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Biomedical subjects

B N Lambrecht

Publications and source records attributed to B N Lambrecht.

At least 19 recordsLinked to original sources
PubMed2006

Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses.

Malignant mesothelioma is a cancer with dismal prognosis. The objective of the present study was to address the role of the immune system, tumour micro-environment and potential immunosuppression in mesothelioma. Expression profiles of 80 cytokines were determined in the supernatant of mesothelioma cell lines and the original patient's pleural effusion. Influx of immune effector cells was detected by immunohistochemistry. Angiogenin, vascular endothelial growth factor, transforming growth factor-beta, epithelial neutrophil-activating protein-78 and several other proteins involved in immune suppression, angiogenesis and plasma extravasation could be detected in both supernatant and pleural effusion. Surrounding stroma and/or infiltrating cells were the most likely source of hepatocyte growth factor, macrophage inflammatory protein (MIP)-1delta, MIP-3alpha, neutrophil-activating peptide-2, and pulmonary and activation-regulated chemokine that can cause leukocyte infiltration and activation. There was a massive influx of CD4+ and CD8+ T-lymphocytes and macrophages, but not of dendritic cells, in human mesothelioma biopsies. It was further demonstrated that human mesothelioma tissue contained significant amounts of Foxp3+CD4+CD25+ regulatory T-cells. When these CD25+ regulatory T-cells were depleted in an in vivo mouse model, survival increased. Mesothelioma is infiltrated by immune effector cells but also contains cytokines and regulatory T-cells that suppress an efficient immune response. Immunotherapy of mesothelioma might be more effective when combined with drugs that eliminate or control regulatory T-cells.

Aged↗
PubMed2005

Dendritic cells in asthma: a function beyond sensitization.

Allergic asthma is one of the most common chronic diseases in western society, characterized by variable airway obstruction, mucus hypersecretion and infiltration of the airway wall with T-helper type 2 (Th2) cells, eosinophils and mast cells. If we are to devise new causal therapies for this disease, it is important to elucidate how Th2 cells are activated and respond to intrinsically harmless allergens. Dendritic cells (DCs) are the most important antigen-presenting cells in the lung and are mainly recognized for their exceptional potential to generate a primary immune response and sensitization to aeroallergens. Much less attention has been paid to the role of DCs in established inflammation. Based on functional studies in a murine model for asthma, in this review article, we propose that DCs are essential for generating allergen-specific effector Th2 responses in ongoing inflammation in sensitized mice. A better understanding of the role of DCs in the maintenance of the inflammatory response to allergens in asthma should lead to new therapeutic approaches intervening at the top of the inflammatory cascade.

Allergens↗
PubMed2005

Dendritic cells and the regulation of the allergic immune response.

Studies in mouse models of asthma have revealed a critical role for airway dendritic cells in the induction of Th2 sensitization to inhaled allergens. Under some conditions, subsets of dendritic cells can also induce tolerance or Th1 responses to the same allergens, depending on the context in which the antigen is seen. This article discusses various aspects of DC biology as it relates to allergic sensitization and also provides a summary of the recent evidence that dendritic cells function beyond sensitization.

Animals↗
PubMed2004

Differential capacity of CD8+ alpha or CD8- alpha dendritic cell subsets to prime for eosinophilic airway inflammation in the T-helper type 2-prone milieu of the lung.

BACKGROUND: Different subsets of dendritic cells (DCs), identified in mouse spleen by their differential expression of CD8 alpha, can induce different T-helper (Th) responses after systemic administration. CD8 alpha(-) DCs have been shown to preferentially induce Th type 2 (Th2) responses whereas CD8 alpha(+) DCs induce Th1 responses. OBJECTIVE: To study if these DC subsets can still induce different Th responses in the Th2-prone milieu of the lung and differentially prime for eosinophilic airway inflammation, typical of asthma. METHODS: Donor mice first received daily Flt3L injections to expand DC numbers. Purified CD8 alpha(+) or CD8 alpha(-) splenic DCs were pulsed with ovalbumin (OVA) or phosphate-buffered saline and injected intratracheally into recipient mice in which carboxyfluorescein diacetate succinimidyl ester-labelled OVA-specific T cell receptor transgenic T cells had been injected intravenously 2 days earlier. T cell proliferation and cytokine production of Ag-specific T cells were evaluated in the mediastinal lymph nodes (MLNs) 4 days later. The capacity of both subsets of DCs, to prime for eosinophilic airway inflammation was determined by challenging the mice with OVA aerosol 10 days later. RESULTS: CD8 alpha(-) DCs migrated to the MLN and induced a vigorous proliferative T cell response accompanied by high-level production of IL-4, IL-5, IL-10 and also IFN-gamma during the primary response and during challenge with aerosol, leading to eosinophilic airway inflammation. In the absence of migration to the MLN, CD8 alpha(+) DCs still induced a proliferative response with identical levels of IFN-gamma but reduced Th2 cytokines compared with CD8 alpha(-) DCs, which led to weak eosinophilic airway inflammation upon OVA aerosol challenge. Unpulsed DCs did not induce proliferation or cytokine production in Ag-specific T cells. CONCLUSION: CD8 alpha(-) DCs are superior compared with CD8 alpha(+) DCs in inducing Th2 responses and eosinophilic airway inflammation in the Th2-prone environment of the lung.

Animals↗
PubMed2002

Effect of ozone exposure on allergic sensitization and airway inflammation induced by dendritic cells.

BACKGROUND: Epidemiological studies suggest that ozone exposure is related to increased asthma symptoms. Dendritic cells (DCs) are the principal antigen-presenting cells in the airways. OBJECTIVE: We have examined whether ambient doses of ozone (100 ppb for 2 h) enhance allergic sensitization and/or airway inflammation in a mouse model. METHODS: C57BL/6 mice were sensitized to inhaled ovalbumin (OVA) by intratracheal instillation of OVA-pulsed DCs on day 0. Daily exposure to OVA aerosol on days 14-20 resulted in an eosinophilic airway inflammation, as reflected in bronchoalveolar lavage fluid and lung histology. In a first experiment, mice were exposed to ozone or room air immediately prior to and following sensitization. Subsequently, we tested the effect of ozone exposure during antigen challenge in DC-sensitized mice. RESULTS: Exposure to ozone during sensitization did not influence airway inflammation after subsequent allergen challenge. In contrast, in sensitized mice, challenge with OVA together with ozone (days 14-20) resulted in enhanced airway eosinophilia and lymphocytosis, as compared with mice exposed to OVA and room air (1.91 x 106 +/- 0.46 x 106 vs. 0.16 x 106 +/- 0.06 x 106 eosinophils/mL lavage fluid; P = 0.015; 0.49 x 106 +/- 0.11 x 106 vs. 0.08 x 106 +/- 0.03 x 106 lymphocytes/mL lavage fluid; P = 0.004). Ozone exposure without subsequent OVA exposure did not cause airway inflammation. CONCLUSION: Ozone exposure does not increase allergic sensitization but enhances antigen-induced airway inflammation in mice that are sensitized via the airways.

Air Pollutants↗
PubMed2001

Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo.

The transcription factor GATA-3 is essential for early T cell development and differentiation of naive CD4(+) T cells into Th2 effector cells. To study the function of GATA-3 during T cell-mediated immune responses in vivo, we investigated CD2-GATA3-transgenic mice in which GATA-3 expression is driven by the CD2 locus control region. Both in the CD4(+) and the CD8(+) T cell population the proportion of cells exhibiting a CD44(high)CD45RB(low)CD62L(low) Ag-experienced phenotype was increased. In CD2-GATA3-transgenic mice, large fractions of peripheral CD4(+) T cells expressed the IL-1 receptor family member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T cell stimulation, the ability to produce IL-2 and IFN-gamma was decreased. Moreover, CD4(+) T cells manifested rapid secretion of the Th2 cytokines IL-4, IL-5, and IL-10, reminiscent of Th2 memory cells. In contrast to wild-type CD4(+) cells, which lost GATA-3 expression when cultured under Th1-polarizing conditions, CD2-GATA3-transgenic CD4(+) cells maintained expression of GATA-3 protein. Under Th1 conditions, cellular proliferation of CD2-GATA3-transgenic CD4(+) cells was severely hampered, IFN-gamma production was decreased and Th2 cytokine production was increased. Enforced GATA-3 expression inhibited Th1-mediated in vivo responses, such as Ag-specific IgG2a production or a delayed-type hypersensitivity response to keyhole limpet hemocyanin. Collectively, these observations indicate that enforced GATA-3 expression selectively inhibits Th1 differentiation and induces Th2 differentiation. The increased functional capacity to secrete Th2 cytokines, along with the increased expression of surface markers for Ag-experienced Th2-committed cells, would argue for a role of GATA-3 in Th2 memory formation.

Animals↗
PubMed2001

Role of dendritic cells and Th2 lymphocytes in asthma: lessons from eosinophilic airway inflammation in the mouse.

Asthma is a chronic disorder of the airways characterized by variable airway narrowing, mucus hypersecretion, and infiltration of the airway wall with eosinophils. It is now believed that asthma is controlled by Th2 lymphocytes producing cytokines such as IL-4, IL-5, IL-9, and IL-13. Animal models of eosinophilic airway inflammation and airway hyperreactivity have been developed to study the contribution of cells or mediators in the pathogenesis of asthma. In this review, we discuss the role of antigen presenting cells, CD4(+) and CD8(+) T lymphocytes, B lymphocytes, NK cells, and mast cells in the induction and maintenance of eosinophilic airway inflammation, mucus hypersecretion, and airway hyperreactivity.

Administration, Inhalation↗
PubMed2001

Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation.

It is increasingly recognised that the immune and nervous systems are closely integrated to optimise defence systems within the lung. In this commentary, the contribution of various neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and somatostatin to the regulation of T cell activation is discussed. These neuropeptides are released not only from nerve endings but also from inflammatory immune cells such as monocytes, dendritic cells, eosinophils and mast cells. On release they can exert both direct stimulatory and inhibitory effects on T cell activation and also indirect effects through their influence on the recruitment and activation of professional antigen-presenting dendritic cells. Neuropeptides should therefore be included in the conceptual framework of the immune regulation of T cell function by dendritic cells.

Allergy and Immunology↗
PubMed2001

Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes.

Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC(+) cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11c(med-hi)/major histocompatibility complex class II (MHCII)(hi) cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11c(hi)MHCII(med) DC group containing a CD8 alpha(hi) subset (non-airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCII(bright) cytoplasmic processes and intracytoplasmatic FITC(+) granules. The fraction of FITC(+) AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)-instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.

Animals↗
PubMed2001

Allergen uptake and presentation by dendritic cells.

Allergic diseases such as atopic dermatitis, rhinitis and asthma are thought to result from a dysregulated immune response to commonly encountered antigens in genetically predisposed individuals. This response leads to chronic eosinophil-rich allergic inflammation and is controlled by Th2 lymphocytes. The first step in the allergic immune response is the uptake and presentation of allergen by professional antigen presenting cells such as dendritic cells, macrophages and B lymphocytes. Immature dendritic cells reside in the epithelia of the skin, upper and lower airways and gut and have the potential to sense foreign antigens and non-specific inflammatory tissue damage. Following recognition and uptake of Ag, mature dendritic cells migrate to the T-cell rich area of draining lymph nodes, display an array of Ag-derived peptides on the surface of major histocompatibility complex molecules and acquire the cellular specialization to select and activate naive Ag-specific T cells. By the nature of the signals they provide to naive T cells, mature dendritic cells are critical for polarizing Th0 helper cells into either Th1 or Th2 effector cells and for inducing long-lived memory Th cells. This article reviews recent information implying dendritic cells in the pathogenesis of allergic disease.

Allergens↗
PubMed2001

Dendritic cells as regulators of the immune response to inhaled allergen: recent findings in animal models of asthma.

Antigen-presenting dendritic cells are essential for the recognition and presentation of allergens to the cells of the immune system. Airway dendritic cells capture allergen in the mucosa and present it to naive T cells after migration into the draining lymph nodes. In this review article, we discuss the most recent findings from animal models of asthma, which highlight an essential role for these cells in the induction and maintenance of eosinophilic airway inflammation. This increasing knowledge might lead to the identification of new targets for the prevention and therapy of asthma.

Administration, Inhalation↗
PubMed2001

Lung dendritic cells and host immunity to infection.

The lung is a portal of entry for numerous microbial pathogens, against which evolution has created an adequate innate and adaptive immune response. Dendritic cells (DCs) are central to the integration of innate and specific immunity. These cells are located within the epithelium and interstitium of the lung where they are influenced by the innate immune system. Upon recognition and internalization of microbial antigens, DCs migrate to the draining lymph nodes of the lung to initiate the specific cellular and humoral immune response. By their capacity to integrate stimuli derived from the pathogen, the host and the environment, they are specialized to induce a protective immune response while at the same time avoiding damage to the host. It is becoming increasingly clear that dendritic cells are involved in the induction of immunity to viruses, bacteria, mycobacteria and fungi. Some pathogens subvert the function of dendritic cells to escape immune recognition. Not surprisingly, if dendritic cell function fails, the consequence for the host is immunodeficiency.

Animals↗
PubMed2000

Induction of rapid T cell activation, division, and recirculation by intratracheal injection of dendritic cells in a TCR transgenic model.

Dendritic cells (DCs) are thought to be responsible for sensitization to inhaled Ag and induction of adaptive immunity in the lung. The characteristics of T cell activation in the lung were studied after transfer of Ag-pulsed bone marrow-derived DCs into the airways of naive mice. Cell division of Ag-specific T cells in vivo was followed in a carboxyfluorescein diacetate succinimidyl ester-labeled cohort of naive moth cytochrome c-reactive TCR transgenic T cells. Our adoptive transfer system was such that transferred DCs were the only cells expressing the MHC molecule required for presentation of cytochrome c to transgenic T cells. Ag-specific T cell activation and proliferation occurred rapidly in the draining lymph nodes of the lung, but not in nondraining lymph nodes or spleen. No bystander activation of non-Ag-specific T cells was induced. Division of Ag-specific T cells was accompanied by transient expression of CD69, while up-regulation of CD44 increased with each cell division. Divided cells had recirculated to nondraining lymph nodes and spleen by day 4 of the response. In vitro restimulation with specific Ag revealed that T cells were primed to proliferate more strongly and to produce higher amounts of cytokines per cell. These data are consistent with the notion that DCs in the lung are extremely efficient in selecting Ag-reactive T cells from a diverse repertoire. The response is initially localized in the mediastinal lymph nodes, but subsequently spreads systemically. This system should allow us to study the early events leading to sensitization to inhaled Ag.

Administration, Intranasal↗
PubMed2000

Sensitization to inhaled antigen by intratracheal instillation of dendritic cells.

BACKGROUND: Airway dendritic cells (DCs) capture and present inhaled antigen. It is not known whether antigen presentation by DCs in the airways is sufficient to induce sensitization to inhaled antigen in vivo. METHODS: Rats were immunized by intratracheal instillation of ovalbumin (OVA) -pulsed bone marrow-derived DCs or macrophages and exposed 10 days later to a 30-min aerosol of OVA on 3 consecutive days. Total and differential cell counts and flow cytometry on bronchoalveolar lavage (BAL) fluid, airway histology and serum OVA-immunoglobulin (Ig) E levels were analysed 24 h after the last exposure. RESULTS: As few as 2 x 104 OVA-DC induced sensitization to inhaled OVA. The secondary response to OVA-aerosol consisted of an antigen-specific increase in the number of bronchoalveolar mononuclear cells, activated CD4-positive alphabeta-TCR T lymphocytes, neutrophils and few eosinophils. Peribronchial and perivascular mononuclear cell infiltrates were seen on histological analysis. There was no production of systemic OVA-IgE. Bone marrow-derived macrophages did not induce sensitization. CONCLUSION: Delivering antigen to the respiratory tract via professional antigen-presenting DCs sensitizes for a secondary response to inhaled antigen leading to airway inflammation. This model will prove very useful for studying the early events of sensitization to inhaled antigen using the respiratory route.

Administration, Inhalation↗
PubMed2000

Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation.

The aim of this study was to investigate whether dendritic cells (DCs) can induce sensitization to aeroallergen in a mouse model of allergic asthma. Ovalbumin-pulsed (OVA-pulsed) or unpulsed myeloid DCs that were injected into the airways of naive mice migrated into the mediastinal lymph nodes. When challenged 2 weeks later with an aerosol of OVA, activated CD4 and CD8 lymphocytes, eosinophils, and neutrophils were recruited to the lungs of actively immunized mice. These CD4(+) lymphocytes produced predominantly IL-4 and IL-5 but also IFN-gamma, whereas CD8(+) lymphocytes produced predominantly IFN-gamma. Histological analysis revealed perivascular and peribronchial eosinophilic infiltrates and goblet cell hyperplasia. Studies in IL-4(-/-) and CD28(-/-) mice revealed that production of IL-4 by host cells and provision of costimulation to T cells by DCs were critical for inducing the response. Lung CD4(+) T cells strongly expressed the Th2 marker T1/ST2, and signaling through this molecule via a ligand expressed on DCs was essential for the establishment of airway eosinophilia. These data demonstrate that DCs in the airways induce sensitization to inhaled antigen and that molecules expressed on the surface of these cells are critical for the development of Th2-dependent airway eosinophilia.

Administration, Inhalation↗
PubMed1999

Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation.

Substance P (SP) is an immunoregulatory tachykinin which augments antigen- and mitogen-induced lymphocyte proliferation via signaling through the neurokinin-1 receptor (NK1-R). Non-neuronal cells of the immune system such as monocytes, T lymphocytes and eosinophils can be a source of SP. We have investigated if antigen-presenting dendritic cells (DC) produce SP. DC were grown from bone marrow precursors using a cocktail of GM-CSF, IL-4 and Flt-3 ligand. Reverse transcriptase-PCR amplification using primers for the mouse preprotachykinin-A gene and direct DNA sequencing of amplified products from purified DC demonstrated the presence of the gamma-transcript of the gene, coding for SP and neurokinin A. At the protein level, mouse DC expressed SP as determined by an enzyme immunoassay and confirmed by immunostaining. The functional role of endogenous SP release was determined. During the interaction with syngeneic or allogeneic DC, the addition of a specific NK1-R antagonist partly reduced proliferation in responding T lymphocytes. This was confirmed by using responders derived from NK1-R-deficient mice. In the absence of DC, proliferation of T cells induced by direct TCR ligation and soluble CD28 was partly dependent on signaling through NK1-R, revealing an autocrine effect of SP production by T cells. In conclusion, these results demonstrate that endogenously produced SP contributes to T cell proliferation induced by DC or TCR / CD28 stimulation.

Animals↗
PubMed1999

Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells.

Tachykinins such as substance P (SP) may be involved in the pathogenesis of inflammatory airway diseases such as asthma. This study investigated the presence of SP and its receptor in the differentiated macrophage-like U-937 cell line and in macrophages from sputum induced in healthy subjects (n=8). In situ hybridization with digoxigenin-labelled sense and antisense complementary ribonucleic acid (cRNA) probes was used to determine the expression of SP and its receptor (neurokinin (NK)1 receptor). SP-immunoreactive material was detected using a rabbit anti-SP antiserum and the alkaline phosphatase anti-alkaline phosphatase technique. Beta-preprotachykinin (PPT)-I messenger ribonucleic acid (mRNA) encoding SP, was detected using in situ hybridization in differentiated U-937 cells as well as in CD45+ human leukocyte antigen (HLA) DR+ sputum macrophages. The expression of the beta-PPT-I mRNA was increased in lipopolysaccharide (LPS)-stimulated U-937 cells. SP-immunoreactive material was found in differentiated U-937 cells and in CD68+ sputum macrophages. NK1 receptor mRNA was detected in differentiated U-937 cells and sputum macrophages. Incubation of U-937 cells with SP considerably increased the expression of NK1 receptor mRNA. This study demonstrates that human monocytes/macrophages express substance P and that this expression is upregulated by lipopolysacharide. Human monocytes/macrophages also express neurokinin1 receptor messenger ribonucleic acid, suggesting an autocrine effect of substance P on these cells.

Enzyme-Linked Immunosorbent Assay↗