Publications by authors named "Ranjan Dohil"

49 Publications

A Unique Esophageal Extracellular Matrix Proteome Alters Normal Fibroblast Function in Severe Eosinophilic Esophagitis.

J Allergy Clin Immunol 2021 Feb 6. Epub 2021 Feb 6.

Department of Pediatrics, University of California, San Diego; Division of Allergy Immunology; Rady Children's Hospital San Diego, California; Department of Medicine, University of California, San Diego. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic Th2 disorder complicated by tissue fibrosis and loss of esophageal luminal patency. The fibrostenotic esophagus does not respond well to therapy but pro-fibrotic therapeutic targets are largely unclear.

Objective: To utilize proteomics and primary cell as a novel approach to determine relevant pro-fibrotic factors.

Methods: We utilized primary esophageal EoE and normal fibroblasts, their derivative extracellular matrixes (ECMs), an approach of fibroblast culture on autologous versus opposing ECM, and proteomics to elucidate EoE ECM proteins that dysregulate cellular function.

Results: We cultured esophageal fibroblasts from normal or severe EoE esophagi on autologous versus opposing extracellular matrix (ECM). The EoE ECM proteome shifted normal esophageal fibroblast protein expression. Proteomic analysis demonstrated that thrombospondin-1 (TSP-1) is detected only in the EoE ECM, is central in the EoE ECM protein-protein interactome, is significantly elevated in active EoE biopsies, and induces fibroblast collagen I production.

Conclusion: EoE fibroblasts secrete a unique ECM proteome that reflects their in vivo state and induces collagen I and α-smooth muscle actin protein expression from normal fibroblasts. TSP-1 is a previously unappreciated pro-fibrotic molecule in EoE.

Clinical Implications: The novel approach of culturing tissue fibroblasts on autologous versus opposing ECM has clinical utility for identifying previously unappreciated disease-specific druggable ECM targets in EoE and, potentially other, fibrotic disorders.
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http://dx.doi.org/10.1016/j.jaci.2021.01.023DOI Listing
February 2021

Plasminogen Activator Inhibitor-1 as a Marker of Esophageal Functional Changes in Pediatric Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol 2020 Sep 30. Epub 2020 Sep 30.

Rady Children's Hospital, San Diego, California; Division of Allergy and Immunology, University of California San Diego, San Diego, California; Department of Medicine and Pediatrics, University of California San Diego, San Diego, California. Electronic address:

Background & Aims: Esophageal remodeling in eosinophilic esophagitis (EoE) can lead to esophageal rigidity with eventual luminal compromise and stenoses. Gauging esophageal functional alterations in EoE is challenging. An epithelial marker of functional remodeling would impact EoE management.

Methods: Esophageal biopsy specimens from children with and without EoE and primary human esophageal epithelial cells were used for PAI-1 immunohistochemistry, and cell proliferation experiments. PAI-1 immunostaining and basal cell hyperplasia were assessed in the context of concurrently obtained esophageal compliance measures on endoscopic functional lumen imaging probe (EndoFLIP).

Results: EndoFLIPs were performed in 45 children (32 with and 13 without EoE). Epithelial PAI-1 was increased in patients with active EoE versus inactive or control patients (P < .01). Esophageal compliance was lower in EoE patients versus controls, particularly in the proximal esophagus (P < .001). Proximal compliance was the strongest predictor of EoE (AUROC 0.88, 95% CI 0.77, 0.98) with esophageal compliance of less than 2.6%mL/mmHg demonstrating 82% sensitivity and 84% specificity for EoE. PAI-1 inhibition significantly diminished esophageal epithelial cell proliferation, suggesting PAI-1 could trigger basal cell hyperplasia. A composite mid-esophageal BZH + PAI-1 score was the strongest predictor of altered compliance (P = .02, AUROC 0.89 (95% CI 0.80, 0.99). PAI-1 inhibition decreased basal cell proliferation.

Conclusions: PAI-1 is significantly elevated in pediatric EoE and distinguishes altered compliance in children. PAI-1 may be a novel disease marker and therapeutic target.
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http://dx.doi.org/10.1016/j.cgh.2020.09.040DOI Listing
September 2020

Increased Production of LIGHT by T Cells in Eosinophilic Esophagitis Promotes Differentiation of Esophageal Fibroblasts Toward an Inflammatory Phenotype.

Gastroenterology 2020 Nov 23;159(5):1778-1792.e13. Epub 2020 Jul 23.

Department of Pediatrics, University of California, San Diego, San Diego; Division of Allergy Immunology; Rady Children's Hospital, San Diego; Division of Gastroenterology, Department of Pediatrics, University of California, San Diego. Electronic address:

Background & Aims: Eosinophilic esophagitis (EoE) is an antigen-mediated eosinophilic disease of the esophagus that involves fibroblast activation and progression to fibrostenosis. Cytokines produced by T-helper type 2 cells and transforming growth factor beta 1 (TGFβ1) contribute to the development of EoE, but other cytokines involved in pathogenesis are unknown. We investigate the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE.

Methods: We analyzed publicly available esophageal CD3 T-cell single-cell sequencing data for expression of LIGHT. Esophageal tissues were obtained from pediatric patients with EoE or control individuals and analyzed by immunostaining. Human primary esophageal fibroblasts were isolated from esophageal biopsy samples of healthy donors or patients with active EoE. Fibroblasts were cultured; incubated with TGFβ1 and/or LIGHT; and analyzed by RNA sequencing, flow cytometry, immunoblots, immunofluorescence, or reverse transcription polymerase chain reaction. Eosinophils were purified from peripheral blood of healthy donors, incubated with interleukin 5, cocultured with fibroblasts, and analyzed by immunohistochemistry.

Results: LIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals, and expressed by several T-cell populations, including T-helper type 2 cells. TNF receptor superfamily member 14 (TNFRSF14, also called HVEM) and lymphotoxin beta receptor are receptors for LIGHT that were expressed by fibroblasts from healthy donors or patients with active EoE. Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription, whereas stimulation with TGFβ1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFβ1 increased expression of HVEM; subsequent stimulation with LIGHT resulted in their differentiation into cells that express markers of myofibroblasts and inflammatory chemokines and cytokines. Eosinophils tethered to esophageal fibroblasts after LIGHT stimulation via intercellular adhesion molecule-1.

Conclusions: T cells in esophageal tissues from patients with EoE express increased levels of LIGHT compared with control individuals, which induces differentiation of fibroblasts into cells with inflammatory characteristics. TGFβ1 increases fibroblast expression of HVEM, a receptor for LIGHT. LIGHT mediates interactions between esophageal fibroblasts and eosinophils via ICAM1. This pathway might be targeted for the treatment of EoE.
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http://dx.doi.org/10.1053/j.gastro.2020.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726704PMC
November 2020

Antifibrotic Effects of the Thiazolidinediones in Eosinophilic Esophagitis Pathologic Remodeling: A Preclinical Evaluation.

Clin Transl Gastroenterol 2020 04;11(4):e00164

Division of Allergy and Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, California, USA.

Introduction: Eosinophilic esophagitis (EoE) is a T-helper 2 (Th2), eosinophilic disease associated with pathologic tissue remodeling that leads to end-organ dysfunction. During early-stage disease, inflammation and subepithelial fibrosis are coupled and reversible, but in late-stage or therapy-resistant disease, there can be uncoupling of these features with progressive esophageal rigidity and strictures contributing to clinical dysphagia and food impactions. No current pharmacotherapeutic interventions directly target esophageal fibrosis. Based on the ability of the thiazolidinediones (TZD) to regulate intestinal and hepatic fibrosis, we tested the antifibrotic effects of the TZDs, rosiglitazone and pioglitazone, in preclinical studies using primary human esophageal fibroblasts.

Methods: Primary fibroblasts isolated from normal or EoE esophagi were treated with transforming growth factor (TGF)-β1 in the absence or presence of TZDs and, in some experiments, without or with budesonide and analyzed by quantitative real-time PCR and immunoblotting. Immunohistochemical analysis of human esophageal biopsies was performed.

Results: EoE esophageal biopsies and esophageal fibroblasts expressed higher levels of the TZD receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), than normal controls. PPAR-γ was inducible by the Th2 cytokine, interleukin 4 (IL-4). TZD significantly reduced TGF-β1-induced myofibroblast and fibrotic gene and protein expression preferentially in EoE, but not normal esophageal fibroblasts. In esophageal fibroblasts, TGF-β1 increased phosphorylated Smad2/3 and p38, but TZDs preferentially inhibited p38 phosphorylation, suggesting signaling pathway-specific effects. The TZDs were more potent than budesonide at decreasing collagen-1α1 expression.

Discussion: The TZDs preferentially exert antifibrotic effects in TGF-β1-activated EoE fibroblasts and provide a preclinical foundation for further investigation of the potential of the TZDs in EoE pathologic remodeling.
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http://dx.doi.org/10.14309/ctg.0000000000000164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263661PMC
April 2020

Evaluation of long-term course in children with eosinophilic esophagitis reveals distinct histologic patterns and clinical characteristics.

J Allergy Clin Immunol 2019 10 28;144(4):1050-1057.e5. Epub 2019 Jun 28.

Division of Allergy and Immunology, University of California, San Diego, La Jolla, Calif; Department of Pediatrics, University of California, San Diego, La Jolla, Calif; Department of Medicine, University of California, San Diego, La Jolla, Calif; Rady Children's Hospital, San Diego, Calif. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic and increasingly prevalent antigen-driven disease. There is a paucity of information on long-term course in children.

Objective: We sought to understand the longitudinal trajectory of pediatric EoE during routine clinical care.

Methods: We prospectively enrolled children into an EoE database and reviewed their medical and pathologic records over 13 years.

Results: From 2011 to 2015, 146 children with EoE seen for their first visit at our center had 2 or more years of follow-up and 3 or more endoscopies over an average follow-up period of 5.13 years (range, 2-13 years). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with less than 15 eosinophils/high-power field (hpf) for greater than 75% of their follow-up period were termed continuous responders (CRs). Children with waxing and waning inflammation of less than 15 eosinophils/hpf for less than 75% but 25% or more of the follow-up period were termed intermittent responders (IRs). Nonresponders (NRs) were defined as having less than 15 eosinophils/hpf for less than 25% of their follow-up. Fifty-nine (40%) of 146 patients were CRs, 65 (45%) of 146 were IRs, and 22 (15%) of 146 were NRs. CRs differed from IRs and NRs on the parameter of male/female ratio (1:1 in CRs, 4:1 in IRs, and 6:1 in NRs; P < .001) and in their initial response to any therapy, including proton pump inhibitors (P < .001). Endoscopic severity correlated with esophageal eosinophilia (r = 0.73, P < .001). On multivariate analysis, female sex and initial therapeutic response to medications or elimination diet were associated with long-term control of esophageal eosinophilia.

Conclusions: Long-term pediatric EoE followed 3 different longitudinal trajectories of inflammation. The long-term histologic groups differed significantly in biological sex and initial therapeutic response.
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http://dx.doi.org/10.1016/j.jaci.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820855PMC
October 2019

Development and Application of a Functional Human Esophageal Mucosa Explant Platform to Eosinophilic Esophagitis.

Sci Rep 2019 04 17;9(1):6206. Epub 2019 Apr 17.

Division of Allergy & Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

There is an increasing prevalence of esophageal diseases but intact human tissue platforms to study esophageal function, disease mechanisms, and the interactions between cell types in situ are lacking. To address this, we utilized full thickness human donor esophagi to create and validate the ex vivo function of mucosa and smooth muscle (n = 25). Explanted tissue was tested for contractile responses to carbachol and histamine. We then treated ex vivo human esophageal mucosa with a cytokine cocktail to closely mimic the Th2 and inflammatory milieu of eosinophilic esophagitis (EoE) and assessed alterations in smooth muscle and extracellular matrix function and stiffening. We found that full thickness human esophagus as well as the individual layers of circular and longitudinal muscularis propria developed tension in response to carbachol ex vivo and that mucosa demonstrated squamous cell differentiation. Treatment of mucosa with Th2 and fibrotic cytokines recapitulated the majority of the clinical Eosinophilic Esophagitis Diagnostic Profile (EDP) on fluidic transcriptional microarray. Transforming growth factor-beta-1 (TGFβ1) increased gene expression of fibronectin, smooth muscle actin, and phospholamban (p < 0.001). The EoE cocktail also increased stiffness and decreased mucosal compliance, akin to the functional alterations in EoE (p = 0.001). This work establishes a new, transcriptionally intact and physiologically functional human platform to model esophageal tissue responses in EoE.
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http://dx.doi.org/10.1038/s41598-019-41147-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470157PMC
April 2019

Esophageal Compliance Quantifies Epithelial Remodeling in Pediatric Patients With Eosinophilic Esophagitis.

J Pediatr Gastroenterol Nutr 2019 04;68(4):559-565

Division of Gastroenterology Hepatology and Nutrition.

Background: The management of eosinophilic esophagitis (EoE) relies on the severity of esophageal eosinophilia, yet there is poor evidence of its prediction of esophageal fibrotic remodeling and subsequent complications such as dysphagia, food impactions, or strictures. Functional luminal imaging planimetry (FLIP) has had limited use in pediatric patients to evaluate esophageal tissue mechanics. We aimed to standardize the FLIP technique and to measure esophageal compliance in children with EoE in comparison to controls.

Methods: Subjects were enrolled into a prospective observational study and had FLIP performed at the time of endoscopy. We calculated esophageal distensibility and compliance for the total and segmental esophagus independently (ie, proximal, middle, and distal esophageal segments). We evaluated esophageal biopsies for eosinophilia and epithelial remodeling, calculated endoscopy scores, and documented patient symptoms.

Results: We enrolled 11 EoE and 12 controls subjects, aged 5 to 18 years old. While EoE subjects had lower esophageal compliance (P = 0.004) than controls, the difference in distensibility did not reach significance (P = 0.151). Epithelial remodeling severity was more strongly correlated with compliance than with distensibility. Epithelial remodeling scores ≥2 had a significant association with lower compliance both segmentally and in the entire esophagus (P = 0.029), but not with distensibility. Compliance measures were more sensitive in detecting subjects with remodeling score ≥2 than distensibility (79% vs 64%).

Conclusions: Compliance is a more sensitive measure of esophageal epithelial remodeling in children compared to distensibility, and a more appropriate measure of esophageal tissue mechanics. Standardized placement of the FLIP catheter is important to accurately assess esophageal compliance.
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http://dx.doi.org/10.1097/MPG.0000000000002202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453699PMC
April 2019

Interleukin 9 Alters Epithelial Barrier and E-cadherin in Eosinophilic Esophagitis.

J Pediatr Gastroenterol Nutr 2019 02;68(2):225-231

Division of Allergy, Immunology.

Background: Eosinophilic esophagitis (EoE) is a chronic TH2-assocated inflammatory condition accompanied by substantial impairments in epithelial barrier function and increased numbers of interleukin 9 (IL-9) expressing inflammatory cells. While IL-9 is known to affect barrier function in the intestine, the functional effects of IL-9 on the esophagus are unclear. Herein we aimed to understand the expression of the IL-9 receptor and effects of IL-9 on the epithelium in EoE.

Methods: We used esophageal biopsies from pediatric EoE patients with active and inactive disease to analyze the expression of the IL-9 receptor, the adherens junction protein E-cadherin and the tight junction protein claudin-1. We treated primary human esophageal epithelial cells with IL-9 to understand its effects on E-cadherin expression and function.

Results: Active EoE subjects had increased epithelial expression of IL-9 receptor mRNA and protein (P < 0.05) and decreased membrane bound E-cadherin (P < 0.01) and claudin-1 (P < 0.05) expression. IL-9 receptor expression and mislocalized claudin-1 positively correlated and while membrane bound E-cadherin expression negatively correlated with the degree of histologic epithelial remodeling (P < 0.05). IL-9 decreased epithelial resistance in stratified primary human esophageal epithelial cells (P < 0.01) and membrane bound E-cadherin in epithelial cell monolayers (P < 0.01).

Conclusions: These data suggest that IL-9, its receptor, and its effects on E-cadherin may be important mechanisms for epithelial barrier disruption in EoE.
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http://dx.doi.org/10.1097/MPG.0000000000002144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344288PMC
February 2019

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.

Gastroenterology 2018 10 6;155(4):1022-1033.e10. Epub 2018 Sep 6.

Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

Background & Aims: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis.

Methods: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences.

Results: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement.

Conclusions: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.
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http://dx.doi.org/10.1053/j.gastro.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174113PMC
October 2018

TGF-β1-induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis.

J Allergy Clin Immunol 2016 09 8;138(3):791-800.e4. Epub 2016 Apr 8.

Division of Allergy and Immunology, Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, and Rady Children's Hospital, San Diego, Calif; Center for Infection, Immunity, and Inflammation, Departments of Pediatrics and Medicine, University of California, San Diego, La Jolla, and Rady Children's Hospital, San Diego, Calif. Electronic address:

Background: Eosinophilic esophagitis (EoE) is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve TGF-β1-mediated fibrosis. Plasminogen activator inhibitor 1 (PAI-1/serpinE1) can be induced by TGF-β1, but its role in EoE is not known.

Objective: We sought to understand the expression and role of PAI-1 in patients with EoE.

Methods: We used esophageal biopsy specimens and plasma samples from control subjects and patients with EoE, primary human esophageal epithelial cells, and fibroblasts from patients with EoE in immunohistochemistry, quantitative PCR, and immunoassay experiments to understand the induction of PAI-1 by TGF-β1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression.

Results: PAI-1 expression was significantly increased in epithelial cells of biopsy specimens from patients with active EoE compared with that seen in biopsy specimens from patients with inactive EoE or control subjects (P < .001). Treatment of primary esophageal epithelial cells with recombinant TGF-β1 increased PAI-1 transcription, intracellular protein expression, and secretion. Esophageal PAI-1 expression correlated with basal zone hyperplasia, fibrosis, and markers of esophageal remodeling, including vimentin, TGF-β1, collagen I, fibronectin, and matrix metalloproteases, and plasma PAI-1 levels correlated with plasma TGF-β1 levels. PAI-1 inhibition significantly decreased baseline and TGF-β1-induced fibrotic gene expression.

Conclusions: PAI-1 expression is significantly increased in the epithelium in patients with EoE and reflects fibrosis, and its inhibition decreases TGF-β1-induced gene expression. Epithelial PAI-1 might serve as a marker of EoE severity and form part of a TGF-β1-induced profibrotic network.
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http://dx.doi.org/10.1016/j.jaci.2016.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014565PMC
September 2016

The TGFβ1 Promoter SNP C-509T and Food Sensitization Promote Esophageal Remodeling in Pediatric Eosinophilic Esophagitis.

PLoS One 2015 14;10(12):e0144651. Epub 2015 Dec 14.

Division of Allergy, Immunology, University of California San Diego, La Jolla, California, United States of America.

Background: Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease associated with substantial esophageal remodeling and fibrosis. The functional TGFβ1 promoter SNP C-509 associates with renal fibrosis and asthma. The effect of TGFβ1 genotype and EoE severity or potential gene-environment interactions have not been previously reported in EoE.

Methods: Genotype at TGFβ1 C-509T and remodeling was analyzed in 144 subjects with EoE. The severity of remodeling and inflammation was analyzed in the context of IgE sensitization to food antigens and C-509T genotype.

Results: The TGFβ1 promoter C-509 genotypes CC, CT, and TT were 35%, 52%, and 13%, respectively. Sixty-six percent of subjects were sensitized to foods by positive skin prick test (SPT) or serum specific IgE. TT genotype subjects had significantly more TGFβ1 (CC subjects = 1300 per mm2; TT = 2250 per mm2) (p<0.05) and tryptase (CC subjects = 145 per mm2: TT = 307 per mm2) (p<0.05) positive cells and higher epithelial remodeling scores (2.4 vs 3.7, p<0.001) than CC subjects. The differences in TGFβ1 and tryptase positive cells as well as fibrosis were significantly increased when there was concurrent food sensitization. Food sensitization alone did not associate with any parameters of inflammation or remodeling.

Conclusions: Our data support a gene-environment interaction between food and genotype at C-509 that modulates disease severity in EoE. Since EoE subjects often continue to consume foods to which they are sensitized, these findings may have clinical relevance for disease management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144651PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678166PMC
June 2016

Rigid substrate induces esophageal smooth muscle hypertrophy and eosinophilic esophagitis fibrotic gene expression.

J Allergy Clin Immunol 2016 Apr 2;137(4):1270-1272.e1. Epub 2015 Nov 2.

Department of Medicine, University of California, San Diego, La Jolla, Calif; Division of Allergy and Immunology, Center for Infection, Immunity, and Inflammation, Department of Pediatrics, University of California, San Diego, La Jolla, Calif; Rady Children's Hospital, San Diego, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2015.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826849PMC
April 2016

Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.

J Allergy Clin Immunol 2015 Sep 30;136(3):792-794.e3. Epub 2015 Jul 30.

Rady Children's Hospital, San Diego, Calif; Division of Allergy and Immunology, Department of Pediatrics, Center for Infection, Immunity, and Inflammation, University of California, La Jolla, Calif.

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http://dx.doi.org/10.1016/j.jaci.2015.05.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562810PMC
September 2015

Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids.

J Allergy Clin Immunol 2016 Jan 30;137(1):147-156.e8. Epub 2015 Jul 30.

Division of Allergy and Immunology, University of California, San Diego, La Jolla, Rady Children's Hospital San Diego, San Diego, Calif; Center for Immunity, Infection, and Inflammation, University of California, San Diego, La Jolla, Rady Children's Hospital San Diego, San Diego, Calif; Department of Pediatrics, University of California, San Diego, La Jolla, Rady Children's Hospital San Diego, San Diego, Calif; Department of Medicine, University of California, San Diego, La Jolla, Rady Children's Hospital San Diego, San Diego, Calif. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic TH2 inflammatory disease characterized by tissue remodeling that leads to esophageal strictures and food impactions. Effects of therapy on long-term remodeling in patients with pediatric eosinophil-associated diseases have not been previously described.

Objective: We sought to understand the long-term control of esophageal remodeling in patients with EoE.

Methods: We assessed endoscopic and histologic remodeling and TGF-β1 expression in esophageal biopsy specimens from children (n = 32) with EoE treated with topical corticosteroids (TCSs) over 10 years (mean, 4.5 years). We used standardized EoE scoring tools to gauge endoscopic and symptom features.

Results: Seven hundred thirty-eight biopsy specimens from 246 endoscopic procedures were evaluated over 10 years. Four hundred eighty-six biopsy specimens had adequate lamina propria for evaluation of subepithelial remodeling. The severity of epithelial esophageal eosinophilia correlated with epithelial remodeling (basal zone hyperplasia, desquamation, and dilated intercellular spaces; P < .0001), lamina propria eosinophilia (P < .0001), and fibrosis (P < .0001). Sixteen subjects were initial responders (<15 eosinophils/high-power field) to TCSs. Responders and nonresponders spent 54% and 97% of their total disease duration with active EoE (P < .001) and 23% and 53% (P < .02) with maximal fibrosis scores, respectively. Responders had lower endoscopy scores during their disease duration (P = .013). Having less than 15 eosinophils/high-power field at any time correlated with lower fibrosis and endoscopic severity. TGF-β1(+) cell counts decreased in responders at the first biopsy, but this was not sustained. Symptoms did not correlate with other disease features.

Conclusions: Children with EoE have substantial esophageal remodeling, which associates with inflammation and can improve in a sustainable manner with TCSs. Although endoscopic features correspond to histologic features, symptoms did not correlate with inflammation or fibrosis.
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http://dx.doi.org/10.1016/j.jaci.2015.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715736PMC
January 2016

MMPs-2 and -14 Are Elevated in Eosinophilic Esophagitis and Reduced Following Topical Corticosteroid Therapy.

J Pediatr Gastroenterol Nutr 2015 Aug;61(2):194-9

*Division of Allergy, Immunology, Center for Immunity, Infection, and Inflammation †Department of Pediatrics, University of California ‡Department of Physiology and Biophysics, University of Arkansas Medical Center, Little Rock.

Objectives: Eosinophilic esophagitis (EoE) is a chronic, antigen-mediated disease in children and adults associated with substantial esophageal remodeling and fibrosis. The expression of the remodeling-associated matrix metalloproteinases (MMPs) has not been previously detailed in EoE.

Methods: MMP-2 and -14 expression and cellular localization were assessed using real-time quantitative polymerase chain reaction and immunohistochemistry/immunofluorescence in EoE fibroblasts, active and inactive pediatric EoE biopsies, and nondiseased control biopsies. The effect of transforming growth factor (TGF)-β1 treatment on MMP-2 expression in cultured esophageal epithelial (HET1A) cells was analyzed.

Results: MMP-2 and -14 mRNA were expressed in EoE fibroblasts and biopsies. Proliferating epithelial cells produced MMP-14 more abundantly in EoE than in controls (P < 0.001) and the degree of epithelial MMP-14 expression correlated positively with basal zone hyperplasia (r = 0.65, P = 0.002). EoE lamina propria had higher numbers of MMP-2- and -14-positive cells (906 ± 167 and 701 ± 93 cells/mm²) as compared with controls (258 ± 93 cells/mm², P < 0.01 and 232 ± 54 cells/mm², P < 0.01), and MMP-14 expression correlated with the severity of fibrosis. Following therapy with topical corticosteroids, MMP-14 and -2 were significantly diminished (P < 0.01). TGF-β1 increased the expression and secretion of MMP-2 from esophageal epithelial HET1A cells.

Conclusions: MMP-2 and -14 are elevated in pediatric patients with EoE and significantly decrease following topical corticosteroid therapy. TGF-β1 increases MMP-2 in esophageal epithelial cells. This alludes to previously unappreciated role for MMPs in EoE-associated esophageal remodeling and a potential positive feedback loop via TGF-β1.
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http://dx.doi.org/10.1097/MPG.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478274PMC
August 2015

Nephropathic cystinosis: an international consensus document.

Nephrol Dial Transplant 2014 Sep;29 Suppl 4:iv87-94

Department of Pediatric Nephrology and Growth and Regeneration, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.

Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
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http://dx.doi.org/10.1093/ndt/gfu090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158338PMC
September 2014

TGF-β1-induced phospholamban expression alters esophageal smooth muscle cell contraction in patients with eosinophilic esophagitis.

J Allergy Clin Immunol 2014 Nov 13;134(5):1100-1107.e4. Epub 2014 May 13.

Division of Allergy and Immunology, University of California, San Diego, Calif; Department of Pediatrics, University of California, San Diego, Calif; Department of Medicine, University of California, San Diego, Calif. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease characterized by esophageal eosinophilia, remodeling, and fibrosis. TGF-β1 is a central regulator of EoE remodeling and increases esophageal smooth muscle (ESM) cell contraction.

Objective: In this study we aimed to understand the molecular mechanisms by which TGF-β1 could induce ESM cell contraction.

Methods: We used primary human ESM cells and esophageal myofibroblasts (EMFs) to assess the mechanisms of TGF-β1-induced contraction. We analyzed the expression, phosphorylation, and function of phospholamban (PLN), a sarcoendoplasmic reticulum regulatory protein induced by TGF-β1. Expression of PLN, phospho-PLN, and its regulatory pathway was analyzed in the ESM of biopsy specimens from patients with EoE and control subjects. Gene silencing in EMFs from patients with EoE was used to understand the role of PLN in contraction.

Results: TGF-β1 induced and phosphorylated PLN in primary human ESM cells and EMFs from patients with EoE. PLN and phospho-PLN levels were increased in smooth muscle from patients with EoE compared with that seen in smooth muscle from control subjects in vivo. PLN inhibition significantly diminished TGF-β1-induced EMF contraction in patients with EoE. PLN expression and ESM/EMF contraction depended on TGF-β receptor I signals.

Conclusion: We describe a previously unrecognized mechanism for ESM cell contraction that depends on TGF-β1, its receptors, and PLN. Because PLN levels are increased in smooth muscle from patients with EoE and PLN silencing diminishes contraction, we provide a novel potential mechanistic framework and therapeutic target for ESM dysfunction in patients with EoE.
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http://dx.doi.org/10.1016/j.jaci.2014.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231011PMC
November 2014

Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.

J Allergy Clin Immunol 2013 Jun 25;131(6):1576-82. Epub 2013 Apr 25.

Division of Allergy and Immunology, University of California, San Diego, Rady Children's Hospital, San Diego, Calif., USA.

Background: Eosinophilic esophagitis (EoE) is a clinicopathologic entity of increasing worldwide prevalence. IL-5 is essential for eosinophil trafficking, and anti-IL-5 therapy decreases esophageal eosinophilia. EoE is associated with prominent mast cell infiltration.

Objective: We investigated whether anti-IL-5 (mepolizumab) treatment reduced esophageal mast cell accumulation in biopsy specimens from pediatric patients with EoE from a previous randomized anti-IL-5 trial.

Methods: A subanalysis was completed for children treated with 0.55, 2.5, or 10 mg/kg mepolizumab monthly for 12 weeks followed by no treatment until week 24. Quantitative immunochemistry was used to assess the numbers of eosinophils, tryptase-positive mast cells, IL-9(+) cells, and mast cell-eosinophil couplets before and after treatment.

Results: Forty-three biopsy specimens had adequate tissue for paired analysis. Forty percent of subjects responded to anti-IL-5 (defined as <15 eosinophils per high-power field [hpf] after mepolizumab therapy), and 77% of all subjects had decreased numbers of mast cells after anti-IL-5. In responders epithelial mast cell numbers decreased from 62 to 19 per hpf (P < .001), were significantly lower than in nonresponders after therapy (P < .05), and correlated with eosinophil numbers (r = 0.75, P < .0001). Mast cells and eosinophils were found in couplets before therapy, and these were significantly decreased only in responders after anti-IL-5 (P < .001). Esophageal eosinophils comprised the majority of cells that made the mast cell growth factor IL-9. IL-9(+) cell numbers decreased from 102 to 71 per hpf (P < .001) after anti-IL-5.

Conclusions: Pediatric patients with EoE had significantly fewer mast cells, IL-9(+) cells, and mast cell-eosinophil couplets in the esophageal epithelium after anti-IL-5 therapy. Because eosinophils were one source of IL-9, they might support esophageal mastocytosis.
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http://dx.doi.org/10.1016/j.jaci.2013.02.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699422PMC
June 2013

Pharmacokinetic Studies of Cysteamine Bitartrate Delayed-Release.

Clin Pharmacol Drug Dev 2013 Apr 12;2(2):178-85. Epub 2013 Mar 12.

Department of Pediatrics, University of California San Diego, La Jolla, CA.

A twice-daily microsphere formulation of cysteamine bitartrate has been developed for cystinosis and other potential applications. To date, there are no published pharmacokinetic data for cysteamine bitartrate delayed-release in healthy adults. Three randomized open-label, crossover studies to determine the effects of fasting, high fat, and carbohydrate meals on the bioavailability of cysteamine bitartrate delayed-release (600 mg) administered in capsule or sprinkle form to healthy adults. Adverse events were monitored. Fifty-eight adults were studied. Cysteamine absorption (AUC0-24 hours ) was the same for capsule and sprinkle forms during all meal/fasting states. The AUC0-24 hours for capsules while fasted, 30 and 120 minutes before a carbohydrate meal and during a high fat meal were 6,313 ± 329, 4,616 ± 878, 6,691 ± 669, 2,572 ± 295 minutes × µM, respectively, and the mean Cmax values were 29.4 ± 1.7, 20.7 ± 4.9, 31.6 ± 3.0, and 10.9 ± 1.7 µM, respectively. The mean Tmax following fasting and high fat meal were about 3 and 6 hours, respectively. Minor transient GI adverse events occurred. Cysteamine bitartrate delayed-release capsule and sprinkle forms are bioequivalent and optimal absorption occurs during fasting state. High fat diet reduces drug absorption, increases the Tmax and should be avoided at the time of drug ingestion. Cysteamine bitartrate delayed-release (RP103) is best ingested >30 minutes before a carbohydrate-rich meal.
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http://dx.doi.org/10.1002/cpdd.12DOI Listing
April 2013

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery.

Fundam Clin Pharmacol 2014 Apr 31;28(2):136-43. Epub 2012 Oct 31.

Department of Pediatric, University of California, San Diego, CA, USA; Rady Children's Hospital, San Diego, CA, USA.

Cysteamine is approved for the treatment of cystinosis and is being evaluated for Huntington's disease and non-alcoholic fatty liver disease. Little is known about the bioavailability and biodistribution of the drug. The aim was to determine plasma, cerebrospinal fluid (CSF), and tissue (liver, kidney, muscle) cysteamine levels following intraduodenal delivery of the drug in rats pretreated and naïve to cysteamine and to estimate the hepatic first-pass effect on cysteamine. Healthy male rats (n = 66) underwent intraduodenal and portal (PV) or jugular (JVC) venous catheterization. Half were pretreated with cysteamine, and half were naïve. Following intraduodenal cysteamine (20 mg/kg), serial blood samples were collected from the PV or the JVC. Animals were sacrificed at specific time points, and CSF and tissue were collected. Cysteamine levels were determined in plasma, CSF, and tissue. The Cmax was achieved in 5-10 min from PV and 5-22.5 min from JVC. The PV-Cmax (P = 0.08), PV-AUC0-t (P = 0.16), JVC-Cmax (P = 0.02) and JVC-AUC0-t (P = 0.03) were higher in naive than in pretreated animals. Plasma cysteamine levels returned to baseline in ≤120 min. The hepatic first-pass effect was estimated at 40%. Peak tissue and CSF cysteamine levels occurred ≤22.5 min, but returned to baseline levels ≤180 min. There was no difference in CSF and tissue cysteamine levels between naïve and pretreated groups, although cysteamine was more rapidly cleared in the pretreated group. Cysteamine is rapidly absorbed from the small intestine, undergoes significant hepatic first-pass metabolism, crosses the blood brain barrier, and is almost undetectable in plasma, CSF, and body tissues 2 h after ingestion. Sustained-release cysteamine may provide prolonged tissue exposure.
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http://dx.doi.org/10.1111/fcp.12009DOI Listing
April 2014

The Effect of Food on Cysteamine Bitartrate Absorption in Healthy Participants.

Clin Pharmacol Drug Dev 2012 Oct;1(4):170-4

Department of Pediatrics, University of California, San Diego, CA, USARady Children's Hospital, San Diego, CA, USARaptor Pharmaceuticals, Novato, CA, USA.

Objectives: Treatment with cysteamine reduces the rate of progression to end-stage kidney disease in cystinosis. Although food is often taken with cysteamine to reduce associated gastrointestinal symptoms, this may alter the bioavailability of cysteamine.

Methods: This is a prospective, randomized, 3-treatment study to determine the effects of fasting and high-fat/calorie and high-protein meals on cysteamine absorption in healthy adult controls. On 3 separate days, serial plasma cysteamine levels were measured after cysteamine bitartrate 500 mg was ingested while fasting and also 30 minutes after high-fat/calorie and high-protein diets. Gastrointestinal (GI) symptoms were also monitored.

Results: Eight participants (5 men) were enrolled. Cysteamine absorption, as measured by area under the cysteamine concentration-time curve (AUC0-∞ ) while fasted and following high-fat/calorie and high-protein meals, was 3618 ± 372 min·μM, 2799 ± 405 min·μM (P = .04 vs fasted), and 2457 ± 353 min·μM (P = .005), respectively, and the mean Cmax values for participants were 26.3 ± 3.5 μM, 22.4 ± 5.6 μM (P = .16 vs fasted), and 17.2 ± 2.6 μM (P = .036 vs fasted), respectively. Mild GI symptoms were reported in 3 participants.

Conclusions: Cysteamine absorption may be decreased by 30% when taken with food as compared with the fasting state. Food causes wide variation in tmax and Cmax for cysteamine.
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http://dx.doi.org/10.1177/2160763X12454423DOI Listing
October 2012

Treatment of cystinosis with delayed-release cysteamine: 6-year follow-up.

Pediatr Nephrol 2013 Mar 25;28(3):507-10. Epub 2012 Sep 25.

Department of Pediatrics, Rady Children's Hospital-San Diego, University of California San Diego, 3030 Children's Way, San Diego, CA 92123, USA.

Background: Patients with nephropathic cystinosis are required to take 6-hourly immediate-release cysteamine (Cystagon®) to reduce disease progression. This arduous regimen affects quality of life, disrupts sleep, and may result in non-compliance with therapy. Enteric-coated cysteamine bitartrate (EC-cysteamine) was developed as a "proof-of-concept" formulation for twice-daily ingestion. Previous reports have shown this therapy to be effective up to a mean of 14 months.

Case-diagnosis/treatment: Two subjects (aged 13 and 15 years) received EC-cysteamine for 5-6 years at 60-65 % of their previous total daily dose of immediate-release cysteamine given at 6-h intervals. White blood cell (WBC) cystine levels were monitored every 1-3 months.

Conclusion: The administration of EC-cysteamine did not result in any change in mean trough WBC cystine levels or any deterioration in the estimated glomerular filtration rate, thyroid, or liver function, suggesting that delayed-release, twice-daily EC-cysteamine is an effective long-term treatment alternative to immediate-release cysteamine given at 6-h intervals.
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http://dx.doi.org/10.1007/s00467-012-2315-5DOI Listing
March 2013

The effect of cysteamine bitartrate on adiponectin multimerization in non-alcoholic fatty liver disease and healthy subjects.

J Pediatr 2012 Oct 24;161(4):639-45.e1. Epub 2012 May 24.

Department of Pediatrics, University of California, San Diego, San Diego, CA 92103-8450, USA.

Objective: To determine the effects of cysteamine on adiponectin multimerization in sera of patients with nonalcoholic fatty liver disease (NAFLD).

Study Design: Sera from 10 children with biopsy-proven NAFLD treated with cysteamine were assayed for adiponectin multimers at baseline, after 24 weeks of treatment, and again 16 weeks after discontinuing treatment. Pretreatment sera from subjects with NAFLD and from adult controls without NAFLD controls (n = 8) were incubated in cysteamine and multimers were measured 1 hour later. A cysteamine/adiponectin multimer dose-response curve was created.

Results: Following 24 weeks of cysteamine therapy, the mean percentage increase for high, medium (MMW), and low (LMW) molecular weight multimers and total adiponectin from baseline was 53% (P = .02), 19% (P = .02), 29.4% (P = .03), and 49.3% (P = .05), respectively. Levels returned to baseline at 16 weeks after stopping therapy, unlike hepatic transaminase levels which remained low. Sera from 0 week, incubated in cysteamine for 1 hour, showed a significant mean percent increase in LMW adiponectin levels and a mean percent reduction in MMW levels compared with baseline in adults with and without NAFLD.

Conclusions: Cysteamine impacts adiponectin multimerization. Long-term cysteamine therapy increases levels of all multimers, whereas, in vitro short-term exposure causes a rapid increase in LMW and reduction in MMW multimers in NAFLD and healthy controls. Cysteamine may be a potential therapeutic agent for conditions associated with insulin-resistance, oxidative stress, and depressed adiponectin levels.
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http://dx.doi.org/10.1016/j.jpeds.2012.04.011DOI Listing
October 2012

A potential new method to estimate tissue cystine content in nephropathic cystinosis.

J Pediatr 2012 Sep 17;161(3):531-535.e1. Epub 2012 Apr 17.

Departments of Pediatrics and Pathology, University of California, San Diego, La Jolla, CA, USA.

Objectives: To evaluate intestinal mucosal cystine crystal (CC) load as a way to estimate tissue cystine content in children with cystinosis.

Study Design: Intestinal mucosal biopsies were obtained endoscopically from children (ages 2-18 years) with cystinosis. Using a special processing technique, CC within histiocytes were easily visible and enumerable in the mucosal tissue. Mean CC counts, calculated from stomach and duodenum combined (CC-GD), were correlated with duration of cysteamine treatment, estimated glomerular filtration rate (eGFR), and mean white blood cells (WBC) cystine levels.

Results: Seventeen subjects (6 male) were enrolled in 2 studies from 2001 and 2003. The CC-GD count (mean 12.5 ± 1.41 crystals/histiocyte) was lower than the colonic crystal count (mean 23.6 ± 3.38, P = .0031). Nine of 17 subjects underwent repeated endoscopy 2 years later and the trend for CC-GD was to decrease over time (P = .065). Biopsies, however, were never completely depleted of CC. In subjects who were diagnosed before age 18 months, the percent change from baseline of both eGFR and CC-GD were inversely correlated (P = .026). Mean WBC cystine levels were positively correlated with CC-GD (P = .023).

Conclusions: CC are easily visible in the intestinal mucosa. CC-GD counts appear to correlate with eGFR and may help monitor response to treatment. Even when mean WBC cystine levels are low, the mucosal CC are not depleted suggesting that tissue cysteamine levels may not achieve therapeutic efficacy.
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http://dx.doi.org/10.1016/j.jpeds.2012.03.011DOI Listing
September 2012

Transient PPI responsive esophageal eosinophilia may be a clinical sub-phenotype of pediatric eosinophilic esophagitis.

Dig Dis Sci 2012 May 2;57(5):1413-9. Epub 2011 Dec 2.

Departments of Pediatrics and Pathology, University of California, San Diego, La Jolla, CA, USA.

Background: Eosinophilic esophagitis (EoE) and gastroesophageal reflux (GERD) both cause esophageal eosinophilia. Reports show that esophageal eosinophilia meeting criteria for EoE may respond to acid suppression mono-therapy. Consensus guidelines have termed this entity "PPI-responsive esophageal eosinophilia" (PPIRee) and recommend a trial with proton-pump inhibitors (PPIs) prior to a definitive EoE diagnosis. The mechanisms of PPIRee and whether this represents a sub-phenotype of GERD, a sub-phenotype of EoE, or its own distinct entity remain unclear.

Methods: A database search revealed children who had an initial histologic response to PPI monotherapy but had recurrence of esophageal eosinophilia and symptoms despite continued PPI therapy. In order to understand the patterns of esophageal inflammatory cells during PPI therapy we performed quantitative immunohistochemistry for mast cells, CD1a positive antigen presenting cells, and CD45RO memory T cells.

Results: Four pediatric patients (mean age 9.5 years) had a mean peak eosinophil count of 52 eos/hpf which initially resolved completely during PPI mono-therapy. However, despite continued PPI therapy, endoscopic abnormalities and pan-esophageal eosinophilia recurred (mean peak eosinophil count of 64 eos/hpf). There was no seasonal variation or lack of PPI adherence that explained the return of eosinopihlia. Similar to eosinophilia, mastocytosis and CD45RO cells were transiently decreased during PPI therapy.

Conclusion: PPIs appear to be capable of transiently resolving multiple inflammatory cell subsets including eosinophils, mast cells, and CD45RO cells. Our data suggest that patients with PPIRee should have continued monitoring for EoE during PPI monotherapy. The numbers of patients in whom PPIRee is a transient phenomenon and whether PPIRee represents a sub-phenotype of EoE in children merits further investigation.
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http://dx.doi.org/10.1007/s10620-011-1991-5DOI Listing
May 2012

Eosinophilic esophagitis: updated consensus recommendations for children and adults.

J Allergy Clin Immunol 2011 Jul 7;128(1):3-20.e6; quiz 21-2. Epub 2011 Apr 7.

Center for Pediatric Eosinophilic Disorders, Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.
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http://dx.doi.org/10.1016/j.jaci.2011.02.040DOI Listing
July 2011

Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction.

J Allergy Clin Immunol 2010 Dec 3;126(6):1198-204.e4. Epub 2010 Nov 3.

Division of Allergy and Immunology, University of California and Rady Children's Hospital, San Diego, USA.

Background: Increased numbers of mast cells are present in the esophageal epithelium in patients with eosinophilic esophagitis (EE). However, mast cell infiltration into the esophageal lamina propria (LP) and smooth muscle (SM) and the effects of their products on SM function has not been determined.

Objective: We investigated mast cell localization and characterization in esophageal SM, the functional significance of mast cell TGF-β1 expression to contraction of human esophageal smooth muscle (HESM) cells in vitro, and the effect of topical corticosteroids on the number of tryptase-positive (MC(T)) and chymase-positive (MC(C)) mast cells in patients with EE.

Methods: MC(T)- and MC(C)-positive mast cell numbers were quantitated in the epithelium, the LP before and after topical corticosteroid therapy, and the muscularis mucosa in patients with EE and control subjects by using immunohistology. Double immunofluorescence was used to assess mast cell production of TGF-β1. The ability of TGF-β1 to influence HESM cell contractility was assessed in vitro.

Results: In the SM in patients with EE, significantly increased numbers of MC(T)- and TGF-β1-positive cells (but only low levels of eosinophils) were detected compared with those seen in control subjects. MC(T) expressed TGF-β1, which increased the contractility of cultured primary HESM cells in vitro. Topical corticosteroid therapy in patients with EE significantly reduced epithelial MC(T) numbers but not LP tryptase-chymase-positive mast cell numbers.

Conclusions: MC(T) numbers, rather than eosinophil numbers, are increased in the SM in patients with EE, express TGF-β1, and increase the contractility of HESM cells in vitro. As such, mast cells localized to SM in patients with EE might modulate esophageal contractility.
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http://dx.doi.org/10.1016/j.jaci.2010.08.050DOI Listing
December 2010

Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study.

Br J Clin Pharmacol 2010 Sep;70(3):376-82

Department of Paediatrics, University of California, San Diego, La Jolla, California, USA.

What Is Already Known About This Subject: Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for cysteamine. Regular cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients.

What This Study Adds: This is the only study that provides pharmacokinetic data for cysteamine delivered in an enteric-release preparation in normal subjects. EC-cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. EC-cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective.

Aims: Cysteamine bitartrate (Cystagon) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects.

Methods: Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded.

Results: Six healthy adults (mean age 20.7 years, range 18-24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml(-1)). The tmax following cysteamine bitartrate non-enteric-coated (mean and SD is 75+/-19 min) was shorter than cysteamine bitartrate enteric-coated (220+/-74 min) (P=0.001), but only the Cmax and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P<0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated.

Conclusion: Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically.
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http://dx.doi.org/10.1111/j.1365-2125.2010.03721.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949910PMC
September 2010

Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial.

Gastroenterology 2010 Aug 7;139(2):418-29. Epub 2010 May 7.

Departments of Pediatrics and Pathology, University of California, San Diego, La Jolla, California; and Rady Children's Hospital San Diego, San Diego, California 92103-8450, USA.

Background & Aims: Eosinophilic esophagitis (EoE) is caused by immunologic reactions to ingested/inhaled allergens. The diagnosis is considered if >or=15 eosinophils per high-powered field (eos/hpf) are detected in mucosal biopsies. Placebo-controlled studies have not been conducted to evaluate the safety and efficacy of oral viscous budesonide (OVB).

Methods: Children with EoE were randomly assigned to groups that were given OVB (n=15) or placebo (n=9). Patients<5 feet and >or=5 feet tall received 1 mg and 2 mg OVB daily, respectively. All patients received lansoprazole. Duration of treatment was 3 months, followed by repeat endoscopy and biopsies. Patients were classified as responders if their peak eosinophil counts were or=20 eos/hpf. Baseline and post-treatment symptoms and endoscopic and histologic features were scored.

Results: Thirteen (86.7%) children given OVB (P<.0001) and none who received placebo (P=.3) were classified as responders. Mean pre-/post-treatment peak eosinophil counts were 66.7 and 4.8 eos/hpf, respectively, in the group given OVB (P<.0001); they were 83.9 and 65.6 eos/hpf, respectively, in the group given placebo (P=.3). In the group given OVB, there were significant reductions from baseline values in proximal (P=.002), mid (P=.0003), and distal (P=.001) esophageal eosinophilia. After OVB therapy, compared with baseline, the mean symptom (P=.0007), endoscopy (P=.0005), and histology scores improved (P=.0035) significantly.

Conclusions: OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.
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http://dx.doi.org/10.1053/j.gastro.2010.05.001DOI Listing
August 2010