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Papers by Eric Brandt

Journal of Allergy and Clinical Immunology, 2015

Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), ... more Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. DEP coexposure with HDM resulted in persistent TH2/TH17 CD127(+) effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased TH2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. These findings suggest that DEP exposure results in accumulation of allergen-specific TH2/TH17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.

Journal of Allergy and Clinical Immunology, 2015

The association between air pollution, including traffic emissions, and increased risk for respir... more The association between air pollution, including traffic emissions, and increased risk for respiratory disease is now widely accepted and may contribute to the dramatic increase in the incidence of asthma in industrialized countries. Allergic asthma is generally regarded as a Th2 disease; however several asthma subgroups have been identified based on different inflammatory profiles including eosinophilic asthma, neutrophilic asthma and mixed neutrophilic/eosinophilic a s t h m a . Neutrophilic i n f l a m m a t i o n i s a hallmark of Th17 responses and mounting evidence suggest a role for Th17 cells in asthma 1 . Indeed, expression levels of IL-17A and IL-17F in human lungs have not only been associated with neutrophilia but also correlate with AHR severity 2 . However, IL-17A delivery or transfer of Th17 cells is not sufficient to induce AHR. Thus, Th17 cells appear to promote disease in the context of allergeninduced Th2 responses.

The Journal of allergy and clinical immunology, 2013

IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A pr... more IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEPs) are a major component of traffic-related air pollution and are implicated in asthma pathogenesis and exacerbation. We sought to determine the mechanism by which DEP exposure affects asthma severity using human and mouse studies. BALB/c mice were challenged with DEPs with or without house dust mite (HDM) extract. Airway inflammation and function, bronchoalveolar lavage fluid cytokine levels, and flow cytometry of lung T cells were assessed. The effect of DEP exposure on the frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma. In mice exposure to DEPs alone did not induce asthma. DEP and HDM coexposure markedly enhanced airway hyperresponsiveness compared with HDM exposure alone and generated a mixed T(H)2 and T(H)17 response, including IL-1...

Clinical & Experimental Allergy

Epidemiologic studies have reported an association between diesel exhaust particle (DEP) exposure... more Epidemiologic studies have reported an association between diesel exhaust particle (DEP) exposure, allergic sensitization, and childhood wheezing, although the mechanisms remain unclear. While DEP is known to augment allergic responses in adult animal models, its effects on sensitization and asthma severity in young animals is unknown. To examine the impact of different doses of DEP and allergen co-exposure on allergic sensitization and asthma characteristics in young mice, and whether Th17 as well as Th2 responses are induced. 3-week-old wild-type Balb/c mice were exposed 9 times over 3 weeks to DEP at 1.2mg/kg or 6.0mg/kg body weight, house dust mite (HDM) at 0.8mg/kg, 1.2mk/kg or 6.0mg/kg of DEP in combination with HDM, or the same volume (50μl) of 0.9% sterile saline RESULTS: In young mice, exposure to 1.2mg/kg of DEP caused no detectable lung inflammation, but 6.0mg/kg of DEP induced neutrophilic influx. Compared to HDM or DEP alone, mice exposed to either dose of DEP together ...

PLOS ONE, 2012

Background: Diesel exhaust particle (DEP) exposure enhances allergic inflammation and has been li... more Background: Diesel exhaust particle (DEP) exposure enhances allergic inflammation and has been linked to the incidence of asthma. Oxidative stress on the thiol molecules cysteine (Cys) and glutathione (GSH) can promote inflammatory host responses. The effect of DEP on the thiol oxidation/reduction (redox) state in the asthmatic lung is unknown.

Journal of immunology (Baltimore, Md. : 1950), 2013

Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly und... more Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant because the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis. MyD88, TLR4, or Toll-IL-1R domain-containing adapter-inducing IFN-β (TRIF)-deficient and wild-type mice were epicutaneously exposed to Aspergillus fumigatus allergen over 3 wk. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of atopic dermatitis, TEWL, allergic sensitization, and epidermal thickness were increased following cutaneous allergen exposure, and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL-1β, TNF-α, and CXCL2) and Th17 genes (IL...

Journal of clinical & cellular immunology, Jan 10, 2011

Atopic dermatitis (AD), a chronic relapsing inflammatory skin disease, is increasing in prevalenc... more Atopic dermatitis (AD), a chronic relapsing inflammatory skin disease, is increasing in prevalence around the world. Intensive research is ongoing to understand the mechanisms involved in the development of AD and offer new treatment options for patients suffering from AD. In this review, we highlight the importance of allergic Th2 responses in the development of the disease and summarize relevant literature, including genetic studies, studies of human skin and mechanistic studies on keratinocytes and mouse models of AD. We discuss the importance of the skin barrier and review recent findings on the pro-Th2 cytokines TSLP, IL-25, and IL-33, notably their ability to polarize dendritic cells and promote Th2 responses. After a brief update on the contribution of different T-cell subsets to AD, we focus on Th2 cells and the respective contributions of each of the Th2 cytokines (IL-4, IL-13, IL-5, IL-31, and IL-10) to AD. We conclude with a brief discussion of the current gaps in our kno...

The Journal of allergy and clinical immunology

Asthma is a major public health burden worldwide. Studies from our group and others have demonstr... more Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined. To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma. We studied wild-type Balb/c and Serpinb3a-null mice in house dust mite or IL-13-induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia. Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a-null mice compared with the wild-type mice after allergen challenge, with minimal effects on inflammation. Expression of sterile alpha motif pointed domain containing v-ets avian erythroblastosis virus E26 oncogene homolog transcription factor (SPDEF), a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13-treated Serpinb3a-null mi...

Journal of Allergy and Clinical Immunology, 2008

Background: Surfactant protein (SP) D has been proposed to be protective in allergic airway respo... more Background: Surfactant protein (SP) D has been proposed to be protective in allergic airway responses. Objective: We aimed to determine the effect of SP-D deficiency on murine and human airway allergy. Methods: Immunologic responses of SP-D gene-deficient mice (Sftpd 2/2 ) at baseline and after 4 intranasal Aspergillus fumigatus exposures were assessed. In addition, the significance of a single nucleotide polymorphism (Met 11 Thr) in the human SP-D gene (known to decrease SP-D function) was investigated. Results: Macrophage and neutrophil bronchoalveolar lavage fluid levels and large airway mucus production were increased in naive Sftpd 2/2 mice in association with increased lung CCL17 levels and CD4 1 T cell numbers. T H 2-associated antibody levels (IgG1 and IgE) were significantly lower in 4-to 5-week-old Sftpd 2/2 mice (P < .05). Accordingly, naive Sftpd 2/2 splenocytes released significantly less IL-4 and IL-13 on anti-CD3/CD28 stimulation (P < .01). After intranasal allergen exposures, a modest decrease in bronchoalveolar lavage fluid eosinophilia and IL-13 levels was observed in Sftpd 2/2 mice compared with values seen in wild-type mice in association with decreased airway resistance (P < .01). A single nucleotide polymorphism in the SFTPD gene, affecting SP-D levels and pathogen binding, was associated with decreased atopy in black subjects and potentially lower asthma susceptibility in white subjects. Conclusion: Sftpd 2/2 mice have an impaired systemic T H 2 response at baseline and reduced inflammation and airway responses after allergen exposure. Translational studies revealed that a polymorphism in the SFTPD gene was associated with lower atopy and possibly asthma susceptibility. Taken together, these results support the hypothesis that SP-D-dependent innate immunity influences atopy and asthma. (J Allergy Clin Immunol 2008;121:1140-7.)

Journal of Allergy and Clinical Immunology, 2009

Background: Intestinal anaphylaxis (manifested by acute diarrhea) is dependent on IgE and mast ce... more Background: Intestinal anaphylaxis (manifested by acute diarrhea) is dependent on IgE and mast cells. Objective: We aimed to define the respective roles of IL-4 and IL-13 and their receptors in disease pathogenesis. Methods: Wild-type mice and mice deficient in IL-4, IL-13, and IL-13 receptor (IL-13R) a1 (part of the type 2 IL-4 receptor [IL-4R]) were sensitized with ovalbumin (OVA)/aluminum potassium sulfate and subsequently given repeated intragastric OVA exposures. The IL-4Ra chain was targeted with anti-IL-4Ra mAb before or after intragastric OVA exposures. Results: IL4 2/2 (and IL4/IL13 2/2 ) mice produced almost no IgE and were highly resistant to OVA-induced diarrhea, whereas allergic diarrhea was only partially impaired in IL13 2/2 and IL13Ra1 2/2 mice. IL13Ra1-deficient mice had decreased IgE levels, despite having normal baseline IL-4 levels. Intestinal mast cell accumulation and activation also depended mainly on IL-4 and, to a lesser extent, on IL-13. Prophylactic anti-IL-4Ra mAb treatment, which blocks all IL-4 and IL-13 signaling, suppressed development of allergic diarrhea. However, treatment with anti-IL-4Ra mAb for 7 days only partially suppressed IgE and did not prevent intestinal diarrhea. Conclusion: Endogenously produced IL-13 supplements the ability of IL-4 to induce allergic diarrhea by promoting oral allergen sensitization rather than the effector phase of intestinal anaphylaxis. (J Allergy Clin Immunol 2009;123:53-8.) Currently, 2% to 6% of the US population has food allergy, 1 a disease characterized by increased total and antigen-specific IgE eosinophilia, mastocytosis, and gastrointestinal dysfunction (eg, From the Divisions of

Journal of Allergy and Clinical Immunology, 2006

Background: Gastrointestinal allergy often precedes or coexists with respiratory allergy. Objecti... more Background: Gastrointestinal allergy often precedes or coexists with respiratory allergy. Objective: We hypothesized that established experimental gastrointestinal allergy would prime for the development of allergic respiratory responses. Methods: BALB/c mice were sensitized with ovalbumin (OVA) in the presence of aluminum potassium sulfate and then subjected to intragastric saline or OVA challenges. After the development of allergen-induced gastrointestinal allergy, mice were intranasally exposed to either saline, OVA, or a neoaeroallergen house dust mite (HDM) extract. Airway inflammation (eg, bronchoalveolar lavage fluid cellularity, cytokine levels, and OVA-specific antibody levels) and airway responsiveness to methacholine exposure were assessed after intranasal allergen exposure. Results: A single intranasal exposure to OVA induced significantly more airway inflammation in intragastric OVAchallenged mice compared with that seen in intragastric salinetreated mice. Kinetic analysis revealed that the observed amplification of lung inflammation was sustained for up to 12 days after the last intragastric OVA challenge after resolution of blood eosinophilia. When mice with gastrointestinal allergy were repeatedly challenged with HDM in the respiratory tract, they experienced enhanced airway inflammation, including bronchoalveolar lavage fluid eosinophilia and increased IL-13 levels. Conclusion: Taken together, our results demonstrate that OVAinduced gastrointestinal allergy enhances not only allergic airway responses to OVA but also to HDM, an unrelated aeroallergen.

Journal of Allergy and Clinical Immunology, 2006

Background: Atopic individuals are predisposed to mounting vigorous T H 2-type immune responses t... more Background: Atopic individuals are predisposed to mounting vigorous T H 2-type immune responses to environmental allergens. The skin is often the first organ that manifests allergic disease and may provide an early entry point for antigen sensitization. Objective: We sought to determine whether epicutaneous exposure to the aeroallergen Aspergillus fumigatus induces nasal allergic responses. Furthermore, we aimed to examine the mechanism involved. Methods: Wild-type and signal transducer and activator of transcription 6 (STAT6)-deficient mice were exposed to epicutaneous A fumigatus and control antigen ovalbumin. Nasal inflammation and responsiveness to methacholine were monitored. Results: Exposure to epicutaneous A fumigatus antigen induced a marked atopic dermatitis-like phenotype in a manner significantly more efficient than epicutaneous ovalbumin. A single A fumigatus intranasal challenge induced clinical nasal responses and hyperresponsiveness to methacholine in the nose as manifested by nasal symptoms, accompanied by allergic airway and nasal inflammation. Mechanistic analysis using gene-targeted mice revealed that the clinical nasal responses and hyperresponsiveness were STAT6-dependent. Although STAT6 was required for changes in nasal responses, it was not required for epicutaneous pathology except eosinophilia. Conclusion: Epicutaneous exposure to the aeroallergen A fumigatus potently primes for STAT6-dependent nasal responses. These results draw attention to the cooperative interaction between the nasal tract and skin.

Journal of Leukocyte Biology, 2006

Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal ... more Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (GI) diseases. Central to eosinophil migration into the GI tract are the integrin-mediated interactions with adhesion molecules. Although the mechanisms regulating eosinophil homing into the small intestine have begun to be elucidated, the adhesion pathways responsible for eosinophil trafficking into the large intestine are unknown. We investigated the role of adhesion pathways in eosinophil recruitment into the large intestine during homeostasis and disease. First, using a hapten-induced colonic injury model, we demonstrate that in contrast to the small intestine, eosinophil recruitment into the colon is regulated by a ␣ 4 ␤ 7 /mucosal addressin cell adhesion molecule-1-independent pathway. Characterization of integrin expression on eosinophils by flow cytometry analysis revealed that colonic CC chemokine receptor 3 ؉ eosinophils express the intercellular adhesion molecule-1 (ICAM-1) counter-receptor integrins ␣ L , ␣ M , and ␤ 2 . Using ICAM-1-deficient mice and anti-ICAM-1 neutralizing antibodies, we show that hapten-induced colonic eosinophilic inflammation is critically dependent on ICAM-1. These studies demonstrate that ␤ 2 -integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment into the colon during GI inflammation associated with colonic injury. J. Leukoc. Biol. 80: 000 -000; 2006. chemokine and cytokine signaling, eosinophil adhesion molecules (e.g., selectins and integrins), and integrin receptors [e.g., vascular cell adhesion molecule-1 (VCAM-1), mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and intercellular adhesion molecule 1 (ICAM-1)] expressed on vascular endothelial cells . Integrins are heterodimeric surface molecules consisting of an ␣and ␤-chain, and eosinophils express members of the ␤ 1 (␣ 4 ␤ 1 and ␣ 6 ␤ 1 )-, ␤ 2 (␣ L ␤ 2 , ␣ M ␤ 2 , ␣ X ␤ 2 , and ␣ D ␤ 2 )-, and ␤ 7 (␣ 4 ␤ 7 )-integrin families [18 -22]. These various integrin molecules interact selectively with adhesion receptors (VCAM-1, MAdCAM-1, ICAM-1, -2, and -3, and fibrinogen) expressed on the vascular endothelium. ␣ 4 ␤ 1 selectively binds to VCAM-1 and fibronectin, and ␣ 6 ␤ 1 is the primary ligand for the extracellular matrix protein laminin. The ␣ 4 ␤ 7 -integrin selectively binds to MAdCAM-1, and lymophocyte function-associated antigen-1 (LFA-1; ␣ L ␤ 2 ) and membrane-activated complex-1 (MAC-1; ␣ M ␤ 2 ) bind to ICAM-1. In addition, LFA-1 (␣ L ␤ 2 ) can bind ICAM-2 and -3, and ␣ D ␤ 2 has been shown to bind VCAM-1 and ICAM-3. Leukocyte integrin/intercellular adhesion molecule interactions, particularly LFA-1/ICAM-1 and very late antigen (VLA)-4/VCAM-1, are regulated by cytokines and chemokines such as IL-1 (␣ and ␤), tumor necrosis fator (TNF; ␣ and ␤), IL-4, and IL-13 [23]. IL-1 and TNF stimulate VCAM-1 and ICAM-1 expression on a variety of cell types. By contrast, IL-4 and IL-13 differentially enhance the expression of VCAM-1, having little impact on ICAM-1. Chemokines alter the activation state and selectivity of adhesion molecules . For example, treatment of eosinophils with MCP-3, RANTES, or eotaxin-2 switches eosinophils from a ␤ 1 -integrin/VCAM-1-dominant to a ␤ 2 -integrin/ICAM-1-dominant, interacting cell .

Studies with murine models demonstrate 2 pathways of systemic anaphylaxis: one mediated by IgE, F... more Studies with murine models demonstrate 2 pathways of
systemic anaphylaxis: one mediated by IgE, FceRI, mast cells,
histamine, and platelet-activating factor (PAF), and the other
mediated by IgG, FcgRIII, macrophages, and PAF. The former
pathway requires much less antibody and antigen than the
latter. As a result, IgG antibody can block IgE-mediated
anaphylaxis induced by small quantities of antigen without
mediating FcgRIII-dependent anaphylaxis. The IgE pathway is
most likely responsible for most human anaphylaxis, which
generally involves small amounts of antibody and antigen;
similarities in the murine and human immune systems suggest
that the IgG pathway might mediate disease in persons
repeatedly exposed to large quantities of antigen. Mice, like
human subjects, can experience IgE/FceRI/mast cell–mediated
gastrointestinal and systemic anaphylaxis in response to
ingested antigen. Gastrointestinal symptoms depend on
serotonin and PAF; mediator dependence of systemic
symptoms has not been determined. Both local and systemic
anaphylaxis induced by ingested antigens might be blocked by
IgA and IgG antibodies. IL-4 and IL-13 signaling through the
IL-4 receptor a chain, in addition to promoting the
mastocytosis and IgE antibody production that mediate most
human anaphylaxis, exacerbates the effector phase of
anaphylaxis by increasing target cell responsiveness to
vasoactive mediators. As a result, IL-4 receptor a chain
antagonists might be particularly effective suppressors of
anaphylaxis.

The Journal of clinical investigation, 2003

Gastrointestinal allergic disorders represent a diverse spectrum of inflammatory diseases that ar... more Gastrointestinal allergic disorders represent a diverse spectrum of inflammatory diseases that are occurring with increasing incidence and severity. An essential question concerning these disorders is to determine the specific cells and mediators responsible for specific clinical manifestations. With this in mind, we developed a murine model of oral allergen-induced intestinal inflammation accompanied by strong Th2-associated humoral and cellular responses and focused on the immunopathogenesis of allergic diarrhea. Exposure of OVA/alum-sensitized mice to repeated doses of intragastric OVA induced genetically restricted, dose-dependent, acute diarrhea associated with increased intestinal permeability, eosinophilia, and mastocytosis. Mice developed limited systemic manifestations of anaphylaxis, even though they developed marked intestinal mucosal mast cell degranulation. Notably, experiments involving mast cell depletion (with anti-c-kit mAb), anti-IgE treatment, and Fc epsilon RI-de...

Asthma is a complex inflammatory pulmonary disorder that is on the rise despite intense ongoing r... more Asthma is a complex inflammatory pulmonary disorder that is on the rise despite intense ongoing research. We aimed to elucidate novel pathways involved in the pathogenesis of asthma. Employing asthma models induced by different allergens (ovalbumin and Aspergillus fumigatus), we uncovered the involvement of two mem- bers of the small proline-rich protein (SPRR) family, SPRR2a and SPRR2b, known to be

Proceedings of The National Academy of Sciences, 2004

Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated w... more Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated with coordinate gene induction. Using DNA microarray analysis, we have identified a large panel of AAI signature genes. Unexpectedly, the allergen-challenged lung (a T helper 2 microenvironment) was found to be associated with the expression of T helper 1-associated CXCR3 ligands, monokine induced by IFN- (Mig), and

Journal of Allergy and Clinical Immunology, 2011

Journal of Allergy and Clinical Immunology, 2015

The Journal of allergy and clinical immunology, 2013

Clinical & Experimental Allergy

PLOS ONE, 2012

Journal of immunology (Baltimore, Md. : 1950), 2013

Journal of clinical & cellular immunology, Jan 10, 2011

The Journal of allergy and clinical immunology

Journal of Allergy and Clinical Immunology, 2008

Journal of Allergy and Clinical Immunology, 2009

Journal of Allergy and Clinical Immunology, 2006

Journal of Leukocyte Biology, 2006

The Journal of clinical investigation, 2003

Proceedings of The National Academy of Sciences, 2004

Journal of Allergy and Clinical Immunology, 2011