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Eckard Hamelmann

Publications and source records attributed to Eckard Hamelmann.

At least 19 recordsLinked to original sources
PubMed2006

Prenatal stress enhances susceptibility of murine adult offspring toward airway inflammation.

Allergic asthma is one of the most prevalent and continuously increasing diseases in developed countries. Its clinical features include airway hyperresponsiveness and inflammation upon allergen contact. Furthermore, an emerging area of research subsumed as fetal programming evaluates the impact of environmental insults in utero on the incidence of diseases in later life. The aim of this study was to identify whether prenatal exposure to stress, which constitutes a severe environmental insult, perpetuates airway inflammation in later life. Our experiments were performed in mice and revealed that prenatally stressed adult offspring indeed show an increased vulnerability toward airway hyperresponsiveness and inflammation. Furthermore, we provide persuasive insights on dysregulated pathways of the cellular and humoral immune response upon Ag challenge in prenatally stressed adult offspring, reflected by a Th2 greater Th1 adaptive immune response and increased CCR3 and IgE levels in vivo. Additionally, APCs derived from prenatally stressed offspring trigger clonal expansion of Th2 cells in vitro. We also deliver experimental evidence for a reduced corticotrophin-releasing hormone expression in the paraventricular nucleus of adult offspring in response to prenatal stress. Furthermore, behavioral analyses indicate an increase in anxiety in these mice. In conclusion, our data will facilitate future research aiming to identify the individual impact, hierarchy, and redundancy of multiple key protagonists in airway inflammation in an interdisciplinary context. This will foster the substantiation of disease-prevention strategies, such as asthma, during the prenatal period.

Animals↗
PubMed2006

Effects of established allergen sensitization on immune and airway responses after secondary allergen sensitization.

BACKGROUND: Spreading of sensitization with clinical manifestation of allergy is often observed in atopic individuals. OBJECTIVE: To investigate the effects of an established primary allergen sensitization on immune responses and airway inflammation/reactivity on secondary allergen sensitization and airway challenges in a murine model. METHODS: Balb/c mice were primarily sensitized intraperitoneally with ovalbumin or PBS, followed by systemic sensitization and airway challenges with latex extract as a secondary, unrelated allergen. Purely sham-sensitized animals were included as controls. In a second set of experiments, the primary and secondary allergens were switched. RESULTS: Sensitization with ovalbumin before sensitization with latex resulted in increased production of total and latex-specific (Hev b 3-specific) IgE and IgG(1), and enhanced secretion of T(H)2-cytokines by spleen mononuclear cells cultured with mitogen compared with single latex-sensitized mice. Furthermore, airway challenges of double-sensitized mice (ovalbumin + latex) with latex caused a significant increase in airway reactivity compared with purely latex-sensitized and challenged animals. These effects were dependent on dosing and timing of the primary sensitization in relation to the secondary sensitization and independent of the primary allergen used. CONCLUSION: Primary sensitization boosted systemic T(H)2 immune responses and enhanced the development of airway reactivity after sensitization and airway challenges with a secondary, unrelated allergen. This effect of consecutive priming was dependent on the strength of the primary sensitization but independent of the allergen used. The results explain the increased susceptibility toward sensitization spreading in atopic individuals. CLINICAL IMPLICATIONS: Because sensitization spreading is facilitated by primary sensitization, early prevention measurements or immunotherapy should be considered at this stage of monosensitization.

Allergens↗
PubMed2006

Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice.

BACKGROUND: New preventive strategies against the development of allergic diseases focus on potentially immunomodulatory components, such as bacterial LPSs. Optimal time frames for initiating immunomodulation to receive a sufficient effect against allergen sensitization are still unclear. OBJECTIVE: Using a mouse model, we investigated the influence of prenatal LPS exposure on later allergen-mediated sensitization and airway inflammation in the offspring. METHODS: Pregnant BALB/c mice were repeatedly exposed to aerosolized LPS (LPS Escherichia coli; 3x per week, day 7 of gestation time up to delivery). Some of the offspring were further exposed to aerosolized LPS before allergen sensitization with ovalbumin (OVA; administered intraperitoneally day 28 up to day 42) and OVA airway challenges (days 56-58). Positive control animals were placebo exposed to PBS instead of LPS, and negative control animals were first placebo exposed and later placebo sensitized with PBS instead of OVA. RESULTS: Compared with positive control animals, prenatal LPS exposure suppressed (1) allergen-specific sensitization (IgE production), (2) eosinophilic airway inflammation (reduced numbers of eosinophils in bronchoalveolar lavage fluids), and (3) in vivo airway reactivity in response to methacholine. These effects occurred only when prenatal was combined with further postnatal LPS exposure. Suppression of allergen-mediated inflammatory responses was associated with increased Toll-like receptor and T-bet expression by lung tissues and a shift toward predominantly T(H)1 immune responses in spleen cells cultured with OVA in vitro. CONCLUSION: Prenatal initiated and postnatal sustained LPS exposure increased endotoxin susceptibility and prevented later allergen sensitization in offspring through inhibition of T(H)2 immune responses. CLINICAL IMPLICATIONS: Immunomodulation with bacterial compounds during gestation time might be an effective mode for first-step primary prevention against allergic diseases.

Aerosols↗
PubMed2006

Detection of allergen-induced airway hyperresponsiveness in isolated mouse lungs.

Airway hyperresponsiveness (AHR) is a hallmark of bronchial asthma. Important features of this exaggerated response to bronchoconstrictive stimuli have mostly been investigated in vivo in intact animals or in vitro in isolated tracheal or bronchial tissues. Both approaches have important advantages but also certain limitations. Therefore, the aim of our study was to develop an ex vivo model of isolated lungs from sensitized mice for the investigation of airway responsiveness (AR). BALB/c mice were sensitized by intraperitoneal ovalbumin (Ova) and subsequently challenged by Ova inhalation. In vivo AR was measured in unrestrained animals by whole body plethysmography after stimulation with aerosolized methacholine (MCh) with determination of enhanced pause (P(enh)). Twenty-four hours after each P(enh) measurement, airway resistance was continuously registered in isolated, perfused, and ventilated lungs on stimulation with inhaled or intravascular MCh or nebulized Ova. In a subset of experiments, in vivo AR was additionally measured in orotracheally intubated, spontaneously breathing mice 24 h after P(enh) measurement, and lungs were isolated further 24 h later. Isolated lungs of allergen-sensitized and -challenged mice showed increased AR after MCh inhalation or infusion as well as after specific provocation with aerosolized allergen. AR was increased on days 2 and 5 after Ova challenge and had returned to baseline on day 9. AHR in isolated lungs after aerosolized or intravascular MCh strongly correlated with in vivo AR. Pretreatment of isolated lungs with the beta(2)-agonist fenoterol diminished AR. In conclusion, this model provides new opportunities to investigate mechanisms of AHR as well as pharmacological interventions on an intact organ level.

Allergens↗
PubMed2006

Toll-like receptors--novel targets in allergic airway disease (probiotics, friends and relatives).

Experimental and epidemiological studies enabled to hypothesize that stimulation of the immune system by selected microbial products may prevent or treat allergic diseases. According to recent advances in molecular immunology, this stimulation acts via group of conserved receptors present on antigen presenting cells, known as toll-like receptors (TLRs). These receptors play an essential role in antigen presentation and latter development of immune response into pro-allergic (Th2), cellular (Th1) or regulatory (Tr1) responses. Since toll-like receptors govern decisive points in immune regulation, an extensive research focuses on agents interfering with their immunomodulatory activities. In this report, we review information on the potential use of microbial products in allergy prevention and therapy, which are believed to target toll-like receptor network. Current toll-like receptor-based approaches, as well as potential use of lipopolysaccharide (and derivates), oligonucleotides, mycobacteria, bacterial extracts, and probiotics are discussed herein.

Animals↗
PubMed2005

Parental tobacco smoking is associated with augmented IL-13 secretion in children with allergic asthma.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) has been shown to increase symptoms of allergic bronchial asthma, but direct effects on the expression of inflammatory markers have not been demonstrated thus far. OBJECTIVE: The aim of this study was to assess the correlation of ETS exposure with the expression of proinflammatory mediators in airway secretions, including IFN-gamma and IL-12, as well as IL-5 and IL-13, in allergic asthmatic schoolchildren and healthy control subjects. METHODS: By using the nasopharyngeal aspiration technique, airway secretions were collected from 24 atopic children with asthma (age, 6-16 years) and 26 healthy control subjects, and the concentration of cytokines was measured with immunoenzymatic methods. RESULTS: IL-13 levels were highly increased in patients with asthma (P < .005), and parental tobacco smoke resulted in a significant increase in airway IL-13 secretion in these children compared with that seen in nonexposed children and healthy control subjects (median, 860 pg/mL vs 242 pg/mL and 125 pg/mL, respectively). Furthermore, a positive correlation between IL-13 levels and serum IgE concentrations (r(s) = 0.55) was found in children with allergic asthma. CONCLUSIONS: These results indicate that ETS augments the expression and secretion of IL-13 in allergic asthma and that nasopharyngeal aspiration is a suitable method to assess cytokine measurements in airways in children. Measurements of IL-13 in secretions might be taken into account as a noninvasive marker of airway inflammation and to assess the detrimental effects of ETS.

Adolescent↗
PubMed2005

T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies.

Current treatment for chronic allergic airway disease with anti-inflammatory agents is effective but not specific, and is symptomatic rather than curative. The present review article outlines the involvement of T cells by dissecting the various steps in which naive CD4+ T cells differentiate to allergen-specific, activated T cells of the TH2 type, which play a pivotal role in the pathogenesis of chronic allergic airway disease. Aiming at a concept for a highly specific therapy of this disease, various T cell costimulatory molecules (CD28, CD27, HVAM, BTLA, ICOS, OX40, CD30, 4-1BB, SLAM, CTLA-4, and PD-1) and the non-costimulatory molecule CD40L, all of them expressed on activated TH2 effector T cells, are discussed as potential targets for an antibody-based therapy. Considering various criteria, including T-cell specific expression and expression characteristics on resting versus activated T cells, reasons are given why ICOS and OX40 can be regarded as optimal targets for such an immunotherapy. Furthermore, arguments are put forward that strongly favor an immunodepletion strategy as compared to an immunoblockade approach, when heading for a specific, long-lasting therapy of chronic allergic airway disease.

Antibodies, Monoclonal↗
PubMed2005

Mothers in stress: consequences for the offspring.

No memories exist on one's time before birth. However, this does not imply that the developing fetus is not susceptible to external impulses. On the contrary, the fetus is extremely vulnerable e.g. to environmental challenges, and a wealth of data reveals that conditions in utero affect the health of the fetus before and after birth. Threats for the growing fetus include psychological challenges perceived by the mother, e.g. high levels of stress during pregnancy. However, stress experienced during pregnancy not only leads to pregnancy complications like miscarriage, pre-eclampsia, preterm parturition, low birth weight or major congenital malformations, stress also increases the risk of the child to develop diseases in the subsequent periods of life. This condition is termed fetal programming of adult disease. Programming agents seem to include growth factors, cytokines and hormones, all of which can be altered by stress. As a consequence, such 'stress-modified' systems of the offspring are more susceptible to environmental influences during later life, e.g. the development of atopic diseases upon exposure to antigens. The present review illuminates the complexity of stress perception on fetal programming focusing predominately on the onset of atopic diseases on the background of published evidence from immunology, endocrinology, neurobiology and neonatology.

Animals↗
PubMed2005

Anti-IgE therapy in allergic asthma.

Despite the advanced and increasing understanding of the pathophysiology of asthma and other allergic diseases, current treatment remains unspecific and targets late events within the allergic cascade. Therefore, a novel and promising approach to treat allergic asthma is antagonizing IgE by anti-IgE antibodies. This review analyzes the role of IgE for the pathology of asthma, summarize the current data about action, safety and efficacy of anti-IgE therapy, and tries to give a rational approach for future indications and directions of treatment with anti-IgE antibodies.

Antibodies, Anti-Idiotypic↗
PubMed2004

CD8(+) T cells regulate immune responses in a murine model of allergen-induced sensitization and airway inflammation.

The role of CD8(+) T cells in the development of allergic airway disease is controversial. On the one hand, CD8(+) T cells are known to inhibit the development of airway hyperreactivity (AHR) in murine models of asthma. In humans, IL-10-producing CD8(+) T cells were shown to act as regulatory cells, inhibiting both proliferation and cytokine secretion of T cells. On the other hand, CD8(+) T cells can promote IL-5-mediated eosinophilic airway inflammation and the development of AHR in animal models. To examine this, we investigated the role of CD8(+) T cells during the induction of allergen-induced AHR and demonstrated a protective effect of CD8(+) T cells. Depletion of CD8(+) T cells prior to the immunization led to increased Th2 responses and increased allergic airway disease. However, after development of AHR, CD8(+) T cells that infiltrated the lungs secreted high levels of IL-4, IL-5 and IL-10, but little IFN-gamma, whereas CD8(+) T cells in the peribronchial lymph nodes or spleen produced high levels of IFN-gamma, but little or no Th2 cytokines. These data demonstrate protective effects of CD8(+)T cells against the induction of immune responses and show a functional diversity of CD8(+) T cells in different compartments of sensitized mice.

Allergens↗
PubMed2004

Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity.

BACKGROUND: Transcriptional factors of the signal transducer and activator of transcription (STAT) family play an important role in orchestrating immune reactions. OBJECTIVE: The aim of the current study was to investigate the role of STAT-1 in murine allergen-induced sensitization and development of airway inflammation (AI) and airway hyperreactivity (AHR), cardinal features of bronchial asthma. METHODS: BALB/c mice were systemically sensitized to ovalbumin and challenged with ovalbumin through the airways. Decoy oligonucleotide (ODN) specific for STAT-1 was applied once locally to the airways of sensitized animals before allergen airway challenges. RESULTS: Single application of decoy ODN markedly and significantly reduced numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids compared with those seen in sensitized and challenged animals receiving mutant control ODN. Associated with this decrease in eosinophilic AI were significantly reduced levels of IL-5 in BAL fluid, of CD40 expression in peribronchial infiltrates, and of vascular cell adhesion molecule 1 expression in vascular endothelial cells, respectively. In addition, development of AHR after allergen sensitization and airway challenges was effectively abolished after local STAT-1 decoy ODN treatment. CONCLUSION: The data indicate that a decoy ODN neutralizing STAT-1 effectively inhibits allergen-induced AI and AHR, probably by attenuating upregulation of costimulatory and adhesion molecules, and suggest a significant role of STAT-1 in asthma pathology.

Allergens↗
PubMed2004

Inducible costimulator-positive T cells are required for allergen-induced local B-cell infiltration and antigen-specific IgE production in lung tissue.

BACKGROUND: Airway inflammation plays a critical role in the pathogenesis of asthma. In susceptible individuals, airway allergen exposure results in the recruitment of inflammatory cells into lung tissue, leading to a local inflammatory response. Central to the induction and regulation of this process are T lymphocytes. OBJECTIVE: Blocking of the newly discovered costimulatory T-cell molecule inducible costimulator (ICOS) with monoclonal antibodies was shown to ameliorate allergic airway inflammation in models of murine asthma. Although these observations indirectly support an association between ICOS and the development of allergic inflammation, the role of the ICOS + T cell in the pathogenesis of allergic airway disease remains unclear. METHODS: We used an adoptive transfer model to analyze further the role of antigen-specific ICOS + T cells during the effector phase of allergic airway inflammation. In vitro stimulated CD4 + T cells from mice transgenic for an ovalbumin-specific T-cell receptor (DO11.10) were sorted into ICOS-enriched and ICOS-depleted T-cell fractions and transferred into BALB/c recipient mice. RESULTS: Transfer of the ICOS-enriched T-cell population followed by allergen airway challenges induced pronounced infiltration of recipient T and B cells and local production of allergen-specific IgE by intrapulmonary plasma cells. In contrast, transfer of the ICOS-depleted T-cell fraction resulted in the recruitment of significantly lower numbers of B cells and no local IgE production. CONCLUSION: These data indicate that expression of ICOS defines a subset of T effector cells that are required for B-cell infiltration and local IgE production in lung tissues on allergen airway exposure.

Allergens↗
PubMed2004

Anti-IgE therapy.

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Antibodies, Anti-Idiotypic↗
PubMed2003

Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10.

The studies performed to date analyzed the overall participation of the inducible costimulator (ICOS) in model diseases, but did not yield information on the nature and function of ICOS-expressing T cells in vivo. We examined ICOS(+) T cells in the secondary lymphoid organs of nonmanipulated mice, in the context of an "unbiased" immune system shaped by environmental antigens. Using single cell analysis, ICOS(low) cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma. ICOS(medium) cells, the large majority of ICOS(+) T cells in vivo, were very tightly associated with the synthesis of the T helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatory effects in vivo. In contrast, ICOS(high) T cells were highly and selectively linked to the anti-inflammatory cytokine IL-10. Overall, these data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties. Further in vivo functional experiments with in vitro-activated T cells strongly suggested that the ICOS(+) population, although representing in vivo only around 10% of T cells bearing early or late activation markers, nevertheless encompasses virtually all effector T cells, a finding with major diagnostic and therapeutic implications.

Adoptive Transfer↗
PubMed2003

Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice.

BACKGROUND: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. OBJECTIVE: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. METHODS: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. RESULTS: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 +/- 0.09 vs 0.02 +/- 0.01 OD units), predominant T(H)2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 +/- 0.2 vs 0.04 +/- 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 +/- 15 vs 64 +/- 7/microL; eosinophils, 28 +/- 5 vs 1 +/- 0/microL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 +/- 1.9 vs 4 +/- 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 +/- 10 vs 32 +/- 5 U/mL) but failed to prevent T(H)2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T(H)2 and T(H)1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T(H)1 immune response. CONCLUSION: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens.

Aerosols↗
PubMed2003

Is there a role for anti-IgE in combination with specific allergen immunotherapy?

PURPOSE OF REVIEW: A line of novel therapeutic approaches that try to interfere more specifically with the immunological mechanisms underlying allergen-induced pathology are currently undergoing clinical evaluation. The most advanced of these is anti-IgE, which directly targets IgE serum antibodies, thus inhibiting the central mechanism of immediate type hypersensitivity reactions. In addition, a lot of interest has recently been focused on allergen-specific immunotherapy due to its potential to cure allergic diseases. In the present review, state-of-the-art treatment of allergic diseases with anti-IgE and allergen-specific immunotherapy is summarized, and the potential of combination therapy with both treatment options is discussed. RECENT FINDINGS: Application of anti-IgE antibodies effectively reduces IgE serum levels regardless of allergen specificity. This treatment has been successfully tested in patients with allergic rhinitis, asthma and food allergy, showing significant efficacy in reducing symptom scores and rescue medication use. Anti-IgE therapy is limited by high costs and the necessity for permanent or every-season treatment. The strongest argument in favor of allergen-specific immunotherapy is the potential to cure allergic diseases, which has been demonstrated in patients with allergic rhinitis, insect venom allergy and, to a lesser degree, asthma. The broader application of allergen-specific immunotherapy is restricted by sometimes life-threatening side effects. A combination of anti-IgE and allergen-specific immunotherapy was shown to be superior to each single treatment protocol in children and adolescents with allergic rhinitis, as demonstrated by efficacy of symptom scores and rescue medication use. SUMMARY: There are strong arguments for a combination of anti-IgE plus allergen-specific immunotherapy for treatment of allergic diseases: improved efficacy, limited side effects, and potential curative effects.

Antibodies, Anti-Idiotypic↗