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Santonicola A, Soldaini C, Ciacci C. New therapies in celiac disease. Curr Opin Gastroenterol 2025; 41:124-131. [PMID: 39862215 DOI: 10.1097/mog.0000000000001080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2025]
Abstract
PURPOSE OF REVIEW Celiac disease (CeD) is a chronic autoimmune disorder of the small intestine triggered by gluten ingestion in genetically predisposed individuals. The cornerstone of CeD management remains a strict adherence to a lifelong gluten-free diet (GFD), although such a dietary restriction can lead to an altered quality of life and may not be easy to follow for many patients. These challenges highlighted the need for alternative therapies. This review aims to explore the latest advancements in these therapeutic avenues, emphasizing mechanisms of action, clinical efficacy, and safety profiles of drugs currently in advanced stages of clinical testing. RECENT FINDINGS Recent advances in the understanding of CeD pathophysiology have catalyzed the development of new therapeutic approaches, which include strategies to modify gluten processing in the gut, block gluten-triggered immune responses, or restore immune tolerance to gluten. SUMMARY While these therapies are not poised to take the place of GFD, they represent promising treatment alternatives that could enhance the quality of life and minimize long-term consequences in CeD patients. Further research, as well as phase III clinical trials of those already conducted, are needed to establish the feasibility of integrating these novel drugs in the clinical management of CeD.
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Affiliation(s)
- Antonella Santonicola
- Gastrointestinal Unit, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
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Herrera-Quintana L, Navajas-Porras B, Vázquez-Lorente H, Hinojosa-Nogueira D, Corrales-Borrego FJ, Lopez-Garzon M, Plaza-Diaz J. Celiac Disease: Beyond Diet and Food Awareness. Foods 2025; 14:377. [PMID: 39941971 PMCID: PMC11817883 DOI: 10.3390/foods14030377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Celiac disease is attributable to a combination of genetic predisposition and exposure to dietary gluten, with immune system involvement. The incidence is increasing globally, and the societal economic burden of celiac disease stretches beyond the cost of gluten-free food. This enteropathy that affects the small intestine has been related to different disorders and comorbidities. Thus, the implications of suffering from this disease are multidimensional and need further consideration. Celiac disease is a serious condition that remains under-recognized, resulting in an increased need for programs for better management. This review aims to summarize the current evidence regarding celiac diseases, with special emphasis on clinical implications, diagnosis, dietary management, socioeconomical aspects, and future perspectives.
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Affiliation(s)
- Lourdes Herrera-Quintana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain;
| | - Beatriz Navajas-Porras
- Department of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, 46017 Valencia, Spain;
| | - Héctor Vázquez-Lorente
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain;
| | - Daniel Hinojosa-Nogueira
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria), 29010 Málaga, Spain;
| | | | - Maria Lopez-Garzon
- Biomedical Group (BIO277), Department of Physical Therapy, Health Sciences Faculty, University of Granada, 18171 Granada, Spain;
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Julio Plaza-Diaz
- School of Health Sciences, Universidad Internacional de La Rioja, Avenida de la Paz, 137, 26006 Logroño, Spain;
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
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Scalvini D, Scarcella C, Mantica G, Bartolotta E, Maimaris S, Fazzino E, Biagi F, Schiepatti A. Beyond gluten-free diet: a critical perspective on phase 2 trials on non-dietary pharmacological therapies for coeliac disease. Front Nutr 2025; 11:1501817. [PMID: 39839296 PMCID: PMC11748180 DOI: 10.3389/fnut.2024.1501817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
Coeliac disease is an immune-mediated chronic enteropathy, with a prevalence of around 1% in the general population and occurring in genetically susceptible individuals after the ingestion of gluten proteins present in wheat, rye and barley. Currently, a strict lifelong gluten-free diet is the cornerstone of treatment of coeliac disease. However, maintaining strict dietary adherence is challenging for many patients, due to the high costs, the highly restrictive nature of the diet and the impact on patients' quality of life. Moreover, a tiny minority of coeliac patients can develop pre-malignant/malignant complications of coeliac disease, a group of conditions, that despite being rare, are still burdened by a poor prognosis due to the lack of effective therapies. Therefore, the development of pharmacological treatments as an alternative to or supportive of a gluten-free diet is still an unmet need. The identification of new pathogenetic targets in the last years has enabled the development of several candidates molecules, many of which have been investigated in phase 2/3 clinical trials. In this narrative review we aim to summarise the investigational therapies that have been evaluated in phase 2/3 trials and provide a critical overview on the latest advances in this field.
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Affiliation(s)
- Davide Scalvini
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Chiara Scarcella
- Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Pavia, Italy
| | - Giulia Mantica
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Erica Bartolotta
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Stiliano Maimaris
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Erica Fazzino
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Federico Biagi
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Pavia, Italy
| | - Annalisa Schiepatti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Pavia, Italy
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Koenitz L, Crean A, Vucen S. Pharmacokinetic differences between subcutaneous injection and intradermal microneedle delivery of protein therapeutics. Eur J Pharm Biopharm 2024; 204:114517. [PMID: 39349073 DOI: 10.1016/j.ejpb.2024.114517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/19/2024] [Accepted: 09/25/2024] [Indexed: 10/02/2024]
Abstract
Protein therapeutics are essential in the treatment of various diseases, but most of them require parenteral administration. Since intravenous and subcutaneous injections are associated with discomfort and pain, other routes have been investigated including intradermal microneedle delivery. Microneedles are shorter than hypodermic needles and therefore minimize contact with pain receptors in deeper skin layers. But the differences in anatomical and physiological characteristics of dermis and subcutis can potentially result in varying protein penetration through the skin, absorption, and metabolism. This review summarizes pharmacokinetic studies that compare the administration of protein therapeutics by subcutaneous injections and different types of microneedles intradermally including hollow, dissolvable, coated, and hydrogel-forming microneedles. Across animal and human studies, hollow microneedle delivery resulted in quicker and higher peak plasma levels of proteins and comparable bioavailability to subcutaneous injections potentially due to the extensive network of lymphatic and blood vessels in the dermis. In case of dissolvable and coated microneedles, drug release kinetics depend on component materials. The dissolution of polymer excipients can slow the release and permeation of protein therapeutics at the administration site and thereby delay absorption. The understanding of drug penetration through different skin layers, its absorption into blood capillaries or lymphatics, and dermal metabolism remains limited. Additionally, the effects of these processes on the differences in pharmacokinetic profiles of proteins following intradermal microneedle administration are not well understood. Greater insights are required for the development of the next generation of intradermal microneedle biotherapeutics.
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Affiliation(s)
- Laura Koenitz
- SSPC, the SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Cork T12 YT20, Ireland.
| | - Abina Crean
- SSPC, the SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Cork T12 YT20, Ireland
| | - Sonja Vucen
- SSPC, the SFI Research Centre for Pharmaceuticals, School of Pharmacy, University College Cork, Cork T12 YT20, Ireland
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Ge HJ, Chen XL. Advances in understanding and managing celiac disease: Pathophysiology and treatment strategies. World J Gastroenterol 2024; 30:3932-3941. [PMID: 39351055 PMCID: PMC11438662 DOI: 10.3748/wjg.v30.i35.3932] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 08/12/2024] [Accepted: 08/26/2024] [Indexed: 09/13/2024] Open
Abstract
In this editorial, we comment on an article published in the recent issue of the World Journal of Gastroenterology. Celiac disease (CeD) is a disease occurring in genetically susceptible individuals, which is mainly characterized by gluten intolerance in the small intestine and clinical symptoms such as abdominal pain, diarrhea, and malnutrition. Therefore, patients often need a lifelong gluten-free diet, which greatly affects the quality of life and expenses of patients. The gold standard for diagnosis is intestinal mucosal biopsy, combined with serological and genetic tests. At present, the lack of safe, effective, and satisfactory drugs for CeD is mainly due to the complexity of its pathogenesis, and it is difficult to find a perfect target to solve the multi-level needs of patients. In this editorial, we mainly review the pathological mechanism of CeD and describe the current experimental and improved drugs for various pathological aspects.
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Affiliation(s)
- Hao-Jie Ge
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
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D'heedene M, Vanuytsel T, Wauters L. Celiac disease: Hope for new treatments beyond a gluten-free diet. Clin Nutr 2024; 43:1240-1249. [PMID: 38648685 DOI: 10.1016/j.clnu.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/02/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is a chronic inflammatory disease of the small intestine induced and maintained by gluten ingestion in susceptible individuals. Current treatment consists of strict adherence to a lifelong gluten-free diet (GFD) which is considered safe and effective in the large majority of patients. However, since adherence to a GFD is difficult and has a negative impact on quality of life, an increasing interest in other treatment options has emerged. Moreover, in some individuals a GFD is not sufficiently effective, necessitating alternative treatments. METHODS By performing a systematic search, we constructed a detailed narrative review. Only treatment options considered relevant and conducted in a phase I, II or III clinical trial were included. RESULTS Based on the pathophysiology of CD, four major therapeutic approaches can be distinguished: firstly, by focusing on intraluminal gluten detoxification before absorption occurs, secondly, by modulating intestinal permeability and preventing paracellular uptake, thirdly, by enhancing immunological tolerance to gluten and finally, by regulating gluten auto-immunity. CONCLUSIONS Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options.
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Affiliation(s)
| | - Tim Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, 49 3000, Leuven, Belgium
| | - Lucas Wauters
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, 49 3000, Leuven, Belgium.
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Noori E, Hashemi N, Rezaee D, Maleki R, Shams F, Kazemi B, Bandepour M, Rahimi F. Potential therapeutic options for celiac Disease: An update on Current evidence from Gluten-Free diet to cell therapy. Int Immunopharmacol 2024; 133:112020. [PMID: 38608449 DOI: 10.1016/j.intimp.2024.112020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024]
Abstract
Celiac disease (CD) is a chronic autoimmune enteropathy and multifactorial disease caused by inappropriate immune responses to gluten in the small intestine. Weight loss, anemia, osteoporosis, arthritis, and hepatitis are among the extraintestinal manifestations of active CD. Currently, a strict lifelong gluten-free diet (GFD) is the only safe, effective, and available treatment. Despite the social burden, high expenses, and challenges of following a GFD, 2 to 5 percent of patients do not demonstrate clinical or pathophysiological improvement. Therefore, we need novel and alternative therapeutic approaches for patients. Innovative approaches encompass a broad spectrum of strategies, including enzymatic degradation of gluten, inhibition of intestinal permeability, modulation of the immune response, inhibition of the transglutaminase 2 (TG2) enzyme, blocking antigen presentation by HLA-DQ2/8, and induction of tolerance. Hence, this review is focused on comprehensive therapeutic strategies ranging from dietary approaches to novel methods such as antigen-based immunotherapy, cell and gene therapy, and the usage of nanoparticles for CD treatment.
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Affiliation(s)
- Effat Noori
- Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran; Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Maleki
- Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Bahram Kazemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojgan Bandepour
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fardin Rahimi
- Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran
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Raju SA, Shiha MG, Penny HA. Monitoring coeliac disease in 2024, time to change practice? Curr Opin Gastroenterol 2024; 40:190-195. [PMID: 38547329 DOI: 10.1097/mog.0000000000001009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
PURPOSE OF REVIEW Persistent villous atrophy is associated with morbidity in coeliac disease and most commonly due to ongoing gluten ingestion. Current methods for assessing gluten exposure and persisting villous atrophy include dietary questionnaires and repeat duodenal biopsy, which have limited accuracy or are invasive. This review discusses adjunctive and/or novel tests that could be used to overcome these challenges. RECENT FINDINGS Small bowel capsule endoscopy is well tolerated and helps to evaluate for persisting villous atrophy and importantly, complications associated with coeliac disease. Testing for urinary and/or stool gluten immunogenic peptides may help identify recent gluten exposure, but further studies are still warranted to evaluate the accuracy and applicability of this approach. Measuring spikes in circulating Interleukin-2 following gluten challenge has shown promise for coeliac disease diagnosis, and thus may serve as a useful confirmatory test in those with persisting symptoms but provides no information on mucosal inflammation. No specific gut microbial signature has been identified in coeliac disease; however, studies have shown a reduced microbial diversity in active disease, which with future refinement may prove clinically useful. SUMMARY There is no evidence to support alternative methods for assessing persisting villous atrophy in coeliac disease over performing an up-to-date duodenal biopsy. Monitoring for adherence to a gluten-free diet remains clinically challenging and should be a priority for future research.
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Affiliation(s)
- Suneil A Raju
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Mohamed G Shiha
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Hugo A Penny
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
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Sollid LM. Tolerance-inducing therapies in coeliac disease - mechanisms, progress and future directions. Nat Rev Gastroenterol Hepatol 2024; 21:335-347. [PMID: 38336920 DOI: 10.1038/s41575-024-00895-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/08/2024] [Indexed: 02/12/2024]
Abstract
Coeliac disease is an autoinflammatory condition caused by immune reactions to cereal gluten proteins. Currently, the only available treatment for the condition is a lifelong avoidance of gluten proteins in the diet. There is an unmet need for alternative therapies. Coeliac disease has a strong association with certain HLA-DQ allotypes (DQ2.5, DQ2.2 and DQ8), and these disease-associated HLA-DQ molecules present deamidated gluten peptides to gluten-specific CD4+ T cells. The gluten-specific CD4+ T cells are the drivers of the immune reactions leading to coeliac disease. Once established, the clonotypes of gluten-specific CD4+ T cells persist for decades, explaining why patients must adhere to a gluten-free diet for life. Given the key pathogenic role of gluten-specific CD4+ T cells, tolerance-inducing therapies that target these T cells are attractive for treatment of the disorder. Lessons learned from coeliac disease might provide clues for treatment of other HLA-associated diseases for which the disease-driving antigens are unknown. Thus, intensive efforts have been and are currently implemented to bring an effective tolerance-inducing therapy for coeliac disease. This Review discusses mechanisms of the various approaches taken, summarizing the progress made, and highlights future directions in this field.
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Affiliation(s)
- Ludvig M Sollid
- Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
- Department of Immunology, Oslo University Hospital, Oslo, Norway.
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Patt YS, Lahat A, David P, Patt C, Eyade R, Sharif K. Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review. Int J Mol Sci 2023; 24:15482. [PMID: 37895160 PMCID: PMC10607730 DOI: 10.3390/ijms242015482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023] Open
Abstract
Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.
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Affiliation(s)
- Yonatan Shneor Patt
- Department of Internal Medicine B, Sheba Medical Center, Ramat Gan 52621, Israel; (Y.S.P.); (P.D.); (C.P.); (R.E.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
| | - Adi Lahat
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan 52621, Israel
| | - Paula David
- Department of Internal Medicine B, Sheba Medical Center, Ramat Gan 52621, Israel; (Y.S.P.); (P.D.); (C.P.); (R.E.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
| | - Chen Patt
- Department of Internal Medicine B, Sheba Medical Center, Ramat Gan 52621, Israel; (Y.S.P.); (P.D.); (C.P.); (R.E.)
- The Adelson School of Medicine, Ariel University, Ariel 40700, Israel
| | - Rowand Eyade
- Department of Internal Medicine B, Sheba Medical Center, Ramat Gan 52621, Israel; (Y.S.P.); (P.D.); (C.P.); (R.E.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
| | - Kassem Sharif
- Department of Internal Medicine B, Sheba Medical Center, Ramat Gan 52621, Israel; (Y.S.P.); (P.D.); (C.P.); (R.E.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan 52621, Israel
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Valvano M, Fabiani S, Monaco S, Calabrò M, Mancusi A, Frassino S, Rolandi C, Mosca M, Faenza S, Sgamma E, Cesaro N, Latella G. Old and New Adjunctive Therapies in Celiac Disease and Refractory Celiac Disease: A Review. Int J Mol Sci 2023; 24:12800. [PMID: 37628981 PMCID: PMC10454405 DOI: 10.3390/ijms241612800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/13/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict GFD) as in the case of Refractory Celiac Disease (RCD) represents a major issue. In this review, we have analysed and discussed data from both randomized controlled trials and observational studies concerning adjunctive therapies as well as novel therapies for the treatment of CD and RCD. The literature search was carried out through Medline and Scopus. In total, 2268 articles have been identified and 49 were included in this review (36 studies resulting from the search strategy and 13 from other sources). Today, GFD remains the only effective treatment, although steroids, mesalamine, and more recently biological therapies have found space in the complex management of RCD. Currently, studies evaluating the effectiveness of novel therapies are still limited and preliminary results have been controversial.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Giovanni Latella
- Gastroenterology Unit, Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi 1, 67100 L’Aquila, Italy; (M.V.); (S.F.); (S.M.); (M.C.); (A.M.); (S.F.); (C.R.); (M.M.); (S.F.); (E.S.); (N.C.)
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Murray JA, Wassaf D, Dunn K, Arora S, Winkle P, Stacey H, Cooper S, Goldstein KE, Manchanda R, Kontos S, Grebe KM. Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial. Lancet Gastroenterol Hepatol 2023; 8:735-747. [PMID: 37329900 DOI: 10.1016/s2468-1253(23)00107-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Coeliac disease management is limited to strict adherence to a gluten-free diet with no approved therapies. This first-in-human phase 1 study evaluated the safety and tolerability of KAN-101, a liver-targeting glycosylation signature conjugated to a deaminated gliadin peptide designed to induce immune tolerance to gliadin. METHODS Adults (aged 18-70 years) with biopsy-confirmed, HLA-DQ2.5 genotype coeliac disease were enrolled from clinical research units and hospitals in the USA. Part A of the trial was an open-label, single ascending dose study of intravenous KAN-101 using sentinel dosing in evaluation of the following cohorts: 0·15 mg/kg, 0·3 mg/kg, 0·6 mg/kg, 1·2 mg/kg, and 1·5 mg/kg. Following safety monitoring committee review of the 0·3 mg/kg dose level in part A, part B was initiated as a randomised, placebo-controlled, multiple ascending dose study. In part B, interactive response technology was used to randomly assign (5:1) patients to receive intravenous KAN-101 (0·15 mg/kg, 0·3 mg/kg, or 0·6 mg/kg) or placebo following a 1:1 assignment of the first two eligible patients in each cohort for sentinel dosing. Patients in part B received three administrations of KAN-101 or placebo followed by a 3-day oral gluten challenge (9 g per day) 1 week after completing dosing. Study personnel and patients were masked to treatment assignments in part B, and not in part A. The primary endpoint was the incidence and severity of adverse events with escalating doses of KAN-101, assessed in all patients who received any amount of study drug based on dose level received. The secondary endpoint was assessment of plasma concentrations and pharmacokinetic parameters of KAN-101 following single and multiple doses, assessed in all patients who received at least one dose and had one or more values for drug concentration. This study is registered with ClinicalTrials.gov, NCT04248855, and is completed. FINDINGS Between Feb 7, 2020, and Oct 8, 2021, 41 patients were enrolled at ten US sites. 14 patients were assigned to part A (four 0·15 mg/kg, three 0·3 mg/kg, three 0·6 mg/kg, three 1·2 mg/kg, one 1·5 mg/kg) and 27 patients to part B (six 0·15 mg/kg with two placebo, seven 0·3 mg/kg with two placebo, and eight 0·6 mg/kg with two placebo). Treatment-related adverse events were reported in 11 (79%) of 14 patients in part A and 18 (67%) of 27 in part B (placebo two [33%] of six patients; KAN-101 16 [76%] of 21 patients), were grade 2 or lower, and were mild to moderate in severity. The most commonly observed adverse events were nausea, diarrhoea, abdominal pain, and vomiting, consistent with symptoms had by patients with coeliac disease on gluten ingestion. No grade 3-4 adverse events, serious adverse events, dose-limiting toxicities, or deaths occurred. Pharmacokinetic analyses showed KAN-101 was cleared from systemic circulation within roughly 6 h with a geometric mean half-life of 3·72 min (CV% 6·5%) to 31·72 min (83·7%), and no accumulation with repeated dosing. INTERPRETATION KAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. FUNDING Kanyos Bio.
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Affiliation(s)
- Joseph A Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Karen Dunn
- North Carolina Clinical Research, Raleigh, NC, USA
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Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study. Lancet Gastroenterol Hepatol 2023; 8:446-457. [PMID: 36898393 DOI: 10.1016/s2468-1253(22)00428-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 12/03/2022] [Accepted: 12/07/2022] [Indexed: 03/09/2023]
Abstract
BACKGROUND A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4+ T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease. METHODS This was a randomised, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, one secondary, and 11 tertiary centres) in the USA, Australia, and New Zealand. Patients with coeliac disease aged 18-70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5 positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0·9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same doseage as those who were non-homozygous. The primary endpoint was change in coeliac disease patient reported outcomes (total gastrointestinal domain) from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analysed in the non-homozygous intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03644069. FINDINGS Between Sept 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 [74%] women, 46 [26%] men; median age 41 years [IQR 33-55]) were randomly assigned. One (1%) of 179 patients was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included eight patients. The study was discontinued after planned interim analysis of 66 patients who were non-homozygous. We report an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints combining data from 67 (66 were assessed in the planned interim analysis for the primary endpoint). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2·86 (SD 2·28) compared with 2·63 (2·07) for the non-homozygous placebo group (p=0·43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in five (3%) of 178 patients (two [2%] of 92 who received Nexvax2 and three [4%] of 82 who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for three (4%) of 78 patients in the non-homozygous placebo group (one each with exacerbation of asthma and appendicitis, and one who had forehead abscess, conjunctivitis, and folliculitis) and one (1%) patient in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 patients who received placebo were nausea (44 [48%] of 92 patients who received Nexvax2 vs 29 (34%) of 86 patients who received placebo), diarrhoea (32 [35%] vs 25 [29%]), abdominal pain (31 [34%] vs 27 [31%]), headache 32 [35%] vs 20 [23%]), and fatigue (24 [26%] vs 31 [36%]). INTERPRETATION Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for coeliac disease. FUNDING ImmusanT.
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Machado MV. New Developments in Celiac Disease Treatment. Int J Mol Sci 2023; 24:ijms24020945. [PMID: 36674460 PMCID: PMC9862998 DOI: 10.3390/ijms24020945] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/18/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Celiac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet (GFD). This is not an easy task due to a lack of awareness of the gluten content in foods and the extensive incorporation of gluten in processed foods. Furthermore, a GFD imposes a sense of limitation and might be associated with decreased quality of life in CD patients. This results in gluten contamination in the diet of four out of five celiac patients adhering to a GFD. Furthermore, one in three adult patients will report persistent symptoms and two in three will not achieve full histological recovery when on a GFD. In recent years, there has been extensive research conducted in the quest to find the holy grail of pharmacological treatment for CD. This review will present a concise description of the current rationale and main clinical trials related to CD drug therapy.
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Affiliation(s)
- Mariana Verdelho Machado
- Gastroenterology Department, Hospital de Vila Franca de Xira, Estrada Carlos Lima Costa, Nª 2, 2600-009 Vila Franca de Xira, Portugal; ; Tel.: +351-263-006-500
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028 Lisbon, Portugal
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15
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Replacing the Burden of the Gluten Free Diet: Then, Now, and the Future. Int J Mol Sci 2022; 23:ijms232315108. [PMID: 36499446 PMCID: PMC9741045 DOI: 10.3390/ijms232315108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/26/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022] Open
Abstract
Without a doubt, a majority of diseases are food-pattern-related. However, one disease stands out as an increasingly more common autoimmune-mediated enteropathy triggered by the ingestion of gluten. Celiac disease (CD) is an old disease, with changing clinical patterns, affecting any age, including infancy and adolescence, and becoming more frequent among the elderly. The gluten-free diet (GFD) has been the sole provider of clinical, serological, and histological improvement for patients with CD for more than seven decades. Nowadays, complete avoidance of dietary gluten is rarely possible because of the wide availability of wheat and other processed foods that contain even more gluten, to the detriment of gluten-free products. Undeniably, there is a definite need for replacing the burdensome GFD. An add-on therapy that could control the dietary transgressions and inadvertent gluten consumption that can possibly lead to overt CD should be considered while on GFD. Nevertheless, future drugs should be able to provide patients some freedom to self-manage CD and increase food independence, while actively reducing exposure and mucosal damage and alleviating GI symptoms. Numerous clinical trials assessing different molecules have already been performed with favorable outcomes, and hopefully they will soon be available for patient use.
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16
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Dieckman T, Koning F, Bouma G. Celiac disease: New therapies on the horizon. Curr Opin Pharmacol 2022; 66:102268. [DOI: 10.1016/j.coph.2022.102268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/24/2022] [Accepted: 06/14/2022] [Indexed: 11/03/2022]
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Levescot A, Malamut G, Cerf-Bensussan N. Immunopathogenesis and environmental triggers in coeliac disease. Gut 2022; 71:gutjnl-2021-326257. [PMID: 35879049 PMCID: PMC9554150 DOI: 10.1136/gutjnl-2021-326257] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/07/2022] [Indexed: 12/21/2022]
Abstract
Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.
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Affiliation(s)
- Anais Levescot
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
| | - Georgia Malamut
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
- Université Paris Cité, APHP Centre, Gastroenterology Department, Hôpital Cochin, Paris, France
| | - Nadine Cerf-Bensussan
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
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18
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Ailioaie LM, Ailioaie C, Litscher G, Chiran DA. Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic. Int J Mol Sci 2022; 23:ijms23147719. [PMID: 35887067 PMCID: PMC9322892 DOI: 10.3390/ijms23147719] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 12/16/2022] Open
Abstract
Celiac disease (CD) comprises over 1% of the world’s population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines.
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Affiliation(s)
- Laura Marinela Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania; (L.M.A.); (C.A.)
| | - Constantin Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania; (L.M.A.); (C.A.)
| | - Gerhard Litscher
- Research Unit of Biomedical Engineering in Anesthesia and Intensive Care Medicine, Research Unit for Complementary and Integrative Laser Medicine, Traditional Chinese Medicine (TCM) Research Center Graz, Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 39, 8036 Graz, Austria
- Correspondence: ; Tel.: +43-316-385-83907
| | - Dragos Andrei Chiran
- Department of Morpho-Functional Sciences I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii St., 700115 Iasi, Romania;
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19
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Ailioaie LM, Ailioaie C, Litscher G, Chiran DA. Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic. Int J Mol Sci 2022. [PMID: 35887067 DOI: 10.3390/ijms23147719.pmid:35887067;pmcid:pmc9322892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
Celiac disease (CD) comprises over 1% of the world's population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines.
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Affiliation(s)
- Laura Marinela Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Constantin Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Gerhard Litscher
- Research Unit of Biomedical Engineering in Anesthesia and Intensive Care Medicine, Research Unit for Complementary and Integrative Laser Medicine, Traditional Chinese Medicine (TCM) Research Center Graz, Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 39, 8036 Graz, Austria
| | - Dragos Andrei Chiran
- Department of Morpho-Functional Sciences I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii St., 700115 Iasi, Romania
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20
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Song Y, Lee S, Bell D, Goudey B, Zhou R. Binding Affinity Calculations of Gluten Peptides to HLA Risk Modifiers: DQ2.5 versus DQ7.5. J Phys Chem B 2022; 126:5151-5160. [PMID: 35796490 DOI: 10.1021/acs.jpcb.2c00962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Free energy perturbation (FEP) calculations can predict relative binding affinities of an antigen and its point mutants to the same human leukocyte antigen (HLA) with high accuracy (e.g., within 1.0 kcal/mol to experiment); however, a more challenging task is to compare binding affinities of wholly different antigens binding to completely different HLAs using FEP. Researchers have used a variety of different FEP schemes to compute and compare absolute binding affinities, with varied success. Here, we propose and assess a unifying scheme to compute the relative binding affinities of different antigens binding to completely different HLAs using absolute binding affinity FEP calculations. We apply our affinity calculation technique to HLA-antigen-T-cell receptor (TCR) systems relevant to celiac disease (CeD) by investigating binding affinity differences between HLA-DQ2.5 (enhanced CeD risk) and HLA-DQ7.5 (CeD protective) in the binary (HLA-gliadin) and ternary (HLA-gliadin-TCR) binding complexes for three gliadin derived epitopes: glia-α1, glia-α2, and glia-ω1. Based on FEP calculations with our carefully designed thermodynamic cycles, we demonstrate that HLA-DQ2.5 has higher binding affinity than HLA-DQ7.5 for gliadin and enhanced binding affinity with a common TCR, agreeing with known results that the HLA-DQ2.5 serotype exhibits increased risk for CeD. Our findings reveal that our proposed absolute binding affinity FEP method is appropriate for predicting HLA binding for disparate antigens with different genotypes. We also discuss atomic-level details of HLA genotypes interacting with gluten peptides and TCRs in regard to the pathogenesis of CeD.
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Affiliation(s)
- Yi Song
- College of Life Sciences, Department of Physics, and Institute of Quantitative Biology, Zhejiang University, Hangzhou 310058, China
| | - Sangyun Lee
- Computational Biology Center, IBM Thomas J Watson Research Center, Yorktown Heights, New York 10598, United States
| | - David Bell
- Computational Biology Center, IBM Thomas J Watson Research Center, Yorktown Heights, New York 10598, United States.,Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, United States
| | - Benjamin Goudey
- School of Computing and Information Systems, The University of Melbourne, Melbourne 3010, Australia
| | - Ruhong Zhou
- College of Life Sciences, Department of Physics, and Institute of Quantitative Biology, Zhejiang University, Hangzhou 310058, China.,Computational Biology Center, IBM Thomas J Watson Research Center, Yorktown Heights, New York 10598, United States.,Department of Chemistry, Columbia University, New York, New York 10027, United States
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21
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Wessels M, Auricchio R, Dolinsek J, Donat E, Gillett P, Mårild K, Meijer C, Popp A, Mearin ML. Review on pediatric coeliac disease from a clinical perspective. Eur J Pediatr 2022; 181:1785-1795. [PMID: 35034201 DOI: 10.1007/s00431-022-04379-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 12/19/2022]
Abstract
Coeliac disease is an immune-mediated condition characterized by chronic inflammation of the small bowel with villous atrophy driven by gluten ingestion in genetically predisposed individuals. It occurs frequently in both children and adults, affecting 1-4% of the population. The disease is associated with both gastrointestinal and extra-intestinal symptoms related to malabsorption and/or immune activation, and autoantibodies to tissue transglutaminase. Removal of gluten from the diet results in resolution of symptoms and enteropathy in the majority of patients. A good diagnostic work-up is important to avoid unnecessary restrictive diets in children. In this review on pediatric coeliac disease, we address epidemiology including predisposing environmental factors and possible preventive strategies, as well as the clinical presentation, diagnosis and follow-up. What is Known: •Primary prevention of coeliac disease is not possible; however, secondary prevention by targeting high-risk groups is recommended. •The diagnosis is safe without duodenal biopsies if specific conditions are met, also in asymptomatic children. What is New: •HLA-DQ typing is not routinely required for the diagnosis, whereas it can rule out coeliac disease if HLA-DQ2 and HLA-DQ8 are absent. •Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance and quality of life.
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Affiliation(s)
- Margreet Wessels
- Department of Pediatrics, Rijnstate Hospital, Arnhem, the Netherlands.
| | - Renata Auricchio
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Jernej Dolinsek
- Department of Pediatrics, Hepatology and Nutrition Unit and Medical Faculty, Dept. of Pediatrics, University Medical Centre Maribor, GastroenterologyMaribor, Slovenia
| | - Ester Donat
- Pediatric Gastroenterology and Hepatology Unit, Celiac Disease and Digestive Immunopathology Unit, Hospital Universitari I Politècnic La Fe, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Peter Gillett
- Department of Pediatric Gastroenterology, Royal Hospital for Children and Young People, Scotland, Edinburgh, UK
| | - Karl Mårild
- Department of Pediatrics, Institute of Clinical Sciences, Department of Pediatric Gastroenterology, Sahlgrenska Academy, Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Caroline Meijer
- Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Alina Popp
- University of Medicine and Pharmacy ''Carol Davila'', National Institute for Mother and Child Health, Bucharest, Romania
| | - M Luisa Mearin
- Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands
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22
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Klonarakis M, Andrews CN, Raman M, Panaccione R, Ma C. Review article: therapeutic targets for the pharmacologic management of coeliac disease-the future beyond a gluten-free diet. Aliment Pharmacol Ther 2022; 55:1277-1296. [PMID: 35229332 DOI: 10.1111/apt.16846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/03/2021] [Accepted: 02/13/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Coeliac disease (CeD) is an immune-mediated small bowel enteropathy resulting from dietary gluten exposure. Presently, the only effective treatment is adoption of a gluten-free diet (GFD), although strict adherence is challenging to maintain, and inadvertent gluten exposures are inevitable for most patients. Hence, there is substantial interest in drug development in CeD and multiple novel therapies are under investigation. AIMS To review existing and upcoming clinical trial programmes for pharmacologic agents for CeD. METHODS A narrative review was performed, informed by a search of MEDLINE, Embase, the Cochrane CENTRAL Library and clinicaltrials.gov. RESULTS We summarise the pathophysiology of CeD and the specific steps that are potentially amenable to pharmacologic treatment. We evaluate the evidence supporting existing and future drug targets, including trials of peptidases, gluten sequestrants, tight junction regulators, anti-transglutaminase 2 therapies, immune tolerizing agents, advanced biologics and small molecules, and microbiome-targeted strategies. We highlight unique considerations for conducting CeD trials, including identifying appropriate study populations, assessing results in the context of a gluten challenge, and interpreting CeD-specific clinical and histologic outcomes. Understanding these factors is crucial for accurately appraising the evidence. Finally, we outline what the future of CeD therapy may hold with the introduction of pharmacotherapies. CONCLUSIONS There is a need for pharmacologic options for CeD, either used adjunctively with a GFD for accidental or intentional gluten exposures or for refractory disease. Multiple promising agents are in development, and these trials are likely to lead to approvals for the first generation of pharmacologic agents for CeD within the next 5 years.
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Affiliation(s)
| | - Christopher N Andrews
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Maitreyi Raman
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada.,Alberta's Collaboration of Excellence for Nutrition in Digestive Diseases, Calgary, Alberta, Canada
| | - Remo Panaccione
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Christopher Ma
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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Treppiccione L, Luongo D, Maurano F, Rossi M. Next generation strategies to recover immunological tolerance in celiac disease. Int Rev Immunol 2022; 42:237-245. [PMID: 35225129 DOI: 10.1080/08830185.2022.2044807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Celiac disease (CD) is an autoimmune disease that occurs in genetically predisposed individuals following the ingestion of gluten. Its prevalence is rising worldwide. A gluten-free (GF) diet is mandatory for the management of CD. However, several issues persist regarding the nutritional quality of GF products. Importantly, deep knowledge about the pathogenic mechanisms in CD highlights the central role of CD4+ T cell-mediated immunity in CD. Furthermore, intestinal T regulatory cells are functional in CD, but cytokines such as IL-15, produced under inflammatory conditions, hamper their activity. This paves the way for the development of immunomodulatory strategies to the GF diet. From this perspective, microbiological approaches were considered able to modulate the gluten-specific immune response. Interestingly, gliadin peptide-based immunotherapy to abolish the inflammatory CD4+T cell-mediated response has been explored in CD patients. Furthermore, different biotechnological approaches based on the use of chemically/enzymatically modified gluten molecules have been proved effective in different models of CD. However, the choice of the right age in infants to introduce the antigen and thus induce tolerance still remains an important issue to solve. Addressing all these points should help to design an effective intervention strategy for preventing CD.
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Affiliation(s)
| | | | | | - Mauro Rossi
- Institute of Food Sciences, CNR, Avellino, Italy
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24
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Abstract
Celiac disease is a chronic, immune-mediated enteropathy driven by dietary gluten found in genetically susceptible hosts. It has a worldwide distribution, is one of the most common autoimmune disorders globally, and is the only autoimmune condition for which the trigger is known. Despite advances in characterizing mechanisms of disease, gaps in understanding of celiac disease pathogenesis remain. A "frontier" concept is considering what moves an HLA-DQ2 or DQ8-positive individual from asymptomatic gluten tolerance to celiac disease manifestation. In this arena, environmental triggers, including age at the time of initial gluten exposure, the occurrence of usual childhood viral infections, and microbiome alterations have emerged as key events in triggering the symptomatic disease. Pathologists play a major role in frontier aspects of celiac disease. This includes the discovery that duodenal mucosal histology in follow-up biopsies does not correlate with ongoing patient symptoms, antitissue transglutaminase antibody titers and diet adherence in celiac disease patients. Further, in light of recent evidence that the detection of monoclonal T-cell populations in formalin-fixed biopsies is not specific for type II refractory celiac disease, pathologists should resist performing such analyses until common causes of "apparent" refractoriness are excluded. The promise of therapies in celiac disease has led to clinical trials targeting many steps in the inflammatory cascade, which depend upon a pathologist's confirmation of the initial diagnosis and evaluation of responses to therapies. As pathologists continue to be active participants in celiac disease research, partnering with other stakeholders, we will continue to impact this important autoimmune disease.
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Affiliation(s)
- Natalie Patel
- El Camino Pathology Medical Group, Mountain View, CA
| | - Marie E Robert
- Department of Pathology and Medicine, Yale University School of Medicine, New Haven, CT
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25
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Anderson RP. Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis. Expert Rev Clin Immunol 2021; 18:75-91. [PMID: 34767744 DOI: 10.1080/1744666x.2021.2006636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. AREAS COVERED The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. EXPERT OPINION Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.
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26
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Tarar ZI, Zafar MU, Farooq U, Basar O, Tahan V, Daglilar E. The Progression of Celiac Disease, Diagnostic Modalities, and Treatment Options. J Investig Med High Impact Case Rep 2021; 9:23247096211053702. [PMID: 34693776 PMCID: PMC8767653 DOI: 10.1177/23247096211053702] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Celiac disease (CD) is an autoimmune disorder that affects genetically predisposed individuals who are sensitive to gluten and related proteins. It affects children and adults with increasing prevalence in the older age groups. Both adaptive and innate immune responses play role in CD pathogenesis which results in damage of lamina propria and deposition of intraepithelial lymphocytes. There are other proposed mechanisms of CD pathogenesis like gastrointestinal infections, intestinal microbiota, and early introduction of gluten. The diagnosis of CD is based on clinical symptoms and serological testing, though a majority of cases are asymptomatic, and small intestinal biopsies are required to confirm the diagnosis. Celiac disease is generally associated with other autoimmune diseases, and it is advisable to test these patients for diseases like type 1 diabetes mellitus, Addison’s disease, thyroid diseases, inflammatory bowel disease, and autoimmune hepatitis. The patient with a new diagnosis of CD requires close follow-up after starting treatment to see symptom improvement and check dietary compliance. A newly diagnosed patient is advised to follow with a dietitian to better understand the dietary restrictions as about 20% of patients stay symptomatic even after starting treatment due to noncompliance or poor understanding of diet restrictions. The most effective treatment for CD is a gluten-free diet, but work on non-dietary therapy is in process and few medications are in the clinical trial phase.
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Affiliation(s)
| | | | - Umer Farooq
- Loyola Medicine/MacNeal Hospital, Berwyn, IL, USA
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27
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Cerf-Bensussan N, Schuppan D. The Promise of Novel Therapies to Abolish Gluten Immunogenicity in Celiac Disease. Gastroenterology 2021; 161:21-24. [PMID: 33891951 DOI: 10.1053/j.gastro.2021.04.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022]
Affiliation(s)
- Nadine Cerf-Bensussan
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Paris, France.
| | - Detlef Schuppan
- Institute of Translational Immunology, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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28
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Kelly CP, Murray JA, Leffler DA, Getts DR, Bledsoe AC, Smithson G, First MR, Morris A, Boyne M, Elhofy A, Wu TT, Podojil JR, Miller SD. TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study. Gastroenterology 2021; 161:66-80.e8. [PMID: 33722583 PMCID: PMC9053078 DOI: 10.1053/j.gastro.2021.03.014] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 03/05/2021] [Accepted: 03/07/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells. RESULTS In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs placebo (2.01 vs 17.58, P = .006). Vh:Cd deteriorated in the placebo group (-0.63, P = .002), but not in the TAK-101 group (-0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4β7+CD4+ (0.26 vs 1.05, P = .032), αEβ7+CD8+ (0.69 vs 3.64, P = .003), and γδ (0.15 vs 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.
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Affiliation(s)
- Ciarán P. Kelly
- Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | | | - Daniel A. Leffler
- Beth Israel Deaconess Medical Center, Harvard Medical School Celiac Research Program, Boston, Massachusetts;,Takeda Pharmaceuticals International Co., Cambridge, Massachusetts
| | - Daniel R. Getts
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois;,Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Adam C. Bledsoe
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Glennda Smithson
- Takeda Pharmaceuticals International Co., Cambridge, Massachusetts
| | - M. Roy First
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois
| | - Amy Morris
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois
| | - Michael Boyne
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois
| | - Adam Elhofy
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois
| | - Tsung-Teh Wu
- Department of Pathology, Mayo Clinic, Rochester, Minnesota
| | - Joseph R. Podojil
- COUR Pharmaceuticals Development Co, Inc, Northbrook, Illinois;,Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Stephen D. Miller
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;,Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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29
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Richardson N, Wraith DC. Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity. IMMUNOTHERAPY ADVANCES 2021; 1:ltab009. [PMID: 35919740 PMCID: PMC9327121 DOI: 10.1093/immadv/ltab009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/28/2021] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
Targeted restoration of immunological tolerance to self-antigens or innocuous environmental allergens represents the ultimate aim of treatment options in autoimmune and allergic disease. Antigen-specific immunotherapy (ASI) is the only intervention that has proven disease-modifying efficacy as evidenced by induction of long-term remission in a number of allergic conditions. Mounting evidence is now indicating that specific targeting of pathogenic T cells in autoinflammatory and autoimmune settings enables effective restoration of immune homeostasis between effector and regulatory cells and alters the immunological course of disease. Here, we discuss the key lessons learned during the development of antigen-specific immunotherapies and how these can be applied to inform future interventions. Armed with this knowledge and current high-throughput technology to track immune cell phenotype and function, it may no longer be a matter of ‘if’ but ‘when’ this ultimate aim of targeted tolerance restoration is realised.
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Affiliation(s)
- Naomi Richardson
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - David Cameron Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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30
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Hardy MY, Goel G, Russell AK, Chen Yi Mei SLG, Brown GJE, Wang S, Szymczak E, Zhang R, Goldstein KE, Neff KM, Williams LJ, Truitt KE, Dzuris JL, Tye-Din JA, Anderson RP. A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease. Front Immunol 2021; 12:661622. [PMID: 34093551 PMCID: PMC8171185 DOI: 10.3389/fimmu.2021.661622] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/04/2021] [Indexed: 12/16/2022] Open
Abstract
Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
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Affiliation(s)
- Melinda Y Hardy
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gautam Goel
- ImmusanT, Inc., Cambridge, MA, United States
| | - Amy K Russell
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | | | - Gregor J E Brown
- Department of Gastroenterology, Alfred Hospital, Prahran, VIC, Australia
| | - Suyue Wang
- ImmusanT, Inc., Cambridge, MA, United States
| | | | - Ruan Zhang
- ImmusanT, Inc., Cambridge, MA, United States
| | | | | | | | | | | | - Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
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31
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Auricchio R, Troncone R. Can Celiac Disease Be Prevented? Front Immunol 2021; 12:672148. [PMID: 34054850 PMCID: PMC8160282 DOI: 10.3389/fimmu.2021.672148] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/20/2021] [Indexed: 12/20/2022] Open
Abstract
Celiac disease (CD) is an autoimmune disorder triggered by gluten in genetically susceptible individuals characterized by a variable combination of gluten-dependent symptoms, presence of specific autoantibodies and enteropathy. The health burden of CD is considerable, as it reduces quality of life and, at a societal level, has extensive negative economic consequences. Prevention strategies are based on the identification of at-risk subjects and identification and elimination of risk factors. A number of prospective observational and interventional studies conducted on the general population, and more often in subjects at-risk, have given important information on the natural history of the disease. Both genetic and environmental factors have been identified with the former, in particular histocompatibility genes, playing a major role. Environmental factors, some operating already before birth, have been identified, with feeding pattern in the first year of life (breast feeding, amount and time of introduction of gluten) and infections being the most relevant. Prospective studies have also allowed the identification of biomarkers predictive of the disease which in perspective could better define the population on which to intervene. Interventions have been so far limited to modifications of feeding patterns. However, as also learnt from diseases that share with CD genetic risk factors and mechanisms of damage, such as type 1 diabetes (T1D), future strategies may be envisaged based on protection from infections, manipulation of microbiota, intervention on T cells.
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Affiliation(s)
- Renata Auricchio
- Department of Medical Translational Sciences & European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
| | - Riccardo Troncone
- Department of Medical Translational Sciences & European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
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32
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Gliadin Sequestration as a Novel Therapy for Celiac Disease: A Prospective Application for Polyphenols. Int J Mol Sci 2021; 22:ijms22020595. [PMID: 33435615 PMCID: PMC7826989 DOI: 10.3390/ijms22020595] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/13/2022] Open
Abstract
Celiac disease is an autoimmune disorder characterized by a heightened immune response to gluten proteins in the diet, leading to gastrointestinal symptoms and mucosal damage localized to the small intestine. Despite its prevalence, the only treatment currently available for celiac disease is complete avoidance of gluten proteins in the diet. Ongoing clinical trials have focused on targeting the immune response or gluten proteins through methods such as immunosuppression, enhanced protein degradation and protein sequestration. Recent studies suggest that polyphenols may elicit protective effects within the celiac disease milieu by disrupting the enzymatic hydrolysis of gluten proteins, sequestering gluten proteins from recognition by critical receptors in pathogenesis and exerting anti-inflammatory effects on the system as a whole. This review highlights mechanisms by which polyphenols can protect against celiac disease, takes a critical look at recent works and outlines future applications for this potential treatment method.
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33
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Abstract
PURPOSE OF REVIEW The current review is prompted by recent studies indicating that adaptive immunity could be sufficient to explain rapid onset symptoms as well as many chronic effects of gluten in celiac disease. RECENT FINDINGS Gluten re-exposure in treated celiac disease drives a coordinated systemic cytokine release response implicating T-cell activation within 2 h. Instead of direct effects of gluten on innate immunity, long lasting memory CD4+ T cells activated within 2 h of ingesting gluten or injecting purified gluten peptides now appear to be responsible for acute digestive symptoms. In addition, memory B cells and plasma cells specific for gluten and transglutaminase 2, rather than innate immune cells, are the preferred antigen-presenting cells for gluten in the gut. A variety of innate immune stimuli such as transient infections and local intestinal microbiome, not necessarily gluten itself, may contribute to disease initiation and transition to overt intestinal mucosal injury. Gluten-specific adaptive immunity in the gut and blood are now shown to be closely linked, and systemic cytokine release after gluten provides an additional explanation for extraintestinal manifestations of celiac disease. SUMMARY Clinical studies utilizing cytokines as new biomarkers for gluten immunity promise to improve understanding of clinical effects of gluten, accelerate therapeutics development, and augment diagnosis.
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Bajaj JS, Brenner DM, Cai Q, Cash BD, Crowell M, DiBaise J, Gallegos-Orozco JF, Gardner TB, Gyawali CP, Ha C, Holtmann G, Jamil LH, Kaplan GG, Karsan HA, Kinoshita Y, Lebwohl B, Leontiadis GI, Lichtenstein GR, Longstreth GF, Muthusamy VR, Oxentenko AS, Pimentel M, Pisegna JR, Rubenstein JH, Russo MW, Saini SD, Samadder NJ, Shaukat A, Simren M, Stevens T, Valdovinos M, Vargas H, Spiegel B, Lacy BE. Major Trends in Gastroenterology and Hepatology Between 2010 and 2019: An Overview of Advances From the Past Decade Selected by the Editorial Board of The American Journal of Gastroenterology. Am J Gastroenterol 2020; 115:1007-1018. [PMID: 32618649 DOI: 10.14309/ajg.0000000000000709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- J S Bajaj
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - D M Brenner
- Northwestern University, Chicago Illinois, USA
| | - Q Cai
- Emory University, Atlanta, Georgia, USA
| | - B D Cash
- McGovern Medical School, Houston, Texas, USA
| | - M Crowell
- Mayo Clinic, Scottsdale, Arizona, USA
| | - J DiBaise
- Mayo Clinic, Scottsdale, Arizona, USA
| | | | - T B Gardner
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - C P Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - C Ha
- Inflammatory Bowel Diseases Center, Cedars-Sinai Medical Center, Los Angeles CA, USA
| | - G Holtmann
- University of Queensland, Brisbane, Australia, USA
| | - L H Jamil
- Beaumont Health-Royal Oak, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA
| | - G G Kaplan
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - H A Karsan
- Atlanta Gastroenterology Associates and Emory University, Atlanta, Georgia, USA
| | - Y Kinoshita
- Steel Memorial Hirohata Hospital and Himeji Brain and Heart Center, Himeji, Japan
| | - B Lebwohl
- Columbia University Irving Medical Center, New York, New York, USA
| | | | | | - G F Longstreth
- Kaiser Permanente Southern California, San Diego, California, USA
| | - V R Muthusamy
- David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | | | - M Pimentel
- Inflammatory Bowel Diseases Center, Cedars-Sinai Medical Center, Los Angeles CA, USA
| | - J R Pisegna
- Department of Veterans Affairs, VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA Los Angeles, California, USA
| | - J H Rubenstein
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, USA
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - M W Russo
- Carolinas Medical Center-Atrium Health, Charlotte, North Carolina, USA
| | - S D Saini
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, USA
- Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | - A Shaukat
- Minneapolis Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota, USA
| | - M Simren
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - T Stevens
- Cleveland Clinic, Cleveland, Ohio, USA
| | - M Valdovinos
- Instituto Nacional de Ciencias Médicas y Nutricion S.Z., Mexico City, Mexico
| | - H Vargas
- Mayo Clinic, Scottsdale, Arizona, USA
| | - B Spiegel
- Inflammatory Bowel Diseases Center, Cedars-Sinai Medical Center, Los Angeles CA, USA
| | - B E Lacy
- Mayo Clinic, Jacksonville, Florida, USA
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35
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Feng X, Liu J, Xu W, Li G, Ding J. Tackling autoimmunity with nanomedicines. Nanomedicine (Lond) 2020; 15:1585-1597. [DOI: 10.2217/nnm-2020-0102] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Tolerogenic immunotherapy aims to blunt pathogenic inflammation without affecting systemic immunity. However, the anti-inflammatory drugs and immunosuppressive biologics that are used in the clinic usually result in nonspecific immune cell suppression and off-target toxicity. For this reason, strategies have been developed to induce antigen-specific immune tolerance through the delivery of disease-relevant antigens by nanocarriers as a benefit of their preferential internalization by antigen-presenting cells. Herein, we discuss the recent advances in the nanotechnology-based antigen-specific tolerance approaches. Some of these designs are based on nanoparticles delivering antigens and immunoregulatory agents to modulate antigen-presenting pathways, while others directly target T cells via nanoparticle-based artificial antigen-presenting cells. These antigen-specific therapies are hoped to replace systemic immune suppression and provide long-term disease remission.
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Affiliation(s)
- Xiangru Feng
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
- University of Science & Technology of China, 96 Jinzhai Road, Hefei, 230026, PR China
| | - Jiaxue Liu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| | - Weiguo Xu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| | - Gao Li
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
- University of Science & Technology of China, 96 Jinzhai Road, Hefei, 230026, PR China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
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36
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Goel G, Daveson AJM, Hooi CE, Tye-Din JA, Wang S, Szymczak E, Williams LJ, Dzuris JL, Neff KM, Truitt KE, Anderson RP. Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease. Clin Exp Immunol 2019; 199:68-78. [PMID: 31505020 DOI: 10.1111/cei.13369] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2019] [Indexed: 12/14/2022] Open
Abstract
Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)-2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten-mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free-diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high-sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL-2, chemokine (C-C motif) ligand 20 (CCL20), IL-6, chemokine (C-X-C motif) ligand (CXCL)9, CXCL8, interferon (IFN)-γ, IL-10, IL-22, IL-17A, tumour necrosis factor (TNF)-α, CCL2 and amphiregulin. IL-2 and IL-17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL-2 increased most (median 57-fold), then CCL20 (median 10-fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL-2, IL-17A, IL-22 and IFN-γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.
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Affiliation(s)
- G Goel
- ImmusanT, Inc., Cambridge, MA,, USA
| | - A J M Daveson
- Faculty of Medicine, University of Queensland, 288 Herston Rd, Herston, 4006, QLD, Australia
| | - C E Hooi
- Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - J A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - S Wang
- ImmusanT, Inc., Cambridge, MA,, USA
| | | | | | | | - K M Neff
- ImmusanT, Inc., Cambridge, MA,, USA
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37
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Truitt KE, Anderson RP. Editorial: a non-dietary treatment for coeliac disease-two steps forward, one step back? Authors' reply. Aliment Pharmacol Ther 2019; 50:956-957. [PMID: 31591779 DOI: 10.1111/apt.15494] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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38
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Mitchell H, Garg M. Editorial: a non-dietary treatment for coeliac disease-two steps forward, one step back? Aliment Pharmacol Ther 2019; 50:955-956. [PMID: 31591769 DOI: 10.1111/apt.15470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Hannah Mitchell
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.,Allied Health, Eastern Health, Box Hill, Victoria, Australia
| | - Mayur Garg
- Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.,Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
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Tye-Din JA, Daveson AJM, Ee HC, Goel G, MacDougall J, Acaster S, Goldstein KE, Dzuris JL, Neff KM, Truitt KE, Anderson RP. Elevated serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease. Aliment Pharmacol Ther 2019; 50:901-910. [PMID: 31483515 DOI: 10.1111/apt.15477] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/10/2019] [Accepted: 08/01/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease. AIM To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients. METHODS 25 coeliac disease patients on a gluten-free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient-Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin-2 was measured at baseline, and 2, 4 and 6 hours. RESULTS Serum interleukin-2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient-reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin-2 correlated with symptom severity, particularly for nausea and vomiting. CONCLUSIONS Serum interleukin-2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin-2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten-free diet.
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Affiliation(s)
- Jason A Tye-Din
- Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, University of Melbourne, Parkville, Vic., Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Vic., Australia
| | | | - Hooi C Ee
- Sir Charles Gairdner Hospital, Perth, WA, Australia
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