232 research outputs found
White Paper AGA: Drug Development for Eosinophilic Esophagitis
Since first characterized in 2 small case series in the early 1990s, eosinophilic esophagitis (EoE) has emerged as a commonly identified cause of esophageal symptoms in children and adults. Although several highly effectively dietary, pharmacologic, and endoscopic therapies have been reported, none is currently approved by either the US Food and Drug Administration (FDA) or European regulatory authorities. Evolving diagnostic criteria have challenged drug development, in particular the recognition of complex interactions with the most prevalent esophageal disorder, gastroesophageal reflux disease (GERD). Heterogeneity in the clinical presentations of affected children and adults has created difficulties with uniform inclusion criteria and the development of disease-specific, patient-reported outcome (PRO) instruments. Furthermore, controversies regarding the appropriate therapeutic endpoints of EoE have impeded the design of clinical trials. Despite these obstacles, collaborative efforts by investigators, industry, the FDA, and patient advocacy groups have resulted in substantial progress in drug development in EoE over the past 2 decades. The purpose of this article is to summarize discussions on EoE based on the 2016 Drug Development Conference sponsored by the Center for Diagnostics and Therapeutics of the American Gastroenterological Association
Eosinophils, probiotics, and the microbiome
There is currently substantial interest in the therapeutic
properties of probiotic microorganisms as recent research suggests that oral administration of specific
bacterial strains may reduce inflammation and alter the
nature of endogenous microflora in the gastrointestinal
tract. Eosinophils are multifunctional tissue leukocytes,
prominent among the resident cells of the gastrointestinal mucosa that promote local immunity. Recent studies
with genetically altered mice indicate that eosinophils not
only participate in maintaining gut homeostasis, but that
the absence of eosinophils may have significant impact
on the nature of the endogenous gut microflora and
responses to gut pathogens, notably Clostridium difficile.
Furthermore, in human subjects, there is an intriguing
relationship between eosinophils, allergic inflammation,
and the nature of the lung microflora, notably a distinct
association between eosinophil infiltration and detection
of bacteria of the phylum Actinobacteria. Among topics
for future research, it will be important to determine
whether homeostatic mechanisms involve direct interactions between eosinophils and bacteria or whether
they involve primarily eosinophil-mediated responses to
cytokine signaling in the local microenvironment. Likewise, although is it clear that eosinophils can and do
interact with bacteria in vivo, their ability to discern
between pathogenic and probiotic species in various
settings remains to be explored
Coordinated Adenine Nucleotide Phosphohydrolysis and Nucleoside Signaling in Posthypoxic Endothelium: Role of Ectonucleotidases and Adenosine A2B Receptors
Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (>60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (>20-and >12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A2B receptor (AdoRA2B) is selectively up-regulated by hypoxia (>5-fold increase in mRNA), and that AdoRA2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia
Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis
Background: Inflammatory bowel diseases,
encompassing Crohn’s disease and ulcerative colitis, are
characterised by persistent leucocyte tissue infiltration
leading to perpetuation of an inappropriate inflammatory
cascade. The neuronal guidance molecule netrin-1 has
recently been implicated in the orchestration of
leucocyte trafficking during acute inflammation. We
therefore hypothesised that netrin-1 could modulate
leucocyte infiltration and disease activity in a model of
inflammatory bowel disease.
Design: DSS-colitis was performed in mice with partial
genetic netrin-1 deficiency (Ntn-1+/- mice) or wild-type
mice treated with exogenous netrin-1 via osmotic pump
to examine the role of endogenous and therapeutically
administered netrin-1. These studies were supported by
in vitro models of transepithelial migration and intestinal
epithelial barrier function.
Results: Consistent with our hypothesis, we observed
induction of netrin-1 during intestinal inflammation in vitro
or in mice exposed to experimental colitis. Moreover,
mice with partial netrin-1 deficiency demonstrated an
exacerbated course of DSS-colitis compared to littermate
controls, with enhanced weight loss and colonic
shortening. Conversely, mice treated with exogenous
mouse netrin-1 experienced attenuated disease severity.
Importantly, permeability studies and quantitative
assessment of apoptosis reveal that netrin-1 signalling
events do not alter mucosal permeability or intestinal
epithelial cell apoptosis. In vivo studies of leucocyte
transmigration demonstrate suppression of neutrophil
trafficking as a key function mediated by endogenous or
exogenously administered netrin-1. Finally, genetic
studies implicate the A2B adenosine receptor in
netrin-1-mediated protection during DSS-colitis.
Conclusions: The present study identifies a previously
unrecognised role for netrin-1 in attenuating experimental
colitis through limitation of neutrophil trafficking
G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ
Proinflammatory consequences have been described for lysophosphatidylcholine, a lipid product of cellular injury, signaling via the
G protein–coupled receptor G2A on myeloid and lymphoid inflammatory cells. This prompted the hypothesis that genetic deletion
of G2A would limit intestinal inflammation in a mouse model of colitis induced by dextran sodium sulfate. Surprisingly, G2A2/2
mice exhibited significantly worsened colitis compared with wild-type mice, as demonstrated by disease activity, colon shortening,
histology, and elevated IL-6 and IL-5 in colon tissues. Investigation of inflammatory cells recruited to inflamed G2A2/2 colons
showed significantly more TNF-a+ and Ly6ChiMHCII2 proinflammatory monocytes and eosinophils than in wild-type colons.
Both monocytes and eosinophils were pathogenic as their depletion abolished the excess inflammation in G2A2/2 mice. G2A2/2
mice also had less IFN-g in inflamed colon tissues than wild-type mice. Fewer CD4+ lymphocytes were recruited to inflamed
G2A2/2 colons, and fewer colonic lymphocytes produced IFN-g upon ex vivo stimulation. Administration of IFN-g to G2A2/2
mice during dextran sodium sulfate exposure abolished the excess colitic inflammation and reduced colonic IL-5 and eosinophil
numbers to levels seen in wild-type mice. Furthermore, IFN-g reduced the numbers of TNF-a+ monocyte and enhanced their
maturation from Ly6ChiMHCII2 to Ly6CintMHCII+
. Taken together, the data suggest that G2A signaling serves to dampen
intestinal inflammation via the production of IFN-g, which, in turn, enhances monocyte maturation to a less inflammatory
program and ultimately reduces eosinophil-induced injury of colonic tissues
Should wheat, barley, rye, and/or gluten be avoided in a 6-food elimination diet?
Eosinophilic esophagitis (EoE), a food antigen-mediated disease, is effectively treated with the dietary elimination of six foods commonly associated with food allergies (milk, wheat, egg, soy, tree nuts/peanuts and fish/shellfish). Because wheat shares homologous proteins (including gluten) with barley and rye and may also be processed with these grains, some clinicians have suggested barley and rye may also trigger EoE as a result of cross-reaction and/or cross-contamination with wheat. In this opinion paper, we discuss the theoretical risks of cross-reactivity and cross-contamination among wheat, barley, and rye proteins (including gluten), assess common practices at EoE treatment centers, and provide recommendations for dietary treatment and future studies of EoE
Novel Peptide Nanoparticle Biased Antagonist of CCR3 Blocks Eosinophil Recruitment and Airway Hyperresponsiveness
Background—Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason may be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance.
Objective—We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G-protein signaling, but enable or promote receptor internalization.
Methods—Self-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by dynamic light scattering and NMR. Inhibitory activity on CCR3 signaling was assessed in vitro using flow cytometry, confocal microscopy, and western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed using a triple allergen mouse asthma model.
Results—R321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. IC50 values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of ERK1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo, R321 effectively blocks eosinophil recruitment into the lungs and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model.
Conclusions—R321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism may hold significant therapeutic promise by eluding the formation of drug tolerance
Addendum Guidelines for the Prevention of Peanut Allergy in the United States: Report of the National Institute of Allergy and Infectious Diseasesâ Sponsored Expert Panel
BackgroundFood allergy is an important public health problem because it affects children and adults, can be severe and even lifeâ threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. AÂ recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanutâ containing foods beginning in infancy.ObjectivesPrompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy.ResultsThe addendum provides three separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanutâ containing foods in the health care provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.ConclusionsGuidelines have been developed for early introduction of peanutâ containing foods into the diets of infants at various risk levels for peanut allergy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135514/1/pde13093_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135514/2/pde13093.pd
Addendum guidelines for the prevention of peanut allergy in the United States
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135363/1/pde13092.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135363/2/pde13092_am.pd
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