A Avagyan

Charité Universitätsmedizin Berlin, Berlin, Land Berlin, Germany

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Publications (13)56.26 Total impact

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    ABSTRACT: Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-γ and IL-10. Further, maternal OVA exposures were associated with development of CD25(+) Foxp3(+) regulatory T cells (T(regs)) in the OVA-sensitized offspring. Depletion of T(regs) or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. In our model, maternal allergen exposures during pregnancy prevented later allergen-mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring.
    Allergy 03/2012; 67(3):353-61. · 5.88 Impact Factor
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    ABSTRACT: Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways. The aim of this study was to identify possible mediators of airway inflammation (AI) in a model of allergic AI via microarray comparisons and to analyse one of these mediators, Lipocalin2 (Lcn2), for its role in a murine model of allergic airway disease. Gene microarrays were used to identify genes with at least a twofold increase in gene expression in the lungs of two separate mouse strains with high and low allergic susceptibility, respectively. Validation of mRNA data was obtained by Western blotting, followed by functional analysis of one of the identified genes, Lcn2, in mice with targeted disruption of specific gene expression. Epithelial cell cultures were undertaken to define induction requirements and possible mechanistic basis of the results observed in the Lcn2 knock-out mice. Lcn2 was up-regulated upon allergen sensitization and airway challenges in lung tissues of both mouse strains and retraced on the protein level in bronchoalveolar lavage fluids. Functional relevance was assessed in mice genetically deficient for Lcn2, which showed enhanced airway resistance and increased AI associated with decreased apoptosis of lung inflammatory cells, compared with wild-type controls. Similarly, application of Lcn2-blocking antibodies before airway challenges resulted in increased inflammation and reduced apoptosis. These data indicate a protective role for Lcn2 in allergic airway disease, suggesting a pro-apoptotic effect as the underlying mechanism.
    Clinical & Experimental Allergy 11/2010; 40(11):1689-700. · 4.79 Impact Factor
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    ABSTRACT: Some helminth infections are negatively associated with the prevalence of allergic disorders, arguing for a modulation of allergic reactions by the parasites, depending on the worm species, intensity and phase of infection and the type of disease. The aim of this study was to analyse the influence of a chronic infection with the gastrointestinal nematode Heligmosomoides polygyrus, in a murine model of allergic airway disease and of atopic dermatitis (AD), respectively. Mice were infected with H. polygyrus and systemically sensitized with the model allergen ovalbumin. Subsequently, the animals were challenged with the allergen either via the airways for induction of airway disease, or via skin patches for induction of dermatitis. Mice concomitantly infected with H. polygyrus showed diminished eosinophil and lymphocyte recruitment into the lungs and decreased allergen-specific IgE levels when compared with sensitized and airway challenged controls. In addition, animals showed a trend towards reduced airway hyper-reactivity. In contrast, no significant differences in the severity of eczematous skin lesions were observed between infected and control animals in the AD model. Although H. polygyrus infection reduced CD8+ and CD4+ T-cell infiltration into the skin and production of allergen-specific IgE, mast cell recruitment was significantly increased in worm-infected mice in the dermatitis model. The worm infection was associated with significantly elevated numbers of Foxp3+ regulatory T cells (Treg) in peribronchial lymph nodes in H. polygyrus-infected sensitized and airway challenged mice. In contrast, Treg cells were basically absent in eczematous skin and their number was not increased in skin-draining lymph nodes of mice with experimental dermatitis. Infection with the gastrointestinal nematode used in our study leads to significant inhibition of mucosa-associated but not cutaneous allergic reactions, pointing to a site specificity of the immunomodulation exerted by helminths. This finding might be an important aspect for future considerations of helminths for treatment of allergic diseases.
    Clinical & Experimental Allergy 07/2009; 39(10):1585-96. · 4.79 Impact Factor
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    ABSTRACT: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days -21, -14, -7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28-30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and -challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-gamma-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA-pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction.
    International Archives of Allergy and Immunology 05/2008; 147(1):25-34. · 2.25 Impact Factor
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    ABSTRACT: The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.
    The Journal of Immunology 04/2008; 180(6):4265-72. · 5.52 Impact Factor
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    ABSTRACT: Numerous epidemiological studies have shown an inverse correlation between helminth infections and the manifestation of atopic diseases, yet the immunological mechanisms governing this phenomenon are indistinct. We therefore investigated the effects of infection with the filarial parasite Litomosoides sigmodontis on allergen-induced immune reactions and airway disease in a murine model of asthma. Infection with L. sigmodontis suppressed all aspects of the asthmatic phenotype: Ag-specific Ig production, airway reactivity to inhaled methacholine, and pulmonary eosinophilia. Similarly, Ag-specific recall proliferation and overall Th2 cytokine (IL-4, IL-5, and IL-3) production were significantly reduced after L. sigmodontis infection. Analysis of splenic mononuclear cells and mediastinal lymph nodes revealed a significant increase in the numbers of T cells with a regulatory phenotype in infected and sensitized mice compared with sensitized controls. Additionally, surface and intracellular staining for TGF-beta on splenic CD4(+) T cells as well as Ag-specific TGF-beta secretion by splenic mononuclear cells was increased in infected and sensitized animals. Administration of Abs blocking TGF-beta or depleting regulatory T cells in infected animals before allergen sensitization and challenges reversed the suppressive effect with regard to airway hyperreactivity, but did not affect airway inflammation. Despite the dissociate results of the blocking experiments, these data point toward an induction of regulatory T cells and enhanced secretion of the immunomodulatory cytokine TGF-beta as one principle mechanism. In conclusion, our data support the epidemiological evidence and enhance the immunological understanding concerning the impact of helminth infections on atopic diseases thus providing new insights for the development of future studies.
    The Journal of Immunology 03/2008; 180(3):1792-9. · 5.52 Impact Factor
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    ABSTRACT: Infection with influenza virus has been associated with seemingly opposing effects on the development of asthma. However, there are no data about the effects of mucosal vaccination with inactivated influenza on the inception of allergic asthma. To assess the immunological effects of inhaled inactivated influenza vaccine, using two different types of flu vaccines, on the inception of allergic sensitization and allergen-mediated airway disease in a mouse model. BALB/c mice were intranasally or intratracheally vaccinated with whole or split influenza virus vaccine (days -1 or -1, 27) before systemic sensitization with ovalbumin (OVA) (days 1, 14) and repeated airway allergen challenges (days 28-30). Allergen sensitization (IgE serum levels), airway inflammation (differential cells in bronchoalveolar lavage fluid) and airway hyper-reactivity (AHR) (in vivo lung function) were analysed. The intranasal instillation of whole influenza vaccine before allergen sensitization significantly reduced the serum levels of total and OVA-specific IgE as well as allergen-induced AHR. Prevention was due to an allergen-specific shift from a predominant T helper (Th)2- towards a Th1-immune response. Application of split influenza vaccine did not show the same preventive effect. Intranasal administration of inactivated whole influenza vaccine reduced subsequent allergen sensitization and prevented allergen-induced AHR. Our results show that the composition of the influenza vaccine has a major influence on subsequent development of allergen-induced sensitization and AHR, and suggest that mucosal inactivated whole influenza vaccination may represent a step towards the development of a preventive strategy for atopic asthma.
    Clinical & Experimental Allergy 09/2007; 37(8):1250-8. · 4.79 Impact Factor
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    ABSTRACT: Microbial intestinal colonization in early in life is regarded to play a major role for the maturation of the immune system. Application of non-pathogenic probiotic bacteria during early infancy might protect from allergic disorders but underlying mechanisms have not been analysed so far. The aim of the current study was to investigate the immune effects of oral application of probiotic bacteria on allergen-induced sensitization and development of airway inflammation and airway hyper-reactivity, cardinal features of bronchial asthma. Newborn Balb/c mice received orally 10(9) CFU every second day either Lactobacillus rhamnosus GG or Bifidobacterium lactis (Bb-12) starting from birth for consecutive 8 weeks, during systemic sensitization (six intraperitoneal injections, days 29-40) and airway challenge (days 54-56) with ovalbumin. The administration of either Bb-12 or LGG suppressed all aspects of the asthmatic phenotype: airway reactivity, antigen-specific immunoglobulin E production and pulmonary eosinophilia (mean: 137 vs. 17 and 13 cellsx10(3)/mL, respectively). Antigen-specific recall proliferation by spleen cells and T-helper type 2 cytokine production (IL-4, IL-5 and IL-10) by mesenteric lymph node cells also showed significant reduction, while TGF production remained unchanged. Oral LGG administration particularly suppressed allergen-induced proliferative responses and was associated with an increase in numbers of TGF-beta-secreting CD4+/CD3+ T cells in mesenteric lymph nodes (6.5, 16.7%) as well as nearly 2-fold up-regulation of Foxp3-expressing cells in peribronchial lymph nodes. Neonatal application of probiotic bacteria inhibits subsequent allergic sensitization and airway disease in a murine model of asthma by induction of T regulatory cells associated with increased TGF-beta production.
    Clinical & Experimental Allergy 05/2007; 37(4):498-505. · 4.79 Impact Factor
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    ABSTRACT: 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. Using a mouse model, we investigated the influence of prenatal LPS exposure on later allergen-mediated sensitization and airway inflammation in the offspring. 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. 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. 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. Immunomodulation with bacterial compounds during gestation time might be an effective mode for first-step primary prevention against allergic diseases.
    Journal of Allergy and Clinical Immunology 10/2006; 118(3):666-73. · 12.05 Impact Factor
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    ABSTRACT: Co-vaccination with cellular pertussis vaccine down-regulates allergic sensitization to diphtheria and tetanus antigens. Using a murine model, we investigated whether vaccination with diphtheria/tetanus toxoids, administered separately or simultaneously with the whole cell vaccine of Bordetella pertussis, inhibits subsequent allergen-induced immune and inflammatory responses. BALB/c-mice were vaccinated intracutaneously with a combination of diphtheria and tetanus toxoids or a combination of diphtheria and tetanus toxoids with a whole cell vaccine of B. pertussis (three times, days -21 to -7) prior to systemic sensitization (days 1-14) and repeated airway challenges (days 28-30) with ovalbumin. Compared with negative controls, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, airway inflammation and development of in vivo airway hyperreactivity. Vaccination with diphtheria and tetanus toxoids prior to sensitization suppressed IgE formation and development of eosinophilic airway inflammation. Co-vaccination with a whole cell pertussis vaccine inhibited allergen sensitization, airway inflammation and development of in vivo airway hyperreactivity. Prevention was due to an allergen-specific and general shift from a predominant Th2 towards a predominant Th1 immune response. Vaccination with diphtheria and tetanus toxoids alone or in combination with whole cell pertussis vaccine prior to allergen sensitization prevented allergen-induced Th2 immune responses. Vaccine antigens may down-regulate allergic responses to a range of common allergens.
    Allergy 08/2006; 61(7):820-7. · 5.88 Impact Factor
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    ABSTRACT: BACKGROUND: Numerous studies suggested that microbial gut colonization in the early in life is believed to be crucial for healthy maturation of the immune system and that application of non-pathogenic probiotic bacteria during an early infancy might be helpful in inhibition of allergic disorders; however the immunological basis of this phenomenon was not intensively studied so far. In this study we investigated the effects of oral application of probiotic bacteria on allergen-induced immune reactions and airway disease in a murine model of asthma. METHODS: Balb/c mice received orally 109 CFU either Lactobacillus rhamnosus GG (LGG) or Bifidobacterium bifidum (Bb-12) starting from birth for consecutive 8 weeks. Induction of the asthmatic phenotype was achieved via six ip injections (days 29 – 39) and three inhalatory challenges (day 54-56) with ovalbumin (OVA). To delineate the allergic immune reaction, airway reactivity (body plethysmography, day 57), systemic sensitization (antigen-specific serum immunoglobulins, antigen-specific proliferation, cytokine production and lymphocyte phenotyping) and pulmonary inflammation (bronchoalveolar lavage cell differentiation) (day 58) were analyzed. RESULTS: Application of either LGG of Bb-12 suppressed all aspects of the asthmatic phenotype: airway reactivity to inhaled methacholine was decreased by appoximately 1/2, antigen-specific immunoglobulin production was suppressed by 15 fold (IgE) and pulmonary eosinophilia was markedly reduced. Antigen-specific recall proliferation and Th2 cytokine production (IL-4, IL-5, IL-10) by spleen cells also showed significant reduction. Flow cytometry analysis of spleen cells showed an increase in numbers of regulatory T cells (CD4+/CD62high/CD25+) in treated and sensitized mice compared to positive controls while splenocyte intracellular IL-10 staining was also increased in probiotic-treated animals. Simultaneously, mitogen-induced proliferative responses was increased in mesenteric lymph nodes of probiotic-treated animals and flow cytometry analysis of these cells showed an increase in numbers of TGF-β-secreting CD4+/CD3+ T cells. Taken together, these results suggest that the alteration of the allergic phenotype was due to generalized immune modulation rather than an allergen-specific mechanism with enhanced proliferation of T regulatory cells. CONCLUSIONS: Neonatal application of probiotic microorganisms downregulates subsequent allergic sensitization and airway disease by induction of T regulatory cells and increasing TGF-β production.
    Conference proceedings. 06/2006;
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2006; 117(2).
  • Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2005; 115(2).

Publication Stats

334 Citations
56.26 Total Impact Points


  • 2006–2012
    • Charité Universitätsmedizin Berlin
      • • Department of Pediatrics, Division of Pneumonology and Immunology
      • • Charité Allergy Center
      Berlin, Land Berlin, Germany
  • 2009
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2007
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States