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Marc E Rothenberg

Publications and source records attributed to Marc E Rothenberg.

At least 55 records · Page 3Linked to original sources
PubMed2005

Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) is frequently associated with atopic disease, including dermatitis and asthma. Data are emerging that atopic skin may provide an early entry point for antigen sensitization. We aimed to test the hypothesis that epicutaneous exposure to antigen primes for subsequent respiratory antigen-induced EE. METHODS: Wild-type and genetically engineered mice were subjected to epicutaneous antigen sensitization and the development of experimental EE, and immune responses were examined. RESULTS: We show that exposure to antigen via the epicutaneous route primes for marked eosinophilic inflammation in the esophagus triggered by a single airway antigen challenge. The development of experimental EE is associated with significant skin eosinophilia, accelerated bone marrow eosinophilopoiesis, blood eosinophilia, and large increases in serum antigen-specific immunoglobulin G1/immunoglobulin E using ovalbumin or Aspergillus fumigatus as the epicutaneous antigen. Mechanistic analysis with gene-targeted mice showed that interleukin-5 was required for esophageal eosinophilia and that interleukin-4, interleukin-13, and STAT6 contributed to a lesser extent. CONCLUSIONS: These findings provide the first evidence that epicutaneous exposure to allergens potently primes for EE via a Th2-dependent mechanism.

Allergens↗
PubMed2005

Eosinophilic esophagitis.

PURPOSE OF REVIEW: Previously perceived as an anomaly, eosinophilic esophagitis is now frequently diagnosed by both pediatric and adult specialists including gastroenterologists, allergists, pathologists, and otolaryngologists. Research efforts initially focused on characterization of the clinical, endoscopic, and histologic features of this disorder. In the last 3 years, the research focus has evolved into understanding its immunologic and demographic features as well as the development of efficacious therapies. RECENT FINDINGS: Population-based demographic studies have documented the unique epidemiologic parameters of eosinophilic esophagitis, some of its natural history, and its increasing frequency. Basic research efforts have identified cytokines relevant toward development of eosinophilic esophagitis, including interleukin-5 and interleukin-13. Clinical efforts have established the efficacy of dietary and medical treatments. Some treatments result in symptomatic improvement with ongoing inflammation, so a debate is ensuing over the long-term effect of asymptomatic esophageal inflammation. SUMMARY: Understanding of eosinophilic esophagitis has evolved to a point at which patients can be appropriately diagnosed and initially treated; however, a paucity of long-term outcome data prevents the creation of uniform recommendations for the clinical care of patients with eosinophilic esophagitis.

Child↗
PubMed2005

Prevalence and outcome of allergic colitis in healthy infants with rectal bleeding: a prospective cohort study.

OBJECTIVES: Allergic colitis is often diagnosed clinically in healthy infants with rectal bleeding and often treated with costly hypoallergenic formula. The true prevalence of allergic colitis is unknown. We tested the hypothesis that allergic colitis is overdiagnosed in healthy infants with rectal bleeding. The authors also determined whether rectal bleeding in infants without allergic colitis would resolve without diet change. METHODS: For the purposes of this study, allergic colitis was defined histologically as colonic mucosa with >or= 6 eosinophils per high power field and/or eosinophils in colonic crypts or muscularis mucosae. We surveyed all 56 Ohio NASPGHAN members to determine standard practice regarding the evaluation of rectal bleeding in infants. In addition, infants <or= 6 months old with rectal bleeding were recruited from the referral area of Cincinnati Children's Hospital Medical Center. All infants underwent flexible sigmoidoscopy with biopsies at 5, 10 and 15 cm. Formula or maternal diet was changed only for infants with histologic findings of allergic colitis as defined. Study subjects were followed for 9 weeks. RESULTS: In the survey of NASPGHAN members, 84% indicated they would empirically change the diet of an infant with rectal bleeding to treat presumed allergic colitis. In our study population, however, only 14 of 22 (64%; 95% confidence interval, 41-83) infants with rectal bleeding had allergic colitis. Five (23%) had normal biopsies and three (14%) had nonspecific colitis. Rectal bleeding in all infants with normal biopsies or nonspecific colitis resolved without diet change except for 1 infant subsequently diagnosed with infantile inflammatory bowel disease. CONCLUSION: A significant proportion of infants with rectal bleeding may not have allergic colitis and may undergo unnecessary, expensive formula or maternal diet changes that may discourage breast-feeding.

Cohort Studies↗
PubMed2004

Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma.

The expression of distinct chemokines within the asthmatic lung suggests that specific regulatory mechanisms may mediate various stages of asthmatic disease. Global transcript expression profiling was used to define the spectrum and kinetics of chemokine involvement in an experimental murine model of asthma. Seventeen chemokines were induced in the lungs of allergen-inoculated mice, as compared with saline-treated mice. Two (CXCL13 and CCL9) of the 17 identified chemokines have not previously been associated with allergic airway disease. Seven (7 of 17; CCL2, CCL7, CCL9, CCL11, CXCL1, CXCL5, CXCL10) of the allergen-induced chemokines were induced early after allergen challenge and remained induced throughout the experimental period. Three chemokines (CXCL2, CCL3, and CCL17) were induced only during the early phase of the inflammatory response after the initial allergen challenge, while seven chemokines (CCL6, CCL8, CCL12, CCL22, CXCL9, CXCL12, and CXCL13) were increased only after a second allergen exposure. Unexpectedly, expression of only three chemokines, CCL11, CCL17, and CCL22, was STAT6 dependent, and many of the identified chemokines were overexpressed in STAT6-deficient mice, providing an explanation for the enhanced neutrophilic inflammation seen in these mice. Notably, IFN-gamma and STAT1 were shown to contribute to the induction of two STAT6-independent chemokines, CXCL9 and CXCL10. Taken together, these results show that only a select panel of chemokines (those targeting Th2 cells and eosinophils) is positively regulated by STAT6; instead, many of the allergen-induced chemokines are negatively regulated by STAT6. Collectively, we demonstrate that allergen-induced inflammation involves coordinate regulation by STAT1, STAT6, and IFN-gamma.

Allergens↗
PubMed2004

Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma.

Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research. To elucidate novel pathways involved in asthma pathogenesis, we used transcript expression profiling in a murine model of asthma. Employing asthma models induced by different allergens (ovalbumin and Aspergillus fumigatus) we uncovered the involvement of ADAM8, a member of a disintegrin and metalloproteinase (ADAM) family. In situ hybridization of mouse lungs revealed strong ADAM8 induction in peribronchial and perivascular inflammatory cells as well as in bronchiolar epithelial cells following allergen challenge. Sequence analysis of lung ADAM8 cDNA identified a novel splice variant of ADAM8 that contained an additional exon in juxtaposition to the transmembrane domain. Allergen-induced ADAM8 mRNA accumulation in the lung was dose- and time-dependent. Transgenic or pharmacologic delivery of interleukin (IL)-4 or IL-13 to the lungs resulted in a marked increase of ADAM8 expression. Gene-targeted mice studies revealed that ovalbumin-induced ADAM8 was largely dependent upon signal transducer and activator of transcription (STAT) 6 and the IL-4 receptor alpha-chain. Thus, ADAM8 is an allergen-, IL-4-, and IL-13-induced gene in the experimental asthmatic lung. Taken together with the role of ADAM33 in asthma, these results suggest that allergic lung responses involve the interplay of diverse members of the ADAM family.

ADAM Proteins↗
PubMed2004

Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9).

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-gamma (Mig), and IFN-gamma-inducible protein of 10 kDa (IP-10). Here we report that Mig functions as a negative regulator of murine eosinophils. Whereas Mig was not able to induce chemotaxis of eosinophils, pretreatment with Mig induced a dose-dependent inhibition of chemoattractant-induced eosinophil transmigration in vitro. Moreover, i.v. administration of low doses of Mig ( approximately 10-30 microg/kg) induced strong and specific dose-dependent inhibition of chemokine-, IL-13-, and allergen-induced eosinophil recruitment and, conversely, neutralization of Mig before allergen challenge increased airway eosinophilia. Importantly, Mig also inhibited a CCR3-mediated functional response in eosinophils. These results indicate that the ultimate distribution and function of inflammatory cells within the allergic lung is dictated by a balance between positively and negatively regulatory chemokines. The identification of a naturally occurring eosinophil inhibitory chemokine pathway in vivo provides a strategic basis for future therapeutic consideration.

Allergens↗
PubMed2004

Transcript signatures in experimental asthma: identification of STAT6-dependent and -independent pathways.

The analysis of polygenic diseases such as asthma poses a challenging problem. In an effort to provide unbiased insight into disease pathogenesis, we took an empirical approach involving transcript expression profiling of lung tissue from mice with experimental asthma. Asthmatic responses were found to involve sequential induction of 4.7% of the tested genome; notably, there was ectopic expression of a series of genes not previously implicated in allergic or pulmonary responses. Genes were widely distributed throughout all chromosomes, but preferentially included genes involved in immunity, development, and homeostasis. When asthma was induced by two independent experimental regimens, unique gene transcript profiles were found depending upon the mode of disease induction. However, the majority of genes were common to both models representing an asthma signature genome. Analysis of STAT6-deficient mice revealed that an unexpectedly large segment of the asthma genes were STAT6 independent; this correlated with sustained inflammatory events in these mice. Notably, induction of asthma in STAT6-deficient mice resulted in gene induction not seen in wild-type mice. These results raise concern that therapeutic blockade of STAT6 in the asthmatic setting may reprogram the genetic signature, resulting in alternative lung pathology, which we indeed observed in STAT6-deficient mice. These results provide unprecedented insight into the complex steps involved in the pathogenesis of allergic airway responses; as such, these results have significant therapeutic and clinical implications.

Administration, Intranasal↗
PubMed2004

Chemokines in eosinophil-associated gastrointestinal disorders.

Eosinophil-associated gastrointestinal disorders (EGDs) are characterized by a pronounced cellular inflammation. Recent clinical and experimental investigations have implicated a family of molecules known as chemokines in the regulation of leukocyte recruitment in these diseases. The underlying cellular and molecular mechanisms involved in chemokine-mediated cellular infiltration are largely unknown. In this review, we describe the role of CD4+ T cells and eosinophils in the clinical manifestations of EGDs and discuss the current understanding of the role of chemokines in the recruitment of these cells in the expression of diseases.

Animals↗
PubMed2004

Eosinophilic gastrointestinal disorders (EGID).

Primary eosinophilic gastrointestinal disorders are defined as disorders that selectively affect the gastrointestinal tract with eosinophil-rich inflammation in the absence of known causes for eosinophilia (eg, drug reactions, parasitic infections, and malignancy). These disorders include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis and are occurring with increasing frequency. Significant progress has been made in elucidating that eosinophils are integral members of the gastrointestinal mucosal immune system and that eosinophilic gastrointestinal disorders are primarily polygenic allergic disorders that involve mechanisms that fall between pure IgE-mediated and delayed T(H)2-type responses. Preclinical studies have identified a contributory role for the cytokine IL-5 and the eotaxin chemokines, providing a rationale for specific disease therapy. An essential question is to determine the cellular and molecular basis for each of these clinical problems and the best treatment regimen, which is the main subject of this review.

Animals↗
PubMed2004

Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) is a recently recognized clinical disorder that is understood poorly. We aimed to determine the efficacy of swallowed fluticasone propionate on the immunopathologic features associated with EE. METHODS: A retrospective analysis was performed on 20 pediatric patients with EE. Inclusion criteria specified a peak eosinophil density of > or =24 cells per 400x field in the esophagus and treatment with swallowed fluticasone between 2 endoscopic assessments. Histologic specimens were examined for eosinophil and CD8(+) lymphocyte infiltration, papillary lengthening, and proliferation of the basal layer as determined by monoclonal anti-Ki-67 (MIB-1) antibody staining. RESULTS: The mean time interval between endoscopic assessments was 4.8 months. The patients were divided equally between allergic and nonallergic groups based on the results of skin-prick testing. All of the nonallergic patients responded to fluticasone propionate. The endoscopic appearance of the mucosa improved and microscopic evaluation showed markedly reduced eosinophil infiltration, reduced basal layer hyperplasia documented by a reduced number of MIB-1(+) cells, and a reduced number of CD8(+) lymphocytes. However, allergic patients were relatively refractory to therapy; 20% had a partial response, whereas 20% had no detectable improvement. Esophageal eosinophil levels before and after therapy in all patients strongly correlated with the level of epithelial cell proliferation as measured by MIB-1 staining. CONCLUSIONS: Collectively, these results suggest that patients treated with swallowed fluticasone have improved endoscopic, histologic, and immunologic parameters associated with EE. However, patients with identifiable allergies who fail dietary elimination may have a blunted response to treatment.

Administration, Oral↗
PubMed2004

T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice.

BACKGROUND & AIMS: Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases. METHODS: Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness. RESULTS: The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro. CONCLUSIONS: These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.

Animals↗
PubMed2004

Arginine in asthma and lung inflammation.

Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research underscoring the need for new scientific inquiry. Using global microarray analysis, we recently discovered that asthmatic responses involve metabolism of arginine by arginase. We found that the cationic amino acid transporter (CAT)2, arginase I, and arginase II were particularly prominent among the allergen-induced gene transcripts. These genes are key regulators of critical processes associated with asthma, including airway tone, cell hyperplasia, and collagen deposition, respectively. Recent data suggest that arginase induction is not just a marker of allergic airway responses, but that arginase is involved in the pathogenesis of multiple aspects of disease. This review focuses on the current body of knowledge on L-arginine metabolism in asthma.

Animals↗
PubMed2004

Foxa2 regulates alveolarization and goblet cell hyperplasia.

The airways are lined by several distinct epithelial cells that play unique roles in pulmonary homeostasis; however, the mechanisms controlling their differentiation in health and disease are poorly understood. The winged helix transcription factor, FOXA2, is expressed in the foregut endoderm and in subsets of respiratory epithelial cells in the fetal and adult lung. Because targeted mutagenesis of the Foxa2 gene in mice is lethal before formation of the lung, its potential role in lung morphogenesis and homeostasis has not been determined. We selectively deleted Foxa2 in respiratory epithelial cells in the developing mouse lung. Airspace enlargement, goblet cell hyperplasia, increased mucin and neutrophilic infiltration were observed in lungs of the Foxa2-deleted mice. Experimental goblet cell hyperplasia caused by ovalbumin sensitization, interleukin 4 (IL4), IL13 and targeted deletion of the gene encoding surfactant protein C (SP-C), was associated with either absent or decreased expression of Foxa2 in airway epithelial cells. Analysis of lung tissue from patients with a variety of pulmonary diseases revealed a strong inverse correlation between FOXA2 and goblet cell hyperplasia. FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung.

Animals↗
PubMed2003

Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.

BACKGROUND: IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. METHODS: We performed an open-label trial of anti-IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. RESULTS: Anti-IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti-IL-5. In addition, anti-IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti-IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. CONCLUSIONS: These results suggest that anti-IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti-IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.

Adolescent↗
PubMed2003

A plant-based allergy vaccine suppresses experimental asthma via an IFN-gamma and CD4+CD45RBlow T cell-dependent mechanism.

Allergic asthma is currently considered a chronic airway inflammatory disorder associated with the presence of activated CD4(+) Th2-type lymphocytes, eosinophils, and mast cells. Interestingly, therapeutic strategies based on immune deviation and suppression have been shown to successfully attenuate the development of the asthma phenotype. In this investigation, we have for the first time used a genetically modified (GM) plant, narrow leaf lupin (Lupinus angustifolius L.), expressing a gene for a potential allergen (sunflower seed albumin) (SSA-lupin) to examine whether a GM plant/food-based vaccine strategy can be used to suppress the development of experimental asthma. We show that oral consumption of SSA-lupin promoted the induction of an Ag-specific IgG2a Ab response. Furthermore, we demonstrate that the plant-based vaccine attenuated the induction of delayed-type hypersensitivity responses and pathological features of experimental asthma (mucus hypersecretion, eosinophilic inflammation, and enhanced bronchial reactivity (airways hyperreactivity). The suppression of experimental asthma by SSA-lupin was associated with the production of CD4(+) T cell-derived IFN-gamma and IL-10. Furthermore, we show that the specific inhibition of experimental asthma was mediated via CD4(+)CD45RB(low) regulatory T cells and IFN-gamma. Thus, our data demonstrate that a GM plant-based vaccine can promote a protective immune response and attenuate experimental asthma, suggesting that plant-based vaccines may be potentially therapeutic for the protection against allergic diseases.

2S Albumins, Plant↗
PubMed2003

Trefoil factor-2 is an allergen-induced gene regulated by Th2 cytokines and STAT6 in the lung.

Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research, underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into the pathogenesis of this disease, we took an empirical approach involving transcript expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens (ovalbumin [OVA] and Aspergillus fumigatus), we found strong induction of trefoil factor-2 (TFF2), a gene involved in epithelial restitution and mucosal secretion in the gastrointestinal tract. Using a combination of pharmacologic delivery and transgenic overexpression, TFF2 was demonstrated to be strongly induced in the lung by interleukin (IL)-4 and IL-13. Notably, TFF2 induction by both OVA and pharmacologic delivery of IL-4 and IL-13 was dependent upon signal transducer and activator of transcription (STAT)6. However, the upregulation of TFF2 by both chronic expression of IL-4 and Aspergillus fumigatus antigen was independent of STAT6. These results establish that TFF2 is an allergen-induced lung gene product differentially regulated by Th2 cytokines and STAT6. Given the important role of trefoil factors in wound healing, epithelial restitution, and maintenance of mucosal integrity in the gastrointestinal tract, these results support a potential role for TFF2, in both the acute and chronic phase of experimental asthma, via separate induction pathways.

Allergens↗