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Showing results for tags 'tolerance'.
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Celiac.com 01/13/2023 - Celiac disease is an autoimmune disorder in which gluten consumption triggers gut damage. The only effective treatment is a strict gluten-free diet. Can hookworms help celiacs eat gluten? The answer is yes and no, coupled with some trade-offs. Here's the rundown. Earlier studies have indicated that hookworm infection may restore some level of gluten tolerance in celiac patients, however, none of these approximately one dozen studies were placebo controlled. We've done a number of articles on hookworms and celiac disease. We've even done an article on health claims from at least one hookworm-infected celiac patient who claimed he was able to safely eat gluten. Can Hookworms Help Celiacs Eat Gluten? To get a more detailed answer, a research team recently undertook a randomized, placebo-controlled trial of hookworm infection in nearly sixty people with celiac disease. The team included John Croese, MD; Gregory C. Miller, FRCPA; Louise Marquart, PhD; Stacey Llewellyn, BSc; Rohit Gupta, FRACP; Luke Becker, BAppSci; Andrew D. Clouston, PhD; Christine Welch, FRACP; Julia Sidorenko, PhD; Leanne Wallace, BSc; Peter M. Visscher, PhD; Matthew L. Remedios, FRACP; James S. McCarthy, MD; Peter O'Rourke, PhD; Graham Radford-Smith, PhD; Alex Loukas, PhD; Mark Norrie, PhD; John W. Masson, FRACP; Richard B. Gearry, PhD; Tony Rahman, PhD; and Paul R. Giacomin, PhD. They are variously associated with the Department of Gastroenterology and Hepatology at The Prince Charles Hospital in Brisbane, Australia; the Center for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia; the Envoi Specialist Pathologists, Brisbane, Australia; the QIMR Berghofer Medical Research Institute, Brisbane, Australia; the Department of Gastroenterology, Townsville University Hospital, Townsville, Australia; the Institute for Molecular Bioscience at the University of Queensland, Brisbane, Australia; the Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia; the Gastroenterology and Hepatology, Logan Hospital, Brisbane, Australia; and the Department of Medicine, University of Otago, Christchurch and Canterbury District Health Board, Christchurch, New Zealand. Study Ran Nearly Two Years In a study that ran for just under two years, a research team of medical professionals treated celiac patients with with a placebo, or with either third stage larvae of the 20 or 40 Necator americanus hookworm (L3-20 group or L3-40 group). Patients then increased their gluten consumption to 5 grams per day for 12 weeks, 1 gram intermittent twice weekly for 12 weeks, and two grams sustained for six weeks, followed by liberal diet for 1 year. About forty to fifty percent of hookworm patients, and about fifty-five percent of placebo subjects made it to the main outcome point of 42 weeks, and hookworm-treated participants did show a sharp reduction in gluten-related events. Duodenal villous height: crypt depth deteriorated similarly compared with their enrollment values in each group, with an average change of −0.6 for the placebo group; -0.5 for the L3-20 group , −1.1 for the L3-40 group. A retrospective analysis showed that nearly one in four L3-treated participants failed to develop successful hookworm infection. Lower Quality of Life Scores for Hookworm Patients Between forty to fifty percent of participants in each group completed the study, but quality of life symptom scores after the gluten challenge were under forty percent in hookworm-positive participants, compared with over forty-five percent for the hookworm negative group. From their findings, the team concludes that hookworm infection DOES NOT restore gluten tolerance enough to allow sustained moderate consumption of gluten of two grams per day or more. However, hookworm infection did lead to better symptom scores after occasional consumption of lower doses of gluten. The findings undercut the idea that hookworm infection is some kind of magic bullet for gluten consumption for people with celiac disease. Hookworm Infection Not a Magic Bullet for Celiacs At best, the data support the idea that hookworm infection can help reduce symptoms of moderate gluten consumption in people with celiac disease, but that any reduction also likely comes with a lower overall quality of life score. This is the most definitive study we've yet seen on the effects of hookworm infection on the ability of celiac disease patients to tolerate gluten. The results are clear that any modest benefits of hookworm infection comes with some potential reduction in quality of life. Still, the ability of hookworms to help reduce symptoms of moderate gluten consumption in people with celiac disease merits further study. It's possible that hookworms hold some secrets in their biochemistry that might help to offer some extra protection against the inflammation triggered by limited gluten consumption. That is some exciting news. Read more at: Clin Transl Gastroenterol. 2020 Dec; 11(12): e00274.
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Celiac.com 10/23/2019 - One approach to celiac disease that's been getting attention lately is the effort to develop ways to prevent the adverse immune reaction that is triggered by gluten that leads to gut damage in untreated celiacs. Several companies have tried that approach, including the promising, but now failed drug NexVax2. The idea is to train the immune system to become tolerant of gluten, kind of like the way allergists train the immune system to tolerate pollen, and thus, reduce or even eliminate allergic reactions. Data from a recent trial of new medical technology provides encouraging evidence that it is possible for people with celiac disease to achieve an immune tolerance to gluten, effectively reversing the autoimmune disease. The technology is a biodegradable nanoparticle containing gluten that teaches the immune system the antigen (allergen) is safe. The nanoparticle, called COUR nanoparticle, CNP-101, conceals the allergen in an innocuous cell covering, and convinces the immune system not to attack it. Celiac patients treated with CNP-101 were able to eat gluten with a substantial reduction in inflammation. The phase 2 results indicate that the treatment protects patients’ small intestine from gluten exposure, and point the way toward treatments that could allow celiac patients safely consume gluten in their diet. In addition to potentially reversing celiac disease, the technology, which uses a nanoparticle containing the antigen triggering the allergy or autoimmune disease, has the potential to treat myriad diseases and allergies, including multiple sclerosis, type 1 diabetes, peanut allergy, asthma, among others. The research team will present their findings on Oct. 22nd at the European Gastroenterology Week conference in Barcelona, Spain. The technology was devised in the lab of Stephen Miller, the Judy Gugenheim Research Professor of Microbiology and Immunology at Northwestern University Feinberg School of Medicine, who has refined it over decades. In addition to providing the first proof that the technology works in patients, the study shows that "we can encapsulate myelin into the nanoparticle to induce tolerance to that substance in multiple sclerosis models, or put a protein from pancreatic beta cells to induce tolerance to insulin in type 1 diabetes models,” said Miller. The technology works by causing the immune system to see the allergen-loaded nanoparticle as innocuous debris, and to disregard it. Once ignored, the nanoparticle and its hidden antigen get eaten by a macrophage, kind of a garbageman that rids the body of cellular debris and pathogens. “The vacuum-cleaner cell presents the allergen or antigen to the immune system in a way that says, ‘No worries, this belongs here,'” Miller said. “The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.” In the celiac trial, Miller's team loaded the nanoparticle with gliadin, the protein in gluten that triggers the adverse reaction in people with celiac disease. After a week of treatment, the patients consumed gluten for two weeks. Untreated celiac patients who ate gluten showed clear immune responses to gliadin and related damage to the small intestine. Meanwhile, celiac patients treated with CNP-101 showed 90% less immune-related inflammation than untreated patients. By preventing the inflammatory response, CNP-101 showed the ability to protect the gut from gluten-related damage. Most autoimmune diseases are currently treated with immune suppressants, which lessen symptoms, but degrade the immune response and carry the potential for toxic side-effects. CNP-101 does not work by suppressing the immune system, but by preventing the inflammatory response, and thus reversing the course of the autoimmune disease. Celiac disease a perfect target for the nanoparticle induced immune tolerance approach, because the triggers are well documented, and the disease has no other treatment than a gluten-free diet. CNP-101 has been granted Fast Track status by the U.S. Food and Drug Administration, and brought to patients in collaboration with Takeda Pharmaceuticals, which has acquired an exclusive global license to develop and commercialize this treatment for celiac disease. In addition to celiac disease, COUR is looking to develop treatments for peanut allergy and multiple sclerosis, and to expand their offerings to other autoimmune conditions, said John J. Puisis, president and chief executive officer of COUR. Read more in sciencedaily.com
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Celiac.com 10/29/2018 - Researchers Emma L. Smith with UCB Pharma Ltd., Slough, United Kingdom, and Mark Peakman from the Department of Immunobiology, King’s College London, London, United Kingdom recently set out to catalog clinical advances in peptide immunotherapy for Type 1 diabetes. Autoimmune and allergic diseases occur when a person’s body has an incorrect immune response to an antigen from the person’s own body, or to an innocuous antigen from outside the body. This triggers a pathogenic T-cell response which causes damage to certain tissues and organs. In Type 1 diabetes, this process results in the destruction of the insulin-secreting β cells, which leads to permanent need for recombinant insulin to make up for the loss. The best way to restore immune homeostasis and prevent further tissue damage is to reduce or cease the pathogenic T-cell response by using antigen-specific peptide immunotherapy. Smith and Peakman found that recent clinical advances with peptide therapy approaches in both Type 1 diabetes and other diseases are beginning to show encouraging results. New treatments that target peptides specific to certain cell types are also moving from the development stages into clinical use. Drug developers still face numerous hurdles in reaching full clinical use, including determining optimal dose and dosing frequency, but peptide immunotherapy for Type 1 diabetes is clearly becoming a very active field of drug development. Read their full report: Front Immunol. 2018; 9: 392.Published online 2018 Feb 28. doi: 10.3389/fimmu.2018.00392PMCID: PMC5836708PMID: 29541078
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Celiac.com 12/05/2012 - Regulatory T cells (Tregs) are play a pivotal role in helping our bodies tolerate self-antigens and dietary proteins. Interleukin (IL)-15 is a cytokine that is overly present in the intestines of patients with celiac disease. Studies have shown that Interleukin (IL)-15 does not interfere with the generation of functional Tregs, but causes human T cells to resist Treg suppression. To better understand how control of effector T cells by regulatory T cells is inhibited, a team of researchers compared Treg numbers and responses of intestinal and peripheral T lymphocytes to suppression by Tregs in celiac disease patients and in a control group. The research team included N.B. Hmida, M. Ben Ahmed, A. Moussa, M.B. Rejeb, Y. Said, N. Kourda, B. Meresse, M. Abdeladhim, H. Louzir, and N. Cerf-Bensussan. They are affiliated with the Department of Clinical Immunology and the Institut Pasteur de Tunis in Tunis, Tunisia. For their study, the team isolated intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) from duodenal biopsy specimens of patients with celiac disease and in a control group. The team then purified CD4+CD25+ T lymphocytes (Tregs) from blood. By analyzing anti-CD3-induced proliferation and interferon (IFN)-γ production in the presence or absence of peripheral Tregs, they were able to test responses of IELs, of LPLs, and peripheral lymphocytes (PBLs) to suppression by Tregs. The team used flow cytometry to measure lamina propria and peripheral CD4+CD25+FOXP3+ T cells. They found that, although patients with active celiac disease showed significantly increased percentages of CD4+CD25+FOXP3+ LPLs, they also showed less inhibited proliferation and IFN-γ production of intestinal T lymphocytes by autologous or heterologous Tregs (P < 0.01). IEL for subjects with celiac disease showed no response to Tregs. Also, the team noted resistance of LPLs and PBLs to Treg suppression in patients with villous atrophy who had substantially higher blood levels of IL-15 compared with patients without villous atrophy and controls. From their results, the research team concludes that effector T lymphocytes in people with active celiac disease become resistant to suppression by Tregs. This resistance may result in loss of tolerance to gluten, and to self-antigens. Source: Am J Gastroenterol. 2012 Apr;107(4):604-11. doi: 10.1038/ajg.2011.397. Epub 2011 Nov 22.
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Celiac.com 09/15/2009 - Active delivery of recombinant autoantigens or allergens to intestinal mucosa by genetically modified Lactococcus lactis (LL) offers a unique therapeutic approach for the induction of tolerance to gluten proteins. A team of researchers recently set out to determine whether oral administration of LL-delivered DQ8-specific gliadin epitope induces Ag-specific tolerance. The research team was made up of Inge L. Huibregtse, Eric V. Marietta, Shadi Rashtak, Frits Koning, Pieter Rottiers, Chella S. David; Sander J. H. van Deventer, and Joseph A. Murray under the auspices of the Center for Experimental and Molecular Medicine of the Academic Medical Center of the University of Amsterdam in the Netherlands. Celiac disease is associated with either HLA-DQ2- or HLA-DQ8-restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of Ag-specific tolerance. The research team engineered LL to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and then observed the induction of Ag-specific tolerance in NOD AB degrees DQ8 transgenic mice. The team measured tolerance by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation, and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8-restricted T cell responses in NOD AB degrees DQ8 transgenic mice. Result was an Ag-specific decrease of the proliferative capacity of inguinal lymph node (ILN) cells and lamina propria cells. Production of IL-10 and TGF-beta and a significant induction of Foxp3(+) regulatory T cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d. These results support the development of orally administered Ag-secreting LL to treat gluten-sensitive disorders. Such treatments may be effective even in cases of established hypersensitivity. Journal of immunology (Baltimore, Md. : 1950) 2009;183(4):2390-6
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