The Rothenberg CURED Lab offers information about news coverage and happenings involving members of our lab, the division, division programs (Drug Allergy Program, Food Allergy Program, Transition and Adult Immunodeficiency Program) and the Cincinnati Center for Eosinophilic Disorders (CCED).
Evaluating Dietary Elimination for Eosinophilic Esophagitis
We are pleased to share that a Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) clinical trial evaluating dietary elimination for eosinophilic esophagitis (EoE) in adults has been published in Lancet: Gastroenterology and Hepatology:
"One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial". “The primary hypothesis of this trial was that the standard six-food elimination diet (removes animal milk, wheat, egg, soy, nuts, fish and shellfish) would be superior to a one-food elimination diet (removes animal milk) in achieving histologic remission in adult EoE,” says Kara Kliewer, RD, PhD, co-first author and CEGIR project manager. “We were surprised when we failed to demonstrate this. Instead, we found that both diets were similarly effective across multiple metrics.”
“The findings from this study are a tribute to the CEGIR team, composed of investigators across the USA working in tandem with patient advocacy groups, including APFED, CURED and EFC, and experts at the NIH. Our findings substantiate the effectiveness of food elimination diets as therapy and support using a one-food elimination diet as an initial approach,” says Marc Rothenberg, MD, PhD, senior author and principal investigator of CEGIR. “that will be effective in about one-third of adults with EoE. This approach may allow quicker effective treatment for some individuals and quicker access to specialized care for others.”
Highlighting Our 2022 Research
We believe in sharing our ideas, our discoveries, and our advancements. Learn more about the research of the Division of Allergy and Immunology at Cincinnati Children's through these narrated videos of recent (January-December 2022) basic and translational research highlights from the division, viewable as a playlist or grouped by topic.
Marc Rothenberg, MD, PhD recently published a summary in The Journal of Allergy and Clinical Immunology [italicize the journal name] about the decades-long journey to an FDA-approved treatment for the severe food allergy eosinophilic esophagitis (EoE).
When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly interleukin 13 (IL-13).
Pre-clinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex-vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 monoclonal antibody in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE.
Dupilumab, a precision therapeutic monoclonal antibody that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive FDA approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic and molecular features of EoE and garner FDA approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.
Read the article - https://www.jacionline.org/article/S0091-6749(22)01332-X/fulltext
Vitamin D levels in the population have dramatically decreased, with 50% of the Western population being vitamin D insufficient (serum levels <30 ng/mL). Vitamin D deficiency has been linked with the risk and severity of numerous inflammatory diseases, including allergies and inflammatory bowel diseases.
The Rothenberg CURED Lab recently published in Gut that vitamin D supplementation may alleviate allergic inflammation in the esophagus, whereas vitamin D deficiency may lead to a higher risk of developing allergic states, such as the severe food allergy eosinophilic esophagitis (EoE). One of the remarkable findings in the study was that vitamin D supplementation did not have a dramatic effect on vitamin D deficient conditions in a healthy state; however, in the vitamin D deficient and allergic state, vitamin D supplementation reversed IL-13-induced responses thought to be germane to EoE, reducing epithelial hyperproliferation and intercellular spaces and improving barrier function.
The study is one of the latest in a growing body of evidence illustrating how human health depends in many ways upon sufficient vitamin D levels.
Read the Cincinnati Children’s science blog - https://scienceblog.cincinnatichildrens.org/vitamin-d-supplementation-alleviates-il-13-induced-esophageal-inflammation/
Read the article - https://gut.bmj.com/content/early/2022/07/31/gutjnl-2022-327276
“My laboratory is taking a multi-disciplinary approach to better understand and treat allergic diseases. It is now clear that early life exposures have an important impact on disease risk susceptibility. A number of years ago, I was approached by a bright high school student, Jamie Tanzer, who had the idea that changes in the composition and usage of laundry detergent over the past several decades, may be a contributing factor to the allergy epidemic. Jamie subsequently worked in my laboratory pursuing this hypothesis. Her research, completed as an undergraduate student at Harvard University, provided proof for this hypothesis, implicating exposure to laundry detergent, as a causal factor in eliciting allergic sensitization including eosinophilic esophagitis. Based on these findings, we need to continue this line of research.” says Dr. Marc Rothenberg.
A recent collaborative study suggests that laundry detergent contains ingredients, including microbial enzymes, that are toxic to cells. As laundry detergent comes into contact with the skin, starting in infancy, it triggers an impaired skin barrier, promoting allergic sensitization.
In the study, mouse skin samples exposed in vitro to microbial proteases or laundry detergent exhibited physical damage, which was more pronounced in neonatal skin than adult skin. Exposure of the skin to microbial proteases in vitro resulted in an increase in the levels of the pro-allergy cytokines interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP). BALB/c wild type mice epicutaneously exposed to LD and ovalbumin (OVA) showed an increase in levels of transepidermal water loss, serum OVA-specific immunoglobulin (Ig) G1 and IgE antibodies, and a local increase of Il33, Tslp, Il4 and Il13 compared with laundry detergent or OVA alone. Following intranasal challenge with OVA, mice epicutaneously exposed to laundry detergent showed an increase in allergen-induced esophageal eosinophilia compared with laundry detergent or OVA alone.
Collectively, these results suggest that laundry detergent may be an important factor that impairs the skin barrier and leads to allergen sensitization in early life and therefore may have a role in the increase in allergic disease.
Read the article - https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268651
The multiple layers (epithelium) of the esophagus provides protection against stimuli, including food, bacteria, and stomach acid. However, the differentiation program that makes these epithelial layers is profoundly changed in eosinophilic esophagitis (EoE), an allergic inflammatory disease of the esophagus.
Soon to be featured on the July 2022 issue cover of the Journal of Clinical Investigation Insight, Rochman et al. used single-cell RNA sequencing to explore gene expression of the human esophageal epithelium during EoE (active and remission) and normal conditions (healthy control). They found that during active EoE, epithelial differentiation was blocked, as reflected by reduction of differentiated cell populations and expansion of proliferating and transitioning cell populations. Changes in differentiation were accompanied by transcription factor dysregulation in differentiated cells.
“Investigating at the single-cell level has revealed how a block in cell populations going through stages of differentiation in disease underlies the structural dysfunction of the epithelial barrier in EoE,” says first author of the study, Mark Rochman, PhD.
Importantly, they further found that the epithelium of EoE in remission more closely resembled the epithelium of active EoE than control epithelium, suggesting that cells remain poised to relapse during disease remission. These data, identifying 6 epithelial populations and their cellular trajectory and spatial localization, provide a framework for larger studies to investigate the complex contribution of the esophageal epithelium to EoE pathogenesis.
“It is exciting how these translational studies are shaping how we think about allergic inflammation in the esophagus and the development of future therapeutics to improve health,” says Marc Rothenberg, MD, PhD, senior author of the study.
Read the article - https://insight.jci.org/articles/view/159093
The Rothenberg CURED Lab is part of the amazing community raising awareness and supporting research of eosinophilic conditions.Thank you for being a part of this community.
“We are working to solve the mysteries of eosinophilic gastrointestinal diseases. Each day, we strive to better understand these diseases and develop better treatment. Indeed, in partnership with patient advocacy groups from around the world and the National Institutes of Health, our research teams in the Rothenberg CURED Lab and the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) are developing key components of clinical trial readiness that allow us to be in best position to solve these diseases and to partner with other entities, including companies, to develop the best treatment and outcomes for patients with these eosinophilic diseases.”
We believe in sharing our ideas, our discoveries, and our advancements. Listen to a talk-along about basic and translational research highlights from the Division of Allergy and Immunology this past year related to eosinophilic diseases in honor of National Eosinophil Awareness Week 2022 (May 15-21, 2022).
Highlights of Eosinophilic Disease-Related Research (May 2021-2022) Video
Mast cells are cells that produce multiple effects and accumulate in the esophagus of patients with eosinophilic esophagitis (EoE). Mast cells are thought to contribute to disease pathogenesis, yet their properties and functions in the esophagus were largely unknown.
We performed a comprehensive molecular and spatial characterization of esophageal mast cells in EoE and found that esophageal mast cells consist of diverse populations. These diverse esophageal mast cell populations had transcriptional signatures that associated with distinct spatial compartments and EoE disease status.
We found that mast cells assume a pro-inflammatory state and locally proliferate in active EoE and remain activated and poised to re-initiate inflammation during disease remission.
This study was published in the Journal of Allergy and Clinical Immunology (article).
Together, we have hope. Together, we are researching ways to provide the best treatment of allergic and immunologic disorders and conduct leading research focused on elucidating the causes, mechanisms and most effective treatment of allergic and immunologic diseases. The Rothenberg CURED Lab is an integral part of the amazing research that goes on in the Division of Allergy and Immunology at Cincinnati Children’s. Learn more about research of the Division of Allergy and Immunology by watching this 2021 Research Highlights video.
Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) was previously undetermined.
In this Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)-supported study, we established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.
This study is published in Gastroenterology and featured in a Cincinnati Children's science blog post.
Eosinophilic gastrointestinal diseases (EGID) are rare allergic conditions of the gastrointestinal tract, with eosinophilic esophagitis (EoE) being the most common and studied. Importantly, diagnosis of EGID is often delayed. We engaged in the U.S. Food and Drug Administration (FDA) workshop hosted on July 21, 2021 to discuss the disease characteristics, natural history, and endpoints to assess treatment benefit in patients with EGID beyond EoE, such as eosinophilic gastritis (EoG) and eosinophilic colitis (EoC).
We and our colleagues recently published an article that summarizes and comments about this FDA workshop. The article is entitled “Impressions and Aspirations from the FDA GREAT VI Workshop on Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis and Perspectives for Progress in the Field” and was published in the Journal of Allergy and Clinical Immunology (read the article free until February 26th) and was featured in a Cincinnati Children's science blog post and Rare Diseases Clinical Research Network blog post.
For the recording of the FDA GREAT VI Workshop on EGIDs Beyond EoE Meeting Recording, visit https://www.fda.gov/drugs/news-events-human-drugs/gastroenterology-regulatory-endpoints-and-advancement-therapeutics-vi-great-vi-workshop-eosinophilic.
A growing body of evidence supports a role for altered barrier function in eosinophilic esophagitis (EoE). The Rothenberg CURED Lab researchers searched for rare EoE-associated gene variants using whole-genome sequencing of 62 families and found that rare gene variants of desmoplakin (DSP) and periplakin (PPL) appear to impair the epithelial barrier. DSP and PPL are part of junctions linking cells together, called intercellular junctions. Dysregulation of intercellular junctions suggests a mechanism whereby inflamed and hyperproliferative esophageal epithelial tissue can be penetrated by allergens, thereby amplifying allergic inflammation. Importantly, the researchers found evidence that loss of DSP and PPL also occurs in non-familial EoE, providing a mechanism that extends the identified pathway beyond rare familial EoE cases. These findings suggest that designing therapeutics to target the intercellular junctions to help normalize epithelial barrier function may reduce the harmful outcomes of EoE.
This study is published in Nature Communications and featured in a Cincinnati Children's science blog post.
Recent public media has focused on the importance of gut microbes in health and disease. Rothenberg CURED Lab researchers investigated fundamental properties of host-microbiota interactions in the esophagus and established the composition, transplantation potential, antibiotic responsiveness, and host-microbiota interactions of the esophagus. Fecal matter transplantation reconstituted the esophageal microbiome, opening up fecal transplants as a consideration for treating esophageal disease. Antibiotic usage predisposed to allergic disease in an eosinophilic esophagitis (EoE) experimental model in mice. The findings have implications for understanding health and disease in the esophagus and managing EoE.
This study is published in Gastroenterology and featured in a Cincinnati Children's science blog post.
Interleukin-33 (IL-33) plays a central role in type 2 immune responses and is generally thought to be released following cellular damage and processed extracellularly. Rothenberg and colleagues describe a novel ripoptosome pathway that is assembled following exposure to various unrelated environmental allergens and that processes IL-33 into an active form intracellularly, thereby identifying an Epithelial Allergen Sensor - RipIL33.
This study is published in Nature Immunology and featured in a Cincinnati Children's science blog post.
“Although a great deal remains to be elucidated, recent data support the hypothesis that common gastrointestinal ailments, such as irritable bowel syndrome and functional abdominal pain, may instead be food-induced allergic disorders,” says Marc Rothenberg.
This news is featured in the Cincinnati Children's science blog and the New York Times.
Congratulations to Tetsuo Shoda, MD, PhD, research associate in the Rothenberg CURED Lab, for receiving a prestigious K99/R00 Pathway to Independence Award of the National Institutes of Health (NIH)!
Tetsuo’s grant, titled “Combinatory Effects of Genetic Variants in Eosinophilic Esophagitis”, received a highly competitive and remarkable final overall impact score of 12! Grants are scored from 10 (high impact) to 90 (low impact).
The purpose of the Pathway to Independence (K99/R00) Program is to increase and maintain a strong cohort of new and talented, NIH-supported, independent investigators. This program is designed to facilitate a timely transition of outstanding postdoctoral researchers or clinician-scientists from mentored research positions to independent, tenure-track or equivalent faculty positions and to provide independent NIH research support during the transition that will help these individuals launch competitive, independent research careers.
Tetsuo came to the Rothenberg CURED Lab from the National Center for Child Health and Development, Japan in 2016. As a clinician and a researcher, he was engaged in treating pediatric patients and studying about pediatric allergy in Japan. His fundamental research interest is pathogenic mechanisms of eosinophilic gastrointestinal disorders (EGID) with a goal of bridging bedside clinical care and benchside research. This K99/R00 award is a notable leap forward in pursuing that goal.
Marc Rothenberg, MD, PhD would like to thank Kenneth Kaufman, PhD and Lisa Martin, PhD for excellent mentorship of Tetsuo and input on his grant.
Rare Disease Day: an Opportunity to Learn More
Eliminating Just One Food Trigger Can Improve Life for People With EoE
Bringing Dietary Therapy for Eosinophilic Oesophagitis Under Scientific Scrutiny
Milk Elimination Diet Shows Promise as First-Line Therapy for Eosinophilic Esophagitis
CEGIR’s Marc Rothenberg Receives AAAAI 2023 Distinguished Scientist Award
2022 Research Highlight Videos: Division of Allergy and Immunology at Cincinnati Children's
Characterizing Eosinophilic Duodenitis
Clinical Trial Research Participation: a few words from Marc Rothenberg, MD, PhD
Marc E. Rothenberg, MD, PhD5/11/2023
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