity, partly due to fungal gliotoxin secretion. Following hyphal stimulation, pDCs released proinflammatory cytokines via a TLR9-independent mechanism. Pulmonary challenge of mice with A. fumigatus resulted in a substantial influx of pDCs into lungs, and pDC-depleted mice were hypersusceptible to invasive aspergillosis. These data demonstrate the antifungal activity of pDCs against A. fumigatus and establish their nonredundant role in host defenses against invasive aspergillosis in vivo. © 2011 Elsevier Inc.

Marshall N.A.,Trinity College Dublin | Galvin K.C.,Trinity College Dublin | Corcoran A.-M.B.,Trinity College Dublin | Boon L.,Bioceros | And 2 more authors.
Cancer Research | Year: 2012

The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor microenvironment. In this study, we show that specific small molecule inhibitors of phosphoinositide 3-kinase (PI3K) relieve immunosuppression to heighten the proinflammatory effects of TLR ligands that support antitumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of interleukin (IL)-10 and TGF-β but did affect IL-12 or IL-1β induction by the TLR5 ligand flagellin. In three different mouse models of cancer, combining flagellin with a class I PI3K inhibitor, either with or without a DC vaccine, delayed tumor growth and increased survival, with some animals exhibiting complete rejection and resistance to secondary challenge. Tumor growth suppression was associated with increased accumulation of polyfunctional T cells that secreted multiple effector cytokines, including IFN-γ, IL-17, and IL-2. Therapeutic protection was abolished in mice deficient in IL-17 or deprived of IFN-γ. Together, our results indicate that PI3K inhibition heighten the antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor T-cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy. ©2011 AACR.

Mus A.M.C.,Erasmus Medical Center | Cornelissen F.,Erasmus Medical Center | Asmawidjaja P.S.,Erasmus Medical Center | Van Hamburg J.P.,Erasmus Medical Center | And 3 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. To examine the role of interleukin-23 (IL-23) in subgroup polarization of IL-17A-positive and/or interferon-γ (IFNγ)-positive T cells in autoimmune disease-prone DBA/1 mice with and without collagen-induced arthritis. Methods. A magnetic-activated cell sorting system was used to isolate CD4+ T cells from the spleen of naive and type II collagen (CII)-immunized DBA/1 mice. These CD4+ T cells were stimulated in vitro under Th0, Th1, or different Th17 culture conditions. Intracellular staining for IL-17A and IFNγ was evaluated by flow cytometry. In addition, Th17 cytokines and T helper-specific transcription factors were analyzed by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results. In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor γt (RORγt), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression. In contrast, transforming growth factor β1 (TGFβ1)/IL-6 was a potent inducer of RORγt, RORα, IL-17A, IL-17F, IL-21, and FoxP3 in these cells. In contrast to TGFβ1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice. Consistent with these findings, IL-23 showed a more pronounced induction of the IL-17A+IFNγ- subset in CD4+ T cells from CII-immunized mice. However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFβ1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice. Conclusion. IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis. These data indicate different mechanisms for IL-23 and TGFβ1/IL-6 at the transcription factor level during Th17 differentiation in autoimmune experimental arthritis. © 2010, American College of Rheumatology.

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