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.
SUMMARY Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. These tumor-resident MSCs are known to affect tumor growth, but the mechanisms are largely unknown. We found that MSCs isolated from spontaneous lymphomas in mouse (L-MSCs) strikingly enhanced tumor growth in comparison to bone marrow MSCs (BM-MSCs). L-MSCs contributed to greater recruitment of CD11b+Ly6C+ monocytes, F4/80+ macrophages, and CD11b+Ly6G+ neutrophils to the tumor. Depletion of monocytes/macrophages, but not neutrophils, completely abolished tumor promotion of L-MSCs. Furthermore, L-MSCs expressed high levels of CCR2 ligands, and monocyte/macrophage accumulation and L-MSC-mediated tumor promotion were largely abolished in CCR2−/− mice. Intriguingly, TNFα-pretreated BM-MSCs mimicked L-MSCs in their chemokine production profile and ability to promote tumorigenesis of lymphoma, melanoma, and breast carcinoma. Therefore, our findings demonstrate that, in an inflammatory environment, tumor-resident MSCs promote tumor growth by recruiting monocytes/macrophages.
Background & Aims Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Herein, we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), currently diagnosed by histology and clinical symptoms. Methods We developed an EoE diagnostic panel (EDP), comprising a 96-gene quantitative PCR array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction, using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14), subsequently vetted using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed paraffin embedded (FFPE) tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. Results The EDP identified adult and pediatric patients with EoE with ~96% sensitivity and ~98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with FFPE tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse following treatment. Conclusions We developed a molecular diagnostic test (referred as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.
Background & Aims We evaluated the efficacy and safety of high-dose swallowed fluticasone propionate (FP) and dose reduction in patients with eosinophilic esophagitis (EoE) and analyzed esophageal transcriptomes to identify mechanisms. Methods We conducted a randomized, multisite, double-blind, placebo-controlled trial of daily 1760 mcg FP in participants 3–30 years old with active EoE. Twenty-eight participants received FP and 14 received placebo. After 3 months, participants given FP who were in complete remission (CR) received 880 mcg FP daily, and participants in the FP or placebo groups who were not in CR continued or started, respectively, 1760 mcg FP daily for 3 additional months. The primary endpoint was histologic evidence for CR. Secondary endpoints were partial remission (PR), symptoms, compliance, esophageal gene expression, esophageal eosinophil count, and the relationship between clinical features and FP responsiveness. Results After 3 months, 65% of subjects given FP and no subjects given placebo were in CR (P=.0001); 12% of those given FP and 8% of those given placebo were in PR. In the FP group, 73% of subjects remained in CR and 20% were in PR after the daily dose was reduced by 50%. Extending FP therapy in FP-resistant participants did not induce remission. FP decreased heartburn severity (P=.041). Compliance, age, sex, atopic status, or anthropomorphic features were not associated with response to FP. Gene expression patterns in esophageal tissues of FP responders were similar to those of patients without EoE; there was evidence for heterogeneous steroid signaling in subjects that did not respond to FP. Conclusions Daily administration of a high dose of FP induces histologic remission in 65%–77% of patients with EoE after 3 months. A 50% dose reduction remained effective in 73%–93% of patients that initially responded to FP. Nonresponders had evidence of steroid resistance; histologic and molecular markers may predict resistance. Clinicaltrials.gov number: NCT00426283
Consensus diagnostic recommendations to distinguish gastro-oesophageal reflux disease (GORD) from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPI) unexpectedly uncovered an entity called “PPI-responsive oesophageal eosinophilia” (PPI-REE). PPI-REE refers to patients with clinical and histologic features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that PPI-REE and EoE patients at baseline are clinically, endoscopically and histologically indistinguishable, and have significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in PPI-REE patients, similar to the effects of topical steroids in EoE patients. Additionally, recent series have reported that EoE patients responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunologic mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic, and therapeutic features cannot be reliably distinguished. For patients with symptoms and histologic features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment, before diet and topical steroids. The reasons why some EoE patients respond to PPI, while others do not, remain to be elucidated.
Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double–deficient or CC chemokine receptor 3–deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer’s patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid-related orphan receptor gamma t–positive (ROR-γt+) innate lymphoid cells (ILCs) while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell–activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β–deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA+ cells and ROR-γt+ ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine.
Background Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing two entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen–driven, Th2-associated allergic disorder, whereas the etiology of PPI-REE remains a mystery. Objective In this study, our aim was to investigate the pathogenesis of PPI-REE using a recently described esophageal based EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts, and to determine if PPI therapy reverses any esophageal transcriptional abnormalities. Methods We evaluated the EDP signature in biopsy samples obtained from adult and pediatric PPI-REE subjects from four institutions and compared the pre and post PPI therapy expression profiles of these subjects with those of active EoE subjects. Results The EDP identified EoE from control subjects with 100% accuracy amongst the four clinical sites. Bioinformatic analysis revealed largely overlapping transcriptomes between PPI-REE and EoE, including the genes for eosinophil chemotaxis (CCL26), barrier molecules (DSG1), tissue remodeling (POSTN), and mast cells (CPA3). After PPI-mono therapy, PPI treatment alone almost completely reversed the allergic inflammatory transcriptome of PPI-REE. Furthermore, we identified a set of candidate genes to differentiate EoE from PPI-REE before treatment. Conclusion These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many subjects with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus may constitute a sub-phenotype of EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE particularly that associated with classic features of allergic inflammation provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.
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