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Celiac.com 11/28/2020 - Non-celiacs show Interleukin 15 production when challenged with gliadin peptides. A recent study by a team of Spanish researchers puts the world on notice that gluten may trigger adverse reactions in both celiacs and non-celiacs alike. The research team was made up of Doctors E. Arranz, D. Bernardo, L. Fernandez-Salazar, J. A. Garrote and their colleague S. Riestra, all based in Spain. According to the current medical wisdom, innate immunity to gluten plays a critical role in the development of celiac disease. This innate immune response is caused by a reaction to the ‘toxic’ gluten peptides that are mediated by a chemical in the white blood cells called interleukin 15, which stimulates these cells to react against foreign proteins like the 19-mer. The reaction is independent of genetic HLA markers associated with celiac disease. This causes epithelial stress and triggers the intraepithelial lymphocytes to turn into natural killer (NK)-like cells, which then causes enterocyte cells to die resulting in a compromised permeability of the cells lining of the gut…and, violà, celiac disease! It is by breaching this intestinal lining that peptides such as the 33-mer, come into contact with the lamina propria, which triggers general immune reactions. The specific response in celiac disease has been pretty well documented, but until recently, no one had described any differential factors between people with celiac disease and those without. Since the toxic 19-mer triggers its damaging effects independent of the celiac associated HLA markers, researchers wondered whether the innate immune response was common in people with and those without celiac disease. They wondered whether the adaptive response is found only in those susceptible to celiac disease. The gliadin-challenged patients with celiac disease who were on a GFD, showed increased nitrite levels, which those without celiac disease did not show. Only patients with celiac disease showed modifications to what are called adaptive mediators (STAT1, STAT3, IFNc). The samples of those celiac patients on a gluten-free diet showed interferon levels that were 80 times higher than those without celiac disease, along with a slightly higher production of nitrites. This appears to be the first time that researchers have described an interleukin 15-mediated innate response to gliadin and gliadin peptides in people without celiac disease, as well as the first time they have described an IL15-mediated innate response to the ‘non-toxic’ deaminated immuno-dominant 33-mer peptide. What this all means is that, for the first time, scientists have documented harmful effects of gluten on people without celiac disease. This hypothesis seems to be born out by the fact that all individuals who took part in the study, both those with and those without celiac disease, showed an innate immune response to gluten, though only those with celiac disease showed an adaptive immune response to gluten. Clearly, before doctors can draw any hard and fast conclusions, they will need to do more studies on larger groups. The research team also suggests that people with celiac disease have a lower threshold for triggering an adaptive TH1 response than do non-celiacs. The reason for the differences in threshold levels between celiacs and non-celiacs might be the result of higher levels of immune reactions in celiac patients compared to those without celiac disease. That’s one possibility. The difference in threshold levels might also have to do with some kind of defect in permeability of the gut membrane in those with celiac disease, or a greater immune sensitivity to equivalent quantities of toxic gliadin fractions which might come from a higher density of interleukin 15 receptors in patients with celiac disease. Source: Gut 2007;56:889–890

Celiac.com 09/25/2019 - Current research suggests that interleukin 15, aka IL-15, plays a key role in celiac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be assessed as a potential treatment for celiac disease. A new study looks at safety and efficacy of AMG 714 in adults with celiac disease exposed to gluten challenge. A team of researchers recently set out examine the effects of AMG 714 in celiac patients who underwent a gluten challenge. The research team included Marja-Leena Lähdeaho, MD, Prof Mika Scheinin, MD, Pekka Vuotikka, MD, Juha Taavela, MD, Alina Popp, MD, Johanna Laukkarinen, MD, Jukka Koffert, MD, Olli-Pekka Koivurova, MD, Prof Marko Pesu, MD, Laura Kivelä, MD, Zsófia Lovró, MD, Joni Keisala, MD, Prof Jorma Isola, MD, Jane R Parnes, MD, Francisco Leon, MD, and Prof Markku Mäki, MD. They are variously affiliated with Tampere University Hospital, Tampere, Finland; the Clinical Research Services Turku, Turku, Finland; the Institute of Biomedicine, University of Turku, Turku, Finland; the Faculty of Medicine and Health Technologies, Tampere University, Tampere, Finland; the Department of Gastroenterology, Turku University Hospital, Turku, Finland; the Tampere Center for Child Health Research, Tampere University and University Hospitals Celimmune, Bethesda, MD; Provention Bio, Oldwick, NJ; and Amgen, Thousand Oaks, CA, USA. The team relied on three clinical sites in Finland to conduct their randomized, double-blind, placebo-controlled, parallel-group, phase 2a trial. They included subjects aged 18–80 years, with a confirmed celiac diagnosis, who had been on gluten-free diet for at least one year before screening. They randomly assigned patients to receive 150 mg AMG 714, 300 mg AMG 714, or a placebo using permuted blocks and stratified by study site and sex. Patients and study staff were blind to treatment assignment. Treatments included two subcutaneous injections every 2 weeks for 10 weeks, for a total of six doses. Patients without severe villous atrophy at baseline received a gluten challenge of 2–4 grams daily, from weeks 2–12. The team used small bowel biopsy samples to assess patient histology at baseline and at week 12. The main measurement of efficacy was the rate of change in villous height-to-crypt depth (VHCD) ratio from baseline to week 12. Other factors included CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), celiac disease GSRS, Bristol stool form scale (BSFS); along with changes in anti-tTG and anti-DGP antibodies from baseline. The main analysis focused on per-protocol 1 patients who received at least one dose of study drug, and who completed the gluten challenge. All patients who received at least one dose of study drug underwent a safety analysis. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19. Between April 13, 2016, and Nov 22, 2016, a total of 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group, the 300 mg AMG 714 group, or the placebo group. Two patients did not start treatment and two did not provide post-treatment biopsy samples. Forty-nine patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The primary endpoint was change in VHCD ratio from baseline after 12 weeks of treatment in patients with celiac disease undergoing gluten challenge, and was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. This study's revelations about the effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 should be done in patients with non-responsive celiac disease. Read more in The Lancet