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1.
Allergy ; 78(5): 1169-1203, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36799120

RESUMEN

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.


Asunto(s)
Asma , Rinitis Alérgica , Rinitis , Humanos , Rinitis/diagnóstico , Rinitis/epidemiología , Rinitis/complicaciones , Asma/diagnóstico , Asma/epidemiología , Asma/etiología , Rinitis Alérgica/complicaciones , Alérgenos , Multimorbilidad
3.
Allergy ; 73(9): 1892-1901, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29790577

RESUMEN

BACKGROUND: Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses. METHODS: This case-control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non-EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1-IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts. RESULTS: Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0-13.1 mg/g protein] vs 0.2 mg/g protein [0.1-0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression. CONCLUSION: These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally.


Asunto(s)
Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/etiología , Inmunoglobulina G/inmunología , Transcriptoma , Biopsia , Estudios de Casos y Controles , Niño , Preescolar , Mucosa Esofágica/inmunología , Mucosa Esofágica/metabolismo , Mucosa Esofágica/patología , Esófago/inmunología , Esófago/metabolismo , Esófago/patología , Femenino , Expresión Génica , Histocitoquímica , Humanos , Inmunoglobulina G/genética , Cadenas Pesadas de Inmunoglobulina/genética , Isotipos de Inmunoglobulinas/inmunología , Masculino
4.
Dis Esophagus ; 30(3): 1-8, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-26857345

RESUMEN

Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P ≤ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P ≤ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P ≤ 0.024 and DIS P ≤ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.


Asunto(s)
Biopsia/estadística & datos numéricos , Esofagitis Eosinofílica/diagnóstico , Eosinófilos , Recuento de Leucocitos/métodos , Índice de Severidad de la Enfermedad , Área Bajo la Curva , Biopsia/métodos , Niño , Esófago/patología , Femenino , Humanos , Modelos Logísticos , Masculino , Estudios Prospectivos , Reproducibilidad de los Resultados
5.
Allergy ; 71(5): 611-20, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26799684

RESUMEN

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross-reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE-mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.


Asunto(s)
Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/etiología , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/etiología , Alérgenos/inmunología , Antiasmáticos/uso terapéutico , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/metabolismo , Epitelio/inmunología , Epitelio/metabolismo , Epitelio/patología , Alimentos/efectos adversos , Hipersensibilidad a los Alimentos/metabolismo , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Hipersensibilidad/patología , Inmunidad Innata , Inmunoglobulina E/inmunología , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Omalizumab/uso terapéutico , Piel/inmunología , Piel/metabolismo , Piel/patología , Células Th2/inmunología , Células Th2/metabolismo , Resultado del Tratamiento
6.
Genes Immun ; 15(6): 361-9, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24920534

RESUMEN

Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder of the esophagus that is compounded by genetic predisposition and hypersensitivity to environmental antigens. Using high-density oligonucleotide expression chips, a disease-specific esophageal transcript signature was identified and was shown to be largely reversible with therapy. In an effort to expand the molecular signature of EoE, we performed RNA sequencing on esophageal biopsies from healthy controls and patients with active EoE and identified a total of 1607 significantly dysregulated transcripts (1096 upregulated, 511 downregulated). When clustered by raw expression levels, an abundance of immune cell-specific transcripts are highly induced in EoE but expressed at low (or undetectable) levels in healthy controls. Moreover, 66% of the gene signature identified by RNA sequencing was previously unrecognized in the EoE transcript signature by microarray-based expression profiling and included several long non-coding RNAs (lncRNA), an emerging class of transcriptional regulators. The lncRNA BRAF-activated non-protein coding RNA (BANCR) was upregulated in EoE and induced in interleukin-13 (IL-13)-treated primary esophageal epithelial cells. Repression of BANCR significantly altered the expression of IL-13-induced proinflammatory genes. Together, these data comprise new potential biomarkers of EoE and demonstrate a novel role for lncRNAs in EoE and IL-13-associated responses.


Asunto(s)
Esofagitis Eosinofílica/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Análisis de Secuencia de ARN/métodos , Transcriptoma , Línea Celular , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Interleucina-13/farmacología , Interferencia de ARN , ARN no Traducido/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba
7.
J Clin Oncol ; 41(36): 5482-5492, 2023 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-38100992

RESUMEN

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

9.
Child Care Health Dev ; 38(4): 477-83, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21671982

RESUMEN

BACKGROUND AND AIMS: Current research outcomes in paediatric eosinophilic oesophagitis (EoE) are directed towards histological improvement with no attention to health-related quality of life (HRQOL). The primary objective of this study was to identify key patient-reported and parent proxy outcome elements of EoE disease-specific HRQOL. METHODS: The research team comprised clinical allergists and gastroenterologists with expertise in paediatric EoE as well as two PhD psychologists with extensive experience in qualitative research. Focused interview techniques were adapted from the Pediatric Quality of Life Inventory 4.0™ methodology and the consolidated criteria for reporting qualitative research. A semi-structured interview guide of open-ended questions was developed, and extensive review of audio-taped transcripts was performed. RESULTS: A total of 42 focus interviews were conducted. Child self-reports were obtained for patients in the 5-7, 8-12 and 13-18 years of age groups, and parent proxy reports were obtained in the 2-4, 5-7, 8-12 and 13-18 years of age groups. We discovered that patients and parents often had different concerns, illustrating unique aspects of EoE-specific HRQOL that were not captured in generic HRQOL instruments. Specific themes that emerged from these interviews included, but are not limited to: feelings of being different than family and peers, diet and medication adherence, difficulties with eating food and worry about symptoms and illness. CONCLUSION: Paediatric EoE patient and parent proxy interviews revealed many EoE-specific aspects of HRQOL that are not captured in generic HRQOL instruments. Outcome measures that reflect patient- and parent proxy-reported HRQOL are a critical need in paediatric EoE.


Asunto(s)
Actitud Frente a la Salud , Esofagitis Eosinofílica/rehabilitación , Calidad de Vida , Actividades Cotidianas , Adolescente , Niño , Preescolar , Comunicación , Esofagitis Eosinofílica/fisiopatología , Esofagitis Eosinofílica/psicología , Esofagitis Eosinofílica/terapia , Conducta Alimentaria , Femenino , Humanos , Relaciones Interpersonales , Masculino , Ohio , Psicometría , Instituciones Académicas , Resultado del Tratamiento
11.
Ann Oncol ; 22(2): 348-54, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20670978

RESUMEN

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Proteínas Recombinantes , Análisis de Supervivencia
12.
Nat Med ; 2(4): 449-56, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8597956

RESUMEN

Eotaxin is an eosinophil-specific chemoattractant that has been recently identified in rodent models of asthma and host response against tumors. To determine whether a similar molecule might play a role in human inflammatory diseases characterized by eosinophilia, we isolated the human eotaxin gene. We demonstrate that human eotaxin is an early response gene of cytokine-stimulated epithelial and endothelial cells, and is induced in peripheral blood eosinophils by interleukin-3. Eotaxin is directly chemotactic for eosinophils, but not mononuclear cells or neutrophils. Eotaxin messenger RNA accumulates markedly in the lesions of patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease), but not in the lesions of patients with diverticulitis. These results now provide a mechanism involving eotaxin to explain the eosinophil infiltration seen in a variety of human disease; as such, an eotaxin antagonist may be a novel therapy for certain human diseases characterized by tissue eosinophilia.


Asunto(s)
Quimiocinas CC , Quimiotaxis de Leucocito , Citocinas/biosíntesis , Eosinofilia/patología , Eosinófilos/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Células Cultivadas , Quimiocina CCL11 , Citocinas/genética , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Eosinofilia/genética , Eosinofilia/metabolismo , Eosinófilos/patología , Epitelio/metabolismo , Epitelio/patología , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-3/farmacología , Datos de Secuencia Molecular , Alineación de Secuencia
13.
Proc Natl Acad Sci U S A ; 105(20): 7240-5, 2008 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-18480254

RESUMEN

IL-13 and IL-4 are central T helper 2 (Th2) cytokines in the immune system and potent activators of inflammatory responses and fibrosis during Th2 inflammation. Recent studies using Il13ra1(-/-) mice have demonstrated a critical role for IL-13 receptor (IL-13R) alpha1 in allergen-induced airway responses. However, these observations require further attention especially because IL-4 can induce similar lung pathology to IL-13, independent of IL-13, and is still present in the allergic lung. Thus, we hypothesized that IL-13Ralpha1 regulates IL-4-induced responses in the lung. To dissect the role of IL-13Ralpha1 and the type I and II IL-4Rs in experimental asthma, we examined lung pathology induced by allergen, IL-4, and IL-13 challenge in Il13ra1(-/-) mice. We report that IL-13Ralpha1 is essential for baseline IgE production, but Th2 and IgE responses to T cell-dependent antigens are IL-13Ralpha1-independent. Furthermore, we demonstrate that increased airway resistance, mucus, TGF-beta, and eotaxin(s) production, but not cellular infiltration, are critically dependent on IL-13Ralpha1. Surprisingly, our results identify a CCR3- and IL-13Ralpha1-independent pathway for lung eosinophilia. Global expression profiling of lungs from mice stimulated with allergen or IL-4 demonstrated that marker genes of alternatively activated macrophages are differentially regulated by the type I and type II IL-4R. Taken together, our data provide a comprehensive mechanistic analysis of the critical role by which IL-13Ralpha1 mediates allergic lung pathology and highlight unforeseen roles for the type II IL-4R.


Asunto(s)
Asma/patología , Perfilación de la Expresión Génica , Interleucina-13/fisiología , Interleucina-4/fisiología , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Animales , Quimiocina CCL11/metabolismo , Eosinófilos/metabolismo , Inflamación , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Transgénicos , Modelos Biológicos , Células Th2/metabolismo
14.
Gut ; 59(1): 12-20, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19528036

RESUMEN

BACKGROUND: Eosinophilic oesophagitis (EO) is an emerging yet increasingly prevalent disorder characterised by a dense and selective eosinophilic infiltration of the oesophageal wall. While EO is considered an atopic disease primarily triggered by food antigens, disparities between standard allergen testing and clinical responses to exclusion diets suggest the participation of distinct antigen-specific immunoglobulin E (IgE) in the pathophysiology of EO. AIM: To find evidence for a local IgE response. METHODS: Endoscopic biopsies of the distal oesophagus of atopic and non-atopic EO and control individuals (CTL) were processed for immunohistochemistry and immunofluorescence to assess the presence of B cells, mast cells, and IgE-bearing cells. Oesophageal RNA was analysed for the expression of genes involved in B cell activation, class switch recombination to IgE and IgE production, including germline transcripts (GLTs), activation-induced cytidine deaminase (AID), IgE heavy chain (Cepsilon) and mature IgE mRNA using polymerase chain reaction and microarray analysis. RESULTS: Regardless of atopy, EO showed increased density of B cells (p<0.05) and of IgE-bounded mast cells compared to CTL. Both EO and CTL expressed muGLT, epsilonGLT, gamma4GLT, AID, Cepsilon and IgE mRNA. However, the frequency of expression of total GLTs (p = 0.002), epsilonGLT (p = 0.024), and Cepsilon (p = 0.0003) was significantly higher in EO than in CTL, independent of the atopic status. CONCLUSION: These results support the heretofore unproven occurrence of both local immunoglobulin class switching to IgE and IgE production in the oesophageal mucosa of EO patients. Sensitisation and activation of mast cells involving local IgE may therefore critically contribute to disease pathogenesis.


Asunto(s)
Linfocitos B/inmunología , Eosinofilia/inmunología , Esofagitis/inmunología , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/biosíntesis , Adolescente , Recuento de Células , Niño , Preescolar , Esófago/inmunología , Femenino , Humanos , Inmunoglobulina E/genética , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Activación de Linfocitos/inmunología , Masculino , Mastocitos/inmunología , Membrana Mucosa/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/genética , Estudios Retrospectivos , Transcripción Genética
15.
J Exp Med ; 181(3): 1211-6, 1995 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-7869037

RESUMEN

Eotaxin is a member of the C-C family of chemokines and is related during antigen challenge in a guinea pig model of allergic airway inflammation (asthma). Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin. Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA. The cDNA encodes a protein of 96 amino acids, including a putative 23-amino acid hydrophobic leader sequence, followed by 73 amino acids composing the mature active eotaxin protein. The protein-coding region of this cDNA is 73, 71, 50, and 48% identical in nucleic acid sequence to those of human macrophage chemoattractant protein (MCP) 3, MCP-1, macrophage inflammatory protein (MIP) 1 alpha, and RANTES, respectively. Analysis of genomic DNA suggested that there is a single eotaxin gene in guinea pig which is apparently conserved in mice. High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels. To determine if eotaxin mRNA levels are elevated during allergen-induced eosinophilic airway inflammation, ovalbumin (OVA)-sensitized guinea pigs were challenged with aerosolized antigen. Compared with the lungs from saline-challenged animals, eotaxin mRNA levels increased sixfold within 3 h and returned to baseline by 6 h. Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response. The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing.


Asunto(s)
Alérgenos/inmunología , Quimiocinas CC , Citocinas/genética , Pulmón/metabolismo , ARN Mensajero/análisis , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Quimiocina CCL11 , ADN Complementario/análisis , Cobayas , Humanos , Hipersensibilidad/metabolismo , Masculino , Datos de Secuencia Molecular
16.
J Exp Med ; 185(4): 785-90, 1997 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-9034156

RESUMEN

The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C-C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.


Asunto(s)
Antígenos/metabolismo , Quimiocinas CC , Citocinas/metabolismo , Eosinofilia/inmunología , Animales , Quimiocina CCL11 , Citocinas/sangre , Citocinas/genética , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Tejido Linfoide/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tráquea/inmunología , Tráquea/patología
17.
J Exp Med ; 166(1): 129-41, 1987 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-3110347

RESUMEN

Normodense human peripheral blood eosinophils were isolated under sterile conditions from the 22/23 and 23/24% interfaces and the cell pellet of metrizamide gradients. After culture for 7 d in RPMI media in the presence of 50 pM biosynthetic (recombinant) human granulocyte/macrophage colony-stimulating factor (rH GM-CSF), 43 +/- 7% (mean +/- SEM, n = 8) of the cells were viable; in the absence of rH GM-CSF, no eosinophils survived. The rH GM-CSF-mediated viability was concentration dependent; increased survival began at a concentration of 1 pM, a 50% maximal response was attained at approximately 3 pM, and a maximal effect was reached at concentrations of greater than or equal to 10 pM rH GM-CSF. In the presence of rH GM-CSF and mouse 3T3 fibroblasts, 67 +/- 6% (mean +/- SEM, n = 8) of the eosinophils survived for 7 d. In a comparative analysis, there was no difference in eosinophil viability after 7 and 14 d (n = 3) in the presence of 50 pM GM-CSF and fibroblasts. Culture with fibroblasts alone did not support eosinophil survival. The addition of fibroblast-conditioned media to rH GM-CSF did not further improve eosinophil viability, indicating a primary role for GM-CSF in supporting these eosinophil cell suspensions ex vivo and a supplementary role for 3T3 fibroblasts. Eosinophils cultured for 7 d localized on density gradient sedimentation at the medium/18, 18/20, and 20/21 interfaces of metrizamide gradients, indicating a change to the hypodense phenotype from their original normodense condition. In addition, the cultured eosinophils generated approximately 2.5-fold more LTC4 than freshly isolated cells when stimulated with the calcium ionophore A23187 and manifested sevenfold greater antibody-dependent killing of S. mansoni larvae than the freshly isolated, normodense cells from the same donor. Thus we demonstrate the rH GM-CSF dependent conversion in vitro of normodense human eosinophils to hypodense cells possessing the augmented biochemical and biological properties characteristic of the hypodense eosinophils associated with a variety of hypereosinophilic syndromes. In addition, these studies provide a culture model of at least 14 d suitable for the further characterization of hypodense eosinophils.


Asunto(s)
Eosinófilos/inmunología , Fibroblastos/fisiología , Interleucina-3/fisiología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos , Calcimicina/farmacología , Recuento de Células , Supervivencia Celular , Células Cultivadas , Centrifugación por Gradiente de Densidad , Eosinófilos/citología , Eosinófilos/efectos de los fármacos , Humanos , Ratones , Neutrófilos/fisiología , Proteínas Recombinantes/fisiología , SRS-A/biosíntesis , Schistosoma mansoni/inmunología , Factores de Tiempo
18.
J Exp Med ; 188(6): 1063-74, 1998 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-9743525

RESUMEN

The movement of leukocytes into tissues is regulated by the local production of chemical mediators collectively referred to as chemoattractants. Although chemoattractants constitute a diverse array of molecules, including proteins, peptides, and lipids, they all appear to signal leukocytes through a related family of seven transmembrane-spanning G protein-coupled receptors. The eosinophil is a potent proinflammatory cell that is attracted into tissues during allergic inflammation, parasitic infection, and certain malignancies. Since the molecular mechanisms controlling eosinophil recruitment are incompletely understood, we performed a degenerate polymerase chain reaction on cDNA isolated from murine eosinophils to identify novel chemoattractant receptors. We report the isolation of a cDNA that encodes a 351-amino acid glycoprotein that is 78% identical to a human gene that has been reported to be a purinoceptor (P2Y7) and a leukotriene B4 (LTB4) receptor (BLTR). Chinese hamster ovary (CHO) cells transfected with this cDNA specifically bound [3H]LTB4 with a dissociation constant of 0.6 +/- 0.1 nM. Furthermore, LTB4 induced a dose-dependent intracellular calcium flux in transfected CHO cells. In contrast, [35S]dATP did not specifically bind to these transfectants. This mRNA was expressed at high levels in interleukin 5-exposed eosinophils, elicited peritoneal macrophages and neutrophils, and to a lesser extent interferon gamma stimulated macrophages. Low levels of expression were detected in the lung, lymph node, and spleen of unchallenged mice. Western blot analysis detected the mBLTR protein in murine eosinophils and alveolar macrophages as well as human eosinophils. In addition, elevated levels of mBLTR mRNA were found in the lungs of mice in a murine model of allergic pulmonary inflammation in a time course consistent with the influx of eosinophils. Our findings indicate that this murine receptor is an LTB4 receptor that is highly expressed on activated leukocytes, including eosinophils, and may play an important role in mediating eosinophil recruitment into inflammatory foci.


Asunto(s)
Eosinófilos/metabolismo , Receptores de Leucotrieno B4/biosíntesis , Receptores de Leucotrieno B4/química , Secuencia de Aminoácidos , Animales , Células CHO , Calcio/metabolismo , Línea Celular , Factores Quimiotácticos Eosinófilos/fisiología , Clonación Molecular , Cricetinae , ADN Complementario/análisis , Modelos Animales de Enfermedad , Eosinófilos/patología , Femenino , Humanos , Leucotrieno B4/metabolismo , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos , Ratones Transgénicos , Datos de Secuencia Molecular , Plásmidos/genética , Unión Proteica , Biosíntesis de Proteínas , ARN Mensajero/biosíntesis , Receptores de Leucotrieno B4/sangre , Receptores de Leucotrieno B4/genética , Receptores de Leucotrieno B4/fisiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/patología , Transfección , Células Tumorales Cultivadas
19.
J Exp Med ; 170(1): 343-8, 1989 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-2787385

RESUMEN

We report that the hypodense eosinophil population in three patients with corticosteroid-unresponsive IHES was uniquely long lived ex vivo in the absence of exogenous cytokines. Serum or plasma from these patients conferred prolonged viability ex vivo to normodense eosinophils from reference donors and converted them to a functionally activated hypodense phenotype. In that antibody against IL-5 neutralized this activity in IHES serum, excessive quantities of this cytokine may account for the characteristic eosinophilia and long-lived, functionally augmented eosinophil phenotype in this disorder.


Asunto(s)
Eosinofilia/sangre , Eosinófilos/patología , Interleucinas/sangre , Adulto , Supervivencia Celular , Eosinofilia/inmunología , Eosinófilos/citología , Humanos , Técnicas In Vitro , Interleucina-5 , Masculino , Persona de Mediana Edad , Fenotipo , Valores de Referencia , Síndrome
20.
Ann Oncol ; 21(4): 754-758, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19887466

RESUMEN

BACKGROUND: The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC). METHODS: A retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade > or =1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan-Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose. RESULTS: Of 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients. CONCLUSIONS: This retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.


Asunto(s)
Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/epidemiología , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma/complicaciones , Carcinoma/patología , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/patología , Complicaciones de la Diabetes/inducido químicamente , Complicaciones de la Diabetes/patología , Neuropatías Diabéticas/patología , Progresión de la Enfermedad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Oxaliplatino , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Estudios Retrospectivos , Células Receptoras Sensoriales/patología
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