Publications by authors named "Ismé M de Kleer"

9 Publications

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The Role of B Cells in Carriage and Clearance of Mycoplasma pneumoniae From the Respiratory Tract of Mice.

J Infect Dis 2018 01;217(2):298-309

Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Erasmus MC University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown.

Methods: In this study, we show in a mouse model that Mp persists in the nose after pulmonary infection, similar to humans.

Results: Infection of mice enhanced Mp-specific immunoglobulin (Ig) M and IgG levels in serum and bronchoalveolar lavage fluid. However, nasal washes only contained elevated Mp-specific IgA. These differences in Ig compartmentalization correlated with differences in Mp-specific B cell responses between nose- and lung-draining lymphoid tissues. Moreover, transferred Mp-specific serum Igs had no effect on nasal carriage in B cell-deficient μMT mice, whereas this enabled μMT mice to clear pulmonary Mp infection.

Conclusions: We report the first evidence that humoral immunity is limited in clearing Mp from the upper respiratory tract.
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http://dx.doi.org/10.1093/infdis/jix559DOI Listing
January 2018

The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment.

Front Med (Lausanne) 2017 22;4:61. Epub 2017 May 22.

Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands.

Yearly more than 15 million babies are born premature (<37 weeks gestational age), accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation can lead to the development of bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes in these preterm neonates. BPD patients have an arrest in alveolar and microvascular development and more frequently develop asthma and early-onset emphysema as they age. Understanding how the alveoli develop, and repair, and regenerate after injury is critical for the development of therapies, as unfortunately there is still no cure for BPD. In this review, we aim to provide an overview of emerging new concepts in the understanding of perinatal lung development and injury from a molecular and cellular point of view and how this is paving the way for new therapeutic options to prevent or treat BPD, as well as a reflection on current treatment procedures.
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http://dx.doi.org/10.3389/fmed.2017.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439211PMC
May 2017

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung.

Immunity 2016 12 6;45(6):1285-1298. Epub 2016 Dec 6.

Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam 3015 GJ, the Netherlands; Laboratory of Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent 9050, Belgium; Department of Pulmonary Medicine, Ghent University, Ghent 9000, Belgium. Electronic address:

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 period of maximal lung remodeling.
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http://dx.doi.org/10.1016/j.immuni.2016.10.031DOI Listing
December 2016

Gut derived lactic acid bacteria induce strain specific CD4(+) T cell responses in human PBMC.

Clin Nutr 2011 Dec 15;30(6):845-51. Epub 2011 Jun 15.

Center for Cellular and Molecular Intervention, Wilhelmina's Children Hospital, University Medical Center Utrecht, The Netherlands.

Background & Aims: Probiotic bacteria are used as food supplement in many different disease settings. The immune modulating capacity of different strains is not always properly tested which might result in a suboptimal choice of strains for clinical use.

Methods: The CD4 T cell responses to 19 different gut derived lactic acid bacteria were tested with different methods to show their diversity in immune modulation and to make a well-founded choice on which strains to use in future clinical trials. After co-culture of PBMC with bacteria, the induction of CD4(+) T cell subsets (regulatory T cells, T helper type (TH)1, TH2 and TH17) was analysed by rtPCR of transcription factor mRNA, intracellular FACS staining of transcription factors and cytokine production.

Results: Bacterial strains all have diverse, unique immune modulatory properties. Strains can induce Treg, TH1, TH2 and TH17 cells which can be shown at different levels of T cell activation, and is consistent for most strains tested. For TH1, TH17 and Treg, a positive correlation between the different methods was found. For TH2 cells the correlation was less consistent.

Conclusions: Probiotic bacteria have very different immune modulating capacities. Analysis of transcription factor mRNA is a suitable method for in vitro characterization of strains prior to clinical application.
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http://dx.doi.org/10.1016/j.clnu.2011.05.005DOI Listing
December 2011

Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new?

Arthritis Res Ther 2009 19;11(3):231. Epub 2009 May 19.

Department of Pediatric Immunology, Wilhelmina Children's hospital, UMCU, Lundlaan 6 3584 EA, Utrecht, The Netherlands.

Juvenile idiopathic arthritis (JIA) is a disease characterized by chronic joint inflammation, caused by a deregulated immune response. In patients with JIA, heat shock proteins (HSPs) are highly expressed in the synovial lining tissues of inflamed joints. HSPs are endogenous proteins that are expressed upon cellular stress and are able to modulate immune responses. In this review, we concentrate on the role of HSPs, especially HSP60, in modulating immune responses in both experimental and human arthritis, with a focus on JIA. We will mainly discuss the tolerogenic immune responses induced by HSPs, which could have a beneficial effect in JIA. Overall, we will discuss the immune modulatory capacity of HSPs, and the underlying mechanisms of HSP60-mediated immune regulation in JIA, and how this can be translated into therapy.
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http://dx.doi.org/10.1186/ar2674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714101PMC
March 2010

Refractory juvenile idiopathic arthritis: using autologous stem cell transplantation as a treatment strategy.

Expert Rev Mol Med 2006 Nov 15;8(26):1-11. Epub 2006 Nov 15.

Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3508 AB Utrecht, The Netherlands.

Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation (ASCT) to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by ASCT is particularly attractive as a means for treating juvenile idiopathic arthritis (JIA). In this disease, ASCT restores self-tolerance both through a cell-intrinsic mechanism, involving the reprogramming of autoreactive T cells, and through a cell-extrinsic mechanism, involving a renewal of the immune balance between CD4+CD25+ regulatory T cells and other T cells. This review describes the clinical results of ASCT performed for this disease and the possible underlying immunological mechanisms.
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http://dx.doi.org/10.1017/S1462399406000135DOI Listing
November 2006

CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.

J Immunol 2004 May;172(10):6435-43

University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Pediatric Immunology and Immunology Advanced Center on Preclinical Immuno-genomics Institute for Translational Medicine, Utrecht, The Netherlands.

This study investigates the role of CD4(+)CD25(+) regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4(+)CD25(bright) T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4(+)CD25(bright) T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4(+)CD25(int) T cells and therefore of CD4(+)CD25(total) in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4(+)CD25(bright) T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4(+)CD25(int) T cell population. The CD4(+)CD25(bright) cells of both patient groups and the CD4(+)CD25(int) cells of pers-OA JIA patients were able to suppress responses of CD25(neg) cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4(+)CD25(bright) T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4(+)CD25(+) Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4(+)CD25(bright) T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4(+)CD25(bright) T cells. These data suggest that CD4(+)CD25(bright) Treg cells play a role in determining the patient's fate toward either a favorable or unfavorable clinical course of disease.
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http://dx.doi.org/10.4049/jimmunol.172.10.6435DOI Listing
May 2004