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Showing results for tags 'immunotherapy'.
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New Horizons in the Treatment of Celiac Disease
Shane Pendley posted an article in Autumn 2002 Issue
Celiac.com 06/10/2023 - If you suffer from celiac disease like I do you are well aware that the current and only treatment recommended for the disease is a lifelong adherence to a strict gluten-free diet. Anyone who has tried a gluten-free diet knows that it works fine as a treatment for the disease, but it also can be difficult to deal with, especially when cooking, dining out, and buying food (it can also be expensive!). According to one line of research done over the past few years, however, there may be hope that one day in the not too distant future we might be able to eat gluten without harm. How—you ask? Immunotherapy In 2001 the Scandinavian Journal of Immunology published an article authored by a group of Italian scientists wherein mice were used to test a new idea called immunomodulation and its ability to treat celiac disease. The scientists purified the protein gliadin (the component of gluten that triggers immune-mediated injury when ingested by people with celiac disease), fractionated it, and then administered the different fragments intra-nasally to laboratory mice (presumably transgenic mice with induced celiac disease, although this is unclear) and noted the results. They found that when a particular fragment of gliadin, which they refer to as alpha-gliadin, was administered intra-nasally it down-regulated T-cell proliferation and interferon-gamma production in response to whole gliadin in vitro. This lead the scientists to make the statement that "these results demonstrate how an immune response to a complex antigen may be controlled by treatment with a purified component and specifically indicate alpha-gliadin to be a good candidate for further identification of short peptides to be used as tolerogens in this model(1)." Although immunomodulation sounds similar to allergy therapy it is not the same since the cells involved are different, as well as the method of induced tolerance. In therapy for allergic reactions tolerance is induced through injections, and the aim is to reduce histamine release, systemic anaphylactic responses, and even severe rhinitis. In immunomodulation the antigen in question is cleaved into smaller antigens, and the mixture of epitopes are used to induce tolerance via mucosal surfaces (i.e., the nose, parts of the respiratory tract, and the alimentary tract, to name a few). From my understanding, these are markedly different approaches, and the mucosal therapy appears to potentially be much more powerful and more selective in immune-suppression resulting ultimately in tolerance to the antigen. It is my hope that this research indicates a new avenue for the treatment of celiac disease, one which may be very soon in coming—possibly within the next decade. Of course, questions arise as to what exactly this particular experiment means, since findings were in vitro (i.e., test tube only, not within the body), were done on mice (murine studies), and do not seem to have been duplicated in humans at this point, suggesting difficulties / logistical problems with the protocol as it exists— using alpha-gliadin as a tolerogen to suppress immune response to dietary gliadin. Nonetheless, at the very least, this research signals that research advances are still being made into the understanding and treatment of celiac disease, and that better therapies and possibly even a cure for this disease may be on the horizon. Reference: Maurano F, Siciliano RA, De Giulio B, Luongo D, Mazzeo MF, Troncone R, Auricchio S, Rossi M. Intranasal administration of one alpha gliadin can downregulate the immune response to whole gliadin in mice. Scand J Immunol 2001 Mar;53(3): 290-5. Istituto di Scienze dell'Alimentazione, CNR, Via Roma 52, 83100 Avellino, Italy.- 2 comments
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Can Gliadin Nanoparticles Cure Celiac Disease in Humans?
Jefferson Adams posted an article in Latest Research
Celiac.com 03/28/2020 - In theory, celiac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. A team of researchers recently set out to investigate the safety and efficacy of negatively charged, 500 nm, poly (lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. The research team included Tobias L. Freitag, Joseph R. Podojil, Ryan M. Pearson, Frank J. Fokta, Cecilia Sahl, Marcel Messing, Leif C. Andersson, Katarzyna Leskinen, Päivi Saavalainen, Lisa I. Hoover, Kelly Huang, Deborah Phippard, Sanaz Maleki, Nicholas J.C. King, Lonnie D. Shea, Stephen D. Miller, Seppo K. Meri, and Daniel R. Getts. Negatively charged, 500 nm, poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease. TIMP-GLIA did not elevate maturation markers on cultured human dendritic cells, or activate T cells from patients with active or treated celiac disease. The team assessed the model 1 delayed-type hypersensitivity, the model 2 HLA-DQ8 transgenic, and the model 3 gliadin memory T cell enteropathy models of celiac disease. Injections of TIMP-GLIA substantially reduced gliadin-specific T cell generation in models 1 and 2. Further, injections reduced inflammatory cytokine secretion in all three models, circulating gliadin-specific IgG/IgG2c in models 1 and 2, ear swelling in model 1, gluten-dependent enteropathy in model 3, and body weight loss in model 3. In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, showed increased levels of FOXP3, and gene expression markers associated with improved tolerance. Injecting gluten-sensitive mice with TIMP-GLIA nanoparticles nearly eliminated the immune response to gliadin, and reduced markers of inflammation and enteropathy. This approach might be refined and used to develop new treatments for celiac disease in humans. Read more in Gastroenterology The researchers are variously affiliated with the Department of Bacteriology and Immunology; the Translational Immunology Research Program; the Department of Microbiology and Immunology at Cour Pharmaceutical Development Company, Northbrook, IL, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Helsinki, Finland; Precision for Medicine, Frederick, MD, USA; the Discipline of Pathology, School of Medical Sciences, Bosch Institute, Sydney Medical School, The University of Sydney, Sydney, Australia; the Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.- 7 comments
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I’ve been diagnosed a celiac since 2016. I am a 68 years old female with Hashimoto’s, and I’ve had IBS symptoms for a few years before that. My diagnosis was positive for DNA markers, positive for IgA, IgE, and IgG but inconclusive for biopsy. My doctor told me because I had 2 out of three, I should go gluten free which I have done and stayed true to it since then. My symptoms have still not resolve to a good extent. She said we have to look for something new. She suggested allergy testing. After testing, I showed no food allergies but after 88 environmental scratches on my back, my back lit up with welts. I’m highly allergic to all grasses, all trees, most molds, pet danders and a half a dozen other things. I showed no symptoms, I didn’t know I had allergies. No runny nose, asthma, coughing or sneezing, just headaches and fatigue. My allergy doctor suggested allergy shots which I happily accepted thinking, “finally” we are figuring this out. Now here’s the kicker after following the instructions, nasal spray‘s, and Benadryl tablet, I received my 2 shots twice a week. I had no reaction The first day to the shots until the next day when I woke up with annoying joint pain in my right wrist and in the palm of my left hand a knot that wasn’t there before. I also had my usual joint pain and fatigue. This was a brand new symptom I have never had before and it has not gone away. With each shot I felt worse and worse. Fatigue, brain fog, and body aches that felt like the flu. I keep chalking it up to a reacting to the allergens. I kept asking, do other people have these symptoms and all said no. I’m three months into the treatment with the same symptoms and wonder if anyone else out there has the same symptoms. I’ve been to a rheumatologist and had x-rays of my wrists and hands and a rheumatoid blood panel, which all turned out negative except for high anti-nuclear antibody titer of 1:160. High positive anti-nuclear antibody IgG of 114. High anti-thyrogobulin IgG concentration of 140. High anti-thyroid Peroxidase IgG concentration of 521. I’ve questioned whether the serum has gluten but it’s just saline. I’m on my highest level of allergens now and will be for three more months before going to one shot a month. Can anyone give me some enlightenment here? Should I continue or not. I’m so far into it now.
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Celiac.com 07/01/2019 - Drugmakers have pulled the plug on a phase II trial of Nexvax2, a promising drug for treating celiac disease. Pharmaceutical company ImmusanT, said that "results from an interim analysis revealed Nexvax2 did not provide statistically meaningful protection from gluten exposure for celiac disease patients when compared with placebo." That's a lot of fancy language to say that the drug simply didn't work. It did no better than a placebo. If there were any other way to spin it, the company would have spun it. They didn't. That basically means total failure. We've written about Nexvax2 over the years, and followed it through its development. It was promising enough to earn fast-track development status by the FDA. The company's press release reads as follows: ImmusanT Discontinues Phase 2 Clinical Trial for Nexvax2® in Patients With Celiac Disease CAMBRIDGE, Mass. – June 25, 2019 – ImmusanT, Inc., a clinical stage company leveraging its Epitope-Specific Immuno-Therapy™ (ESIT™) platform to deliver first-in-class peptide-based immunomodulatory vaccine therapies to patients with autoimmune diseases, has discontinued the Phase 2 global study for its lead candidate, Nexvax2®, intended as a treatment for celiac disease. Similar to earlier Phase 1 results, Nexvax2 was found to be safe and generally well tolerated. There were no concerning safety issues identified during the study. ImmusanT will be actively investigating data gathered from the trial to further understand this outcome. The company will provide further information once available." So, to boil it down: The drug is safe and well tolerated, but it doesn't work any better than a placebo. The company will not pursue further testing. That's sad news and an ignoble end for a drug that held such high hopes. Few topics have generated as much excitement among celiac sufferers as the tantalizing possibility of a vaccine. Many eagerly hoped for success, while some wouldn't take it on a bet. It's unclear what this means for the technology behind Nexvax 2, as the underlying mechanics for this vaccine, Epitope-Specific Immuno-Therapy (ESIT), were to serve as the platform for future autoimmune treatments. Stay tuned for more on this and related stories.
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Celiac.com 10/29/2018 - Researchers Emma L. Smith with UCB Pharma Ltd., Slough, United Kingdom, and Mark Peakman from the Department of Immunobiology, King’s College London, London, United Kingdom recently set out to catalog clinical advances in peptide immunotherapy for Type 1 diabetes. Autoimmune and allergic diseases occur when a person’s body has an incorrect immune response to an antigen from the person’s own body, or to an innocuous antigen from outside the body. This triggers a pathogenic T-cell response which causes damage to certain tissues and organs. In Type 1 diabetes, this process results in the destruction of the insulin-secreting β cells, which leads to permanent need for recombinant insulin to make up for the loss. The best way to restore immune homeostasis and prevent further tissue damage is to reduce or cease the pathogenic T-cell response by using antigen-specific peptide immunotherapy. Smith and Peakman found that recent clinical advances with peptide therapy approaches in both Type 1 diabetes and other diseases are beginning to show encouraging results. New treatments that target peptides specific to certain cell types are also moving from the development stages into clinical use. Drug developers still face numerous hurdles in reaching full clinical use, including determining optimal dose and dosing frequency, but peptide immunotherapy for Type 1 diabetes is clearly becoming a very active field of drug development. Read their full report: Front Immunol. 2018; 9: 392.Published online 2018 Feb 28. doi: 10.3389/fimmu.2018.00392PMCID: PMC5836708PMID: 29541078
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Celiac.com 06/19/2013 - Currently, immunosuppressant drugs are the only real treatment option for most autoimmune disorders, such as celiac disease and Type 1 diabetes. However, researchers are busily exploring the possibilities offered therapeutic vaccines, known as antigen-specific immunotherapy. ImmusanT is one company working to develop a vaccine that will allow patients with celiac disease to safely eat gluten (the antigen). That vaccine is presently undergoing clinical trials. ImmusanT and its research partners are looking to build on their expertise in celiac disease to improve their understanding of antigen-specific immunotherapy for other autoimmune diseases. In Current Opinion in Immunology, researchers Bob Anderson and Bana Jabri describe how identification of pathogenic T cell epitopes (segment of the antigen) and recent initiatives to optimize immune monitoring have helped drive rational vaccine design in human autoimmune diseases. Celiac disease has provided researchers with the first opportunity to design and test epitope-specific immunotherapy with a thorough understanding of disease-causing T cell epitopes. This approach offers "truly customized immunotherapy for patients with celiac disease according to their genetics and the molecular specificity of their immune response to gluten," said Bob Anderson, PhD, MBChB, Chief Scientific Officer of ImmusanT. Because celiac disease shares key features, such as susceptibility genes, presence of autoantibodies and destruction of specific cells, with other autoimmune disorders, like Type 1 diabetes and rheumatoid arthritis, it provides a model for understanding and exploring the triggers and drivers of autoimmunity, in general, write Drs. Bana Jabri and Ludvig Sollid in the Perspectives section in Nature Reviews Immunology. By factoring in the association with the major histocompatibility complex (MHC), post-translation modifications, the antigen and the tissue, researchers can design methods that help to the spot potential drivers of autoimmune disease. Because peptide-specific therapy specifically targets the immune cells that drive the disease process, "it offers the potential to prevent and cure disease, without inducing general immunosuppression," said Bana Jabri, MD, PhD, Director, University of Chicago Celiac Center; Professor, Department of Medicine, Pathology and Pediatrics, University of Chicago; and Senior Scientific Advisor to ImmusanT. Ludvig M. Sollid, MD, PhD, is Director, Centre for Immune Regulation; Professor of Medicine, Department of Immunology, University of Oslo; Consultant, Oslo University Hospital-Rikshospitalet; and member of ImmusanT's Scientific Advisory Board. Dr. Jabri is Co-Chair of the 15(th) International Celiac Disease Symposium to be hosted by the University of Chicago Celiac Disease Center, September 22-25, 2013. The event will draw the world's top scientists and physicians to discuss the most recent scientific advances in managing and treating celiac disease and gluten-related disorders.
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Celiac.com 04/24/2009 - Currently, one of the more promising areas of celiac disease research looks to be in peptide-based therapies. One of the keys to creating an effective peptide-based therapy for celiac disease lies in identifying the gluten peptides that trigger intestinal T cell responses when people with celiac disease consume wheat, rye, or barley. A team of Italian researchers recently set out to do just that. The team was made up of A. Camarca, R.P. Anderson, G. Mamone, O. Fierro , A. Facchiano, S. Costantini, D. Zanzi, J. Sidney, S. Auricchio, A. Sette, R. Troncone, and C. Gianfrani. Their efforts were supported by the Institute of Food Sciences-National Research Council, Avellino, Italy. Their research carries strong implications for a peptide-based therapy in celiac disease. Presently, several gluten peptides are known to be active in celiac disease. The identification of additional gluten peptides eliciting intestinal T cell responses is critical for designing a successful peptide-based immunotherapy for celiac disease. In their study, the research team assessed the recognition profile of gluten immunogenic peptides in adult HLA-DQ2(+) celiac patients. They did so by creating several lines of polyclonal, gliadin-reactive T cells from jejunal mucosa. They then tested for both proliferation and IFN-gamma production in reaction to 21 peptides from wheat glutenins and alpha-, gamma-, and omega-gliadins. They then conducted a magnitude analysis of the IFN-gamma responses to determine the spectrum of individual peptide activity, and to rank them accordingly. Notably, 12 of the 14 patients responded to a different array of peptides. All alpha-gliadin stimulatory peptides mapped the 57-89 N-terminal region, thus affirming the importance of the known polyepitope 33-mer, although only 50% of subjects recognized 33-mer. By contrast, 11 of 14 celiac subjects, nearly 80%, responded to gamma-gliadin peptides. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, posessing only a single copy of DQ2-alpha-I and DQ2-alpha-II epitopes, displayed the same potency as 33-mer in triggering intestinal T cell responses. One particular peptide from omega-gliadin, QPQQPFPQPQQPFPWQP, though structurally related to the alpha-gliadin 17-mer, is a separate epitope and activated in 5 out of 14 subjects. The team's data reveal that intestinal T cells respond to a wide array of peptides, and that this heterogeneity emphasizes the relevance of gamma- and omega-gliadin peptides in celiac disease pathogenesis. Their findings indicate that, in DQ2(+) celiac patients, the most active gluten peptides are alpha-gliadin (57-73), gamma-gliadin (139-153), and omega-gliadin (102-118). J Immunol. 2009 Apr 1;182(7):4158-66.
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