Harald Renz

The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo

The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130-fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25- lung T cells selectively expressed the IL-6R alpha chain and showed IL-6-dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti-IL-6R antibody-treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.

The impact of perinatal immune development on mucosal homeostasis and chronic inflammation

The mucosal surfaces of the gut and airways have important barrier functions and regulate the induction of immunological tolerance. The rapidly increasing incidence of chronic inflammatory disorders of these surfaces, such as inflammatory bowel disease and asthma, indicates that the immune functions of these mucosae are becoming disrupted in humans. Recent data indicate that events in prenatal and neonatal life orchestrate mucosal homeostasis. Several environmental factors promote the perinatal programming of the immune system, including colonization of the gut and airways by commensal microorganisms. These complex microbial–host interactions operate in a delicate temporal and spatial manner and have an important role in the induction of homeostatic mechanisms.

Early identification of atopy in the prediction of persistent asthma in children

The long-term solution to the asthma epidemic is thought to be prevention, and not treatment of established disease. Atopic asthma arises from gene-environment interactions, which mainly take place during a short period in prenatal and postnatal development. These interactions are not completely understood, and hence primary prevention remains an elusive goal. We argue that primary-care physicians, paediatricians, and specialists lack knowledge of the role of atopy in early life in the development of persistent asthma in children. In this review, we discuss how early identification of children at high risk is feasible on the basis of available technology and important for potential benefits to the children. Identification of an asthmatic childs atopic status in early life has practical clinical and prognostic implications, and sets the basis for future preventative strategies.

Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse.

Inhalation of an antigen, ovalbumin (OVA), in the absence of adjuvant has been demonstrated to induce an immune response that is associated with increased airway responsiveness. Determination of OVA-specific serum IgE and IgG antibody responses revealed an early increase in antibody titers that were initially restricted to the IgE class. Subsequently, IgG antibody titers increased and IgE antibody plateaued. Furthermore, we observed a tenfold increase in the number of lymphocytes caused by a predominant expansion of CD3+ T cells in the peribronchial-associated lymph modes (PBLNs) of sensitized animals compared with the numbers of cells in control animals or in the gut-associated lymphoid tissue. The sensitized animals demonstrated an increase in airway responsiveness to intravenous methacholine challenge. Analysis of in vitro immunoglobulin production by spleen mononuclear cells revealed increased spontaneous IgE production that was more than fourfold enhanced in the presence of OVA, but IgG production was not increased. Spleen and PBLN lymphocytes, but not lymphocytes from gut-draining lymph nodes, demonstrated a proliferative response to OVA. Control animals exhibited no proliferative response to OVA. Histopathologic examination of the sensitized lung revealed an absence of acute inflammatory cells (e.g., neutrophils and macrophages), lymphocytes, or monocytes at the time of the increased airway hyperresponsiveness. These data indicate that, after sensitization of mice by inhalation of antigen, the animals develop a specific IgE antibody response, expansion of PBLN lymphocyte numbers, and increased airway hyperresponsiveness in the absence of signs of airway inflammation.

Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78

The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny.

BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model

BACKGROUND Epidemiologic studies suggest an inverse correlation between infections and development of atopy. The purpose of this study was to test the hypothesis whether a preexisting Th1-type immune response elicited by BCG immunization could suppress allergic sensitization and airway hyperreactivity in an animal model. METHODS BALB/c mice were immunized with BCG and/or sensitized to ovalbumin. RESULTS BCG immunization alone resulted in cutaneous type-IV hypersensitivity reactions to tuberculin and granulomatous lesions in the liver. Splenic mononuclear cells (MNCs) produced increased levels of IFN-gamma after activation by Concanavalin A (ConA). Ovalbumin sensitization alone resulted in increased production of IL-4 after activation by ConA. Ovalbumin-sensitized animals also demonstrated markedly elevated anti-ovalbumin IgE/IgG1 serum antibody titers and increased airway reactivity after allergen challenges by means of the airways. BCG immunization 14 days before the start of ovalbumin sensitization markedly hindered the development of allergic responses as indicated by (1) increased IFN-gamma and normalized IL-4 and IL-10 production by splenic MNCs after activation with ConA, (2) a reduced proliferation rate of splenic MNCs after ovalbumin restimulation, (3) partial prevention of ovalbumin-specific IgE/IgG1 serum antibody titers but elevated (nonallergic) anti-ovalbumin IgG2a serum antibody titers, (4) prevention of airway responsiveness, (5) reduced eosinophilic influx into the airway lumen, and (6) reduced levels of IL-4 and IL-5 in broncho alveolar lavage fluids. CONCLUSION In this model BCG immunization established a Th1-type immune response that hinders allergic sensitization and the development of increased airway reactivity.

Prevalence and role of serum IgE antibodies to the StaphylococcuS aureus–derived superantigens SEA and SEB in children with atopic dermatitis

BACKGROUND The skin of patients with atopic dermatitis exhibits a striking susceptibility to colonization and infection with Staphylococcus aureus. In this context it has been previously shown that S aureus-derived superantigens could function as classic allergens, inducing production of functionally relevant specific IgE antibodies. OBJECTIVE The aim of this study was to determine the prevalence and the role of circulating staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE antibodies in children with atopic dermatitis. METHODS In a cross-sectional study of 58 children with atopic dermatitis, the presence of IgE antibodies to SEA and SEB was correlated with the severity of the disease and the total and other unrelated allergen-specific IgE titers and density of colonization with S aureus strains on atopic skin and episodes of superficial S aureus skin infections. RESULTS Twenty of 58 children (34%) were sensitized to superantigens (45% to SEB, 10% to SEA, 45% to SEA and SEB). In this group, severity of atopic dermatitis and levels of specific IgE to food and air allergens were significantly higher. The degree of disease severity correlated to a higher extent with the presence of SEA/SEB-specific antibodies than with total serum IgE levels. Density of colonization with superantigen-secreting S aureus strains was higher in the superantigen IgE-positive group. Sixty-three percent of these children experienced repeated episodes of superficialS aureus skin infections. CONCLUSIONS Sensitization to S aureus-derived superantigens may be involved in disease exacerbation. The presence of SEA/SEB-specific antibodies had additional explanatory value for disease severity and therefore may be helpful in the characterization of children with severe atopic dermatitis.

Prenatal lipopolysaccharide‐exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma

Background Epidemiological evidence underlines the impact of prenatal environmental factors on the development of postnatal allergies. In this regard an inverse correlation between lipopolysaccharide (LPS) exposure and development of childhood allergy has been found.

Perinatal maternal application of Lactobacillus rhamnosus GG suppresses allergic airway inflammation in mouse offspring

Background Clinical studies indicate that maternal exposure to probiotic bacteria may protect from the development of allergic disease later in life.

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.

BACKGROUND The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). METHODS We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1). RESULTS After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo. CONCLUSIONS Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).