Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial

Leonard, Maureen M.; Silvester, Jocelyn A.; Leffler, Daniel A.; Fasano, Alessio; Kelly, Ciarán P.; Lewis, Suzanne K.; Goldsmith, Jeffrey D.; Greenblatt, Elliot; Kwok, William W.; McAuliffe, William J.; Galinsky, Kevin; Siegelman, Jenifer; Chow, I-Ting; Wagner, John A.; Sapone, Anna; Smithson, Glennda

doi:10.1053/j.gastro.2020.10.040

Cited by 63 publications

(69 citation statements)

References 53 publications

(78 reference statements)

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“…To confirm the panel could detect biologically relevant immune cell changes in CeD patients, cryopreserved PBMCs from 10 untreated healthy donors and 10 CeD patients challenged with gluten (to elicit an immune response) were collected and processed as described in the Methods section. As shown elsewhere (Leonard et al, 2020) and in Figure 5, CeD patients challenged with gluten demonstrated increases in activated gut‐homing T cells compared with healthy controls consistent with previous reports (Cook et al, 2017; Fallang et al, 2009; Granzotto et al, 2009; Han et al, 2013; Mazzarella, 2015; Sollid et al, 2012). In particular, increases in αE, α4, and β7 integrin, as well as CD38 staining, were observed in T cells, and more specifically effector memory Thelper and CD8 cells.…”

Section: Resultssupporting

confidence: 91%

Development and validation of a high‐parameter mass cytometry workflow to decipher immunomodulatory changes in celiac disease

Estevam

Krutzik

Tuig

et al. 2021

Cytometry Part B Clinical

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The advent of time‐of‐flight mass cytometry (CyTOF) has enabled high dimensional and unbiased examination of the immune system to simultaneous interrogate a multitude of parameters and gain a better understanding of immunologic data from clinical trial samples. Here we describe the development and validation of a 33‐marker mass cytometry workflow for measuring gastrointestinal (GI) trafficking peripheral blood mononuclear cells (PBMCs) in patients with celiac disease (CeD). This panel builds upon identification of well‐characterized immune cells and expands to include markers modulated in response to gluten challenge in patients with CeD. The CeD panel was optimized and validated according to accepted industry practice for validation of flow cytometry assays and builds upon established sample processing workflows for mass cytometry studies. Several critical parameters were evaluated during the assay development phase of this study including optimization of the sample processing steps, antibody specificity, and ensuring the panel as a whole performed to expectation. The panel was then validated using a fit‐for‐purpose approach tailored to the intended use of the data in the clinical trial. Validation included assessment of analytical parameters essential to understanding the reliability and robustness of the CeD panel such as intra‐assay precision, inter‐assay precision, inter‐operator precision and sample processing stability. Together, this validated mass cytometry workstream provides robust and reproducible high‐dimensional analysis of human peripheral blood immune cells to characterize patient samples from clinical trials.

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Section: Resultssupporting

confidence: 91%

Development and validation of a high‐parameter mass cytometry workflow to decipher immunomodulatory changes in celiac disease

Estevam

Krutzik

Tuig

et al. 2021

Cytometry Part B Clinical

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“…It is less invasive than a duodenal biopsy and can be used as a method to monitor therapeutic impact while evaluating a much larger portion of the small intestine. VCE is unable to directly measure cellular changes, but rather records macroscopic changes in tissue ( 20 , 30 ).…”

Section: Pharmacodynamic Biomarkers and Measuring Therapeutic Intervention In Cedmentioning

confidence: 99%

“…Anti-TTG antibodies have been used as a PD biomarker to understand immune response to gluten challenge ( 19 , 20 , 54 ) and have been incorporated into clinical trials for this purpose ( 9 , 10 ). These antibodies are not considered by most to be pathogenic in the intestinal damage seen in CeD, but may be a contributor to extraintestinal manifestations, such as dermatitis herpetiformis or central nervous system lesions ( 55 – 57 ).…”

Section: Pharmacodynamic Biomarkers and Measuring Therapeutic Intervention In Cedmentioning

confidence: 99%

“…These antibodies are not considered by most to be pathogenic in the intestinal damage seen in CeD, but may be a contributor to extraintestinal manifestations, such as dermatitis herpetiformis or central nervous system lesions ( 55 – 57 ). Antibody response requires repeated gluten exposure, takes at least 2 weeks to appear after initial gluten challenge, and is still high 3–4 weeks after the last gluten exposure ( 20 , 54 ). Although anti-TTG antibody measurement is useful for CeD diagnosis, it is certainly not a dynamic biomarker.…”

Section: Pharmacodynamic Biomarkers and Measuring Therapeutic Intervention In Cedmentioning

confidence: 99%

“…After a single gluten dose in patients on a GFD, levels of several inflammatory cytokines increase ( 58 ). IL-2 is one of the most consistently upregulated cytokines in patients and peaks 4 hours after gluten challenge, becoming undetectable in most patients by 6 days after initial gluten exposure ( 20 ). The presence of IL-2 in patients correlated with CeD symptoms, and no changes in IL-2 were seen in healthy participants with gluten challenge ( 58 , 59 ).…”

Section: Pharmacodynamic Biomarkers and Measuring Therapeutic Intervention In Cedmentioning

confidence: 99%

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The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

et al. 2021

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Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.

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Evolution in coeliac disease diagnosis and management

Tye‐Din

2024

JGH Open

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The traditional gut‐centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease ‐ well demonstrated in children ‐ are growing for adults. Novel biomarkers such as interleukin‐2 that identify the gluten‐specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case‐finding strategy and enthusiasm for population screening is growing. The gluten‐free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly‐responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super‐sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.

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Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial

Cited by 63 publications

References 53 publications

Development and validation of a high‐parameter mass cytometry workflow to decipher immunomodulatory changes in celiac disease

Development and validation of a high‐parameter mass cytometry workflow to decipher immunomodulatory changes in celiac disease

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

Evolution in coeliac disease diagnosis and management

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