Research at the Celiac Center
Research at the Celiac Center
Updated November 2011
Celiac Center Research
An Invitation to Donate
Here at the Celiac Center, we rely on several different avenues to support our research in celiac disease – grants from outside sponsors, donations from celiac organizations and, most personally, from our patients. We are most grateful for donations in any amount to fund current and future studies on celiac disease – with your help we have become one of the leading celiac research centers in the U.S. We encourage you to consider making a donation, perhaps in someone’s name, or making us a part of your estate planning. Thank you very much in advance.
For donations, please contact:
Margaret Sasaki
Senior Major Gifts Officer
617-667-7431
mpsasaki@bidmc.harvard.edu
Are you interested in celiac disease research?
The Celiac Center at Beth Israel Deaconess Medical Center is one of the leading sites for celiac disease research worldwide. In order to continue to make important advancements in our understanding and treatment of celiac disease, we are constantly in need of individuals with celiac disease to participate in research studies. We would like to invite you to join our Celiac Research Contact List so that we may provide you with information on current and upcoming study opportunities.
Important points to consider:
• Participation in this database and any studies you may be contacted about is strictly voluntary.
• Your decision to, or not to, participate will not affect your relationship with your clinicians or with Beth Israel Deaconess Medical Center.
• You can remove your information from this Contact List at any time by contacting the Celiac Center.
• This database will be maintained by the Department of Gastroenterology under Dr. Daniel Leffler’s supervision.
If you would like to be included on the Celiac Research Contact List and hear about research studies you might be interested in, please contact the Celiac Center at 617-667-8397 or celiac@bidmc.harvard.edu with as much of the following information as you would like to provide:
• Name
• The best way to contact you (phone number, address and/or email address)
• Date of birth (some studies have age requirements)
• Date of diagnosis of celiac disease
• Was the diagnosis of celiac disease confirmed with an intestinal biopsy (yes/no)
• If you do NOT want to be contacted if the study involves a gluten challenge
• If you do NOT want to be contacted if the study involves an endoscopy
• If you do NOT want to be contacted if the study involves trying a new drug for celiac disease
Our Thanks and Appreciation
We would like to give heartfelt thanks to our supporters who make large and long-term studies possible:
Alba Therapeutics
Alvine Research
CSA/USA, Inc
The Healthy Villi Greater Boston Celiac/DH Support Group
National Institutes of Health (NIDDK) (see Basic and Translational Research section)
The Sidney Frank Foundation
In particular, we offer our special thank you to the many individuals who have made charitable donations to the Celiac Center from their own personal resources.
Projects Funded by Our Supporters:
Alba Therapeutics
“A Phase 2b, Randomized, Double-Blind, Placebo Controlled, Dose Ranging, Multicenter Study to Determine the Safety, Tolerance, and Efficacy of AT-1001 in Celiac Disease Subjects During Gluten Challenge”
Many thanks to the 20+ individuals who participated in the second Alba clinical trial to test the efficacy, safety and tolerability of a drug that might be used to treat celiac disease. Data analysis by the drug sponsor is underway and we hope to share the results in the coming year. With your help we continue to be one of the leading sites in the U.S. for emerging celiac disease research. Your continued participation is essential to seeing this field move forward.
Alvine Pharmaceuticals, Inc.
“Circulating Markers of Celiac Disease Activity During Gluten Challenge – A Pilot Study”
Despite great advances in our understanding of celiac disease, there is currently no validated instrument for monitoring the activity of this common disorder other than small intestinal biopsy. The identification of accurate non-invasive measures of celiac disease activity would be of great value in clinial practice, are prerequisite to the testing of new treatment modalities and may also offer insight into disease pathogenesis. Currently, patient care and clinical research in celiac disesae are hindered by the lack of validated non-invasive measures of disease activity. We hypothesize that a combination of disease specific surveys and biological markers will allow development of a composite index which will accurately reflect disease activity.
The specific aims of this study are; 1) To develop and evaluate survey tool for use in celiac disease. Measurements will include: A. symptoms, B. gluten free diet adherence and C. health related quality of life. 2) To rigorously evaluate and compare the ability of non-invasive tests of celiac disease activity to predict change in villous height to crypt depth ratio during gluten challenge. 3) To develop a composite model of celiac disease activity using measures from aims 1 and 2 correlated with intestinal histologic change during gluten challenge. Validity will be assessed in two independant cohorts, and data from these studies will be used to design a final multi-center validation study.
Celiac Sprue Association/USA, Inc., and The Healthy Villi
“Correlates of Gluten Free Diet Adherence in Adults with Celiac Disease”
Researchers in the Celiac Center have been working on a number of ongoing studies examining the symptoms of celiac disease and adherence to the gluten free diet. This work has generated important data on quality of life, the psychological factors that influence diet adherence, and on the nutritional quality of the gluten free diet and has launched two novel survey tools which will aid clinicians in standardizing symptoms and gluten free dietary adherence.
The Sidney Frank Foundation
“Campaign to Improve Awareness of Celiac Disease Amongst Primary Care Physicians”
Although the most current epidemiological studies have shown that the prevalence of CD in the general population of Europe and the U.S. is between 0.5 and 1%, the majority of cases continue to be undiagnosed (Catassi et al., 2007; Zipser, Farid, Baisch, Patel, & Patel, 2005). The two primary reasons as to why CD is believed to remain undiagnosed despite the prevalence of CD predicted by surveys and epidemiological studies using the mass serological screening include the lack of awareness and education of the disease among PCPs, as well as the atypical symptoms that patients tend to present.
Furthermore, PCPs are regularly presented with patients experiencing CD but who have yet to be diagnosed, thus allowing for the case-finding strategy to be one of the most effective ways to increase the diagnostic rate of CD (Catassi, Kryszak, Louis-Jacques, et al., 2007; Fasano & Catassi, 2001; Hin, Bird, Fisher, Mahy, & Jewell, 1999). The case-finding strategy consists of identifying the most common symptoms and comorbidity associated with CD and then seeking out patients who fulfill the criteria. Once the case-finding strategy has been used to discover at-risk individuals, serological tests, including the tTG, should be used to screen the individuals. Catassi et al. (2007) report that CD is particularly frequent amongst patients presenting with thyroid disease, chronic diarrhea, and irritable bowel syndrome. Hin et al. (1999) have found that non-specific symptoms including anemia, diabetes, chronic fatigue, and a family history of CD were the most common among patients with undiagnosed CD. Hin et al. (1999) also suggest that the case finding strategy should be used and in doing so PCPs should emphasize on direct questioning since anemia and chronic fatigue may not be symptoms a patient typically states, as compared to more noticeable symptoms such as gastrointestinal. In fact, Hin et al. (1999) reports that of the 225 patients presenting with gastrointestinal symptoms, only five of those patients were diagnosed with CD. Primary care physicians should learn to search outside the box by focusing on current findings as opposed to conforming to the common perception that CD was amongst those who experienced gastrointestinal symptoms such as chronic diarrhea, abdominal distention, and weight loss (Fasano & Catassi, 2001). Other non-classic symptoms include osteoporosis, infertility, neurologic problems, dental enamel hypoplasia, and dermatitis herpetiformis. One way for PCPs to deem the case-finding strategy would be to remember the phrase, “think of celiac disease and you will find it” (Fasano & Catassi, 2001).
In sum, it is evident that PCPs are in need of a consistent and proper method to learn about CD. The investigators propose to develop a set of educational tools for this population to use based on the most recent research.
The Celiac Center team has thus partnered with local and national organizations to create two online continuing medical education programs on celiac disease aimed primarily at primary care providers. Links to these programs are below:
http://cme.hms.harvard.edu/index.asp
http://www.celiaccmecentral.com/
Recent Abstracts
The following abstracts were presented at the International Celiac Conference in Amsterdam, The Netherlands in April 2009 and Digestive Disease Week in Chicago, May 2009.
Leffler DA, Dennis M, Edwards George J, Jamma S, Cook F, Schuppan D, Kelly CP.
The CSI: A Validated Disease Specific Symptom Index for Adults with Celiac Disease Abstract. International Celiac Conference, Amsterdam, The Netherlands, April 2009.
Dennis M, Leffler D, George J, Jamma S, Gahl J, Liu J, Hansen J, Schuppan D, Kelly CP. Nutritional intake of adults with celiac disease in the U.S.: are they meeting their needs? Abstract. International Celiac Conference, Amsterdam, The Netherlands, April 2009.
Jamma S, Leffler DA, Dennis M, Bakht R, Kelly CP. Small Intestinal release mesalamine for treatment of refractory celiac disease. Abstract. International Celiac Conference, Amsterdam, The Netherlands, April 2009.
Recent Publications
Textbook Chapters:
Leffler D, Kelly CP. Celiac Disease: What The Last Few Years Have Taught Us. Advances in Digestive Disease, AGA Institute Press. Edited by Colin W. Howden. 2007
Journals:
Shah S, Leffler D. Celiac Disease: An Under-Appreciated Issue in Woman’s Health. Woman’s
Health. 2010, In Press.
Jamma S, Leffler DA, Dennis M, Schuppan D, Sheth S, Kelly CP. Small Intestinal Release Mesalamine for Treatment of Refractory Celiac Disease. Journal of Clinical Gastroenterology. 2010 In Press
Leffler DA, Dennis M, Edwards George JB, Jamma S, Magge S, Cook EF, Schuppan D, Kelly CP. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol. 2009 May;7(5):530-6, 536.e1-2. Epub 2009 Jan 11. PubMed PMID: 19268725.
Leffler DA, Edwards-George J, Dennis M, Schuppan D, Cook F, Franko DL,
Blom-Hoffman J, Kelly CP. Factors that influence adherence to a gluten-free diet
in adults with celiac disease. Dig Dis Sci. 2008 Jun;53(6):1573-81. PubMed PMID:
17990115.
Leffler DA, Edwards George JB, Dennis M, Cook EF, Schuppan D, Kelly CP. A
prospective comparative study of five measures of gluten-free diet adherence in
adults with coeliac disease. Aliment Pharmacol Ther. 2007 Nov 1;26(9):1227-35.
PubMed PMID: 17944737.
Leffler D, Magallon J, Najar Goldar-Najafi A, Feller-Kopman D, Kelly CP. A Hidden Danger. Sepsis in Celiac Disease, case report and review of the literature. Hospital Physician. 2006 Oct;42(10):21-26
Leffler D, Dennis M, George J, Kelly CP. The Interaction Between Eating disorders and Celiac Disease: An Exploration of Ten Cases. Eur J Gastroenterol Hepatol. 2007 Mar;19(3):251-5.
Leffler D, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and Predictors of Diagnosis in Non-Responsive Celiac Disease. Clin Gastroenterol Hepatol. 2007 Apr;5(4):445-50
Basic and Translational Research
Detlef Schuppan, MD, PhD, and his research team have developed a mouse model that will, for the first time, allow testing of novel therapies in an animal model (in vivo) rather than in a petri dish (in vitro). Therapies to induce a cure, such as induction of tolerance to dietary gluten, will also be explored. Below is the abstract from one of their latest studies that report intentional triggering of gluten sensitive enteropathy in lab mice.
This work was supported by NIH grant # 1 R21 DKO73254-01 to D.S.
Abstract
Gliadin-primed CD4+CD45RBlowCD25- effector/memory T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice
Tobias Freitag (1), Svend Rietdijk (2), Yvonne Junker (1), Yury Popov (1), Atul K. Bhan (3), Ciaran P. Kelly (1), Cox Terhorst (2) & Detlef Schuppan (1)
- 1. Celiac Center, Division of Gastroenterology,Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
- 2. Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215;
- 3. Immunopathology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Published in Gut 2009;58:1597-1605.
Background and aims: Celiac disease (cd) is a common small intestinal inflammatory disorder that results from a breach of intestinal tolerance to dietary gluten proteins, driven by gluten-reactive effector T cells. We aimed to assess the pathogenic role of gluten-reactive effector T cells and to generate a model of gluten-induced enteropathy. Methods: CD4+CD25- T cell fractions were adoptively transferred into lymphopenic mice, leading to "baseline" small intestinal inflammation. Results: Rag1-/- recipients of gliadin-presensitized CD4+CD45RBlowCD25- effector/memory T cells, but not CD4+CD45RBhigh naive T cells, gained less weight and suffered from more severe duodenitis when challenged with oral gluten than recipients on gluten-free diet, or recipients of control (ovalbumin)-presensitized T cells. This was accompanied by deterioration of mucosal histological features characteristic of cd, and increased Th1/Th17 cell polarization in the duodenum and the periphery. Interestingly, reintroduction of a gluten-free diet led to weight gain, improvement of histological duodenitis, and a decrease in duodenal IFN and IL-17 transcripts. Moreover, B cell-competent nude recipients of gliadin-presensitized effector/memory T cells produced high levels of serum anti-gliadin IgA and IgG1/IgG2c only when challenged with oral gluten. Conclusions: CD4+ effector T cell immunity to gluten leads to a breach of oral gluten tolerance and small intestinal pathology in lymphopenic mice, similar to human cd. This model will be useful for the study of cd pathogenesis, but also for testing novel non-dietary therapies for cd.
Detlef Schuppan, and his research team have studied a novel role of a non-gluten wheat protein in stimulating the so-called innate immune system. In contrast to the fairly well understood role of the adaptive immune system (intestinal gluten specific T cells) innate immunity is an immediate response to foreign protein or non-protein components, such as bacterial antigens, but also wheat proteins that are different from those that drive adaptive immunity. This innate response occurs not only in celiacs but also in non-celiac individuals and could explain the so-called gluten sensitivity in patients who have no classical celiac disease. On the other hand, the innate response to this novel non-gluten protein from wheat and related cereals is likely to increase T cell immunity and inflammation to the gluten components in celiac patients.
This work is supported by NIH grant # 1R21AI078385A1-01 to D.S.
Abstract
A non-gluten component of wheat is a strong stimulator of innate immune responses in vitro and in vivo and acts via Toll like receptor 4
Yvonne Junker1, Donatella Barisani2, Daniel A. Leffler1, Towia Libermann3, Simon Dillon3, Herbert Wieser4, Sebastian Zeissig5, Detlef Schuppan1
1Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
2Department of Experimental and Environmental Medicine and Medical Biotechnology, University of Milano-Bicocca, Monza, Italy
3Proteomics and Transcriptomics Core, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
4German Research Center of Food Chemistry and Hans-Dieter-Belitz-Institute for Cereal Grain Research, Garching, Germany
5Division of Gastroenterology and Hepatology, Brigham and Women’s Hospital, Harvard Medical School, USA
Background: Celiac disease is a small intestinal enteropathy caused by a Th1 mediated inflammatory response to certain gluten peptides that bind to HLA-DQ2/-DQ8. However, only 2-5% of individuals expressing DQ2/DQ8 develop celiac disease, indicating that additional mechanisms such as innate immune responses to gluten might be involved in disease pathogenesis. Our aim was to explore the specificity and nature of the innate immune trigger and its cellular receptor.
Methods and Results: A peptic tryptic digest of gliadin but not zein (from corn) stimulated IL-8 and TNF-alpha secretion from monocytic cell lines and human monocyte derived dendritic cells (DCs), both from celiac disease patients and healthy controls. Cytokine secretion in DCs could be blocked by preincubation with TLR4 neutralizing antibody. This effect was not due to LPS contamination, since proteinase K digestion abrogated the stimulatory effect of gliadin peptides but not of purified LPS. Peritoneal macrophages from MyD88-/- or C3H/HeJ mice that lack TLR-4 did not show innate immune responses upon gliadin stimulation as compared to macrophages from wild type mice. Moreover, intraperitoneal injection of gliadin led to increased serum levels of TNF-alpha and KC (IL-8) similarly in C57BL/6 and Rag1-/- mice but not in MyD88-/- mice. When C57BL/6 mice were gavaged with LPS, gliadin, or zein only the gliadin extract upregulated duodenal KC, MCP-1 and IL-1β (but not TNF-α) transcripts proving the protein’s resistance to gastric/intestinal degradation. To further define the TLR4-stimulating peptides gliadins from the pure wheat strain “Rektor” were separated into their α-, γ- and ω-fractions via HPLC. However, none of the gliadin fractions contained reproducible activity, as also evidenced by screening of overlapping gliadin 20mers in selected cases. Comparison of all gliadin fractions by SDS-PAGE electrophoresis and mass spectrometry analysis revealed a non-gluten protein from wheat which co-purifies with gliadins and which subsequently could be confirmed as the stimulatory protein.
Conclusions: A non-gluten protein of wheat and related grains can elicit a strong innate immune response in vitro and in vivo via activation of TLR-4. The identity of the protein is currently confirmed and will be presented. This finding will have implications for both celiac sprue and other intestinal inflammatory diseases.
Correspondence should be addressed to: Detlef Schuppan, Professor of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, DA 506, 330 Brookline Avenue, Boston, MA 02215, USA. Phone: 617-667-2371; Fax: 617-667 2767; Email: dschuppa@bidmc.harvard.edu.
Basic and Translational Research Articles
Ciccocioppo R, Finamore A, Mengheri E, Millimaggi D, Esslinger B, Dieterich W, Papola F, Colangeli S, Tombolino V, Schuppan D, Corazza GR. Isolation and characterization of circulating tissue transglutaminase-specific T cells in coeliac disease. Int J Immunopathol Pharmacol. 2010;23:179-91.
Jamma S, Rubio-Tapia A, Kelly CP, Murray J, Sheth S, Schuppan D, Dennis M, Leffler DA. Celiac crisis is a rare but serious complication of celiac disease in adults. Clin Gastroenterol Hepatol 2010 Apr 24 [Epub ahead of print].
Marietta E, Schuppan D, Murray JA. In vitro and in vivo models of celiac disease.Exp Opin Drug Discov 2010, in press.
Schuppan D, Junker Y, Barisani D. Celiac Disease: From Pathogenesis to novel therapies. Gastroenterology 2009;137:1912-33.
Leffler DA, Dennis M, Edwards George J, Jamma S, Cook E, Schuppan D, Kelly CP. A Validated Disease Specific Symptom Index for Adults with Celiac Disease. Clin Gastroenterol Hepatol 2009;7:1328-34.
Leffler DA, Dennis M, Edwards George JB, Jamma S, Magge S, Cook EF, Schuppan D, Kelly CP. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol 2009;7:530-6.
Freitag T, Rietdijk S, Junker Y, Popov Y, Bhan AK, Kelly CP, Terhorst C, Schuppan D. Gluten-sensitive enteropathy can be induced by adoptive transfer of gliadin-primed CD4+ T cells: a mouse model for celiac disease. Gut 2009;58:1597-1605.
Elli L, Bergamini CM, Bardella MT, Schuppan D. Transglutaminases in
inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver
Dis. 2009 541-50.
Garud S, Leffler D, Dennis M, Edwards-George J, Saryan D, Sheth S, Schuppan D,
Jamma S, Kelly CP. Interaction between psychiatric and autoimmune disorders in
coeliac disease patients in the Northeastern United States. Aliment Pharmacol
Ther. 2009;29:898-905.
Rakhimova M, Esslinger B, Schulze-Krebs A, Hahn EG, Schuppan D, Dieterich W.
In vitro differentiation of human monocytes into dendritic cells by
peptic-tryptic digest of gliadin is independent of genetic predisposition and the
presence of celiac disease. J Clin Immunol. 2009:29-37.
Schuppan D, Kelly CP. Is duodenal biopsy required in all patients with
suspected celiac disease?. Nat Clin Pract Gastroenterol Hepatol. 2008;5(2):70-1.
Schuppan D, Junker Y. Turning swords into plowshares: transglutaminase to
detoxify gluten. Gastroenterology. 2007;133:1025-8.
Dieterich W, Schuppan D. Is gliadin harmful from the first morsel?. Dig Liver
Dis. 2007 Oct;39(10):917-21.
Textbook Chapters
Schuppan D, Junker Y. Celiac disease. In: Frontiers in Gastroenterology: Clinical Update on Inflammatory Disorders of the GI Tract. Mayerle J, Tilg H, eds. Karger, Basel, Switzerland; 2010. p.83-94.
Schuppan D, Dieterich W. Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults. Uptodate in Medicine.
Leffler D, Schuppan D. Update on Serologic Testing in Celiac Disease. Am J Gastroenterol. 2010, in press.
Leffler DA, Schuppan D. Blood tests in celiac disease. In: Real Life with Celiac Disease Dennis, M, Leffler DA, eds. AGA Press, Bethesda, MD; 2010. p.29-36.
Leffler DA, Schuppan D. Future therapies for celiac disease. In: Real Life with Celiac Disease Dennis, M, Leffler DA, eds. AGA Press, Bethesda, MD; 2010. p.345-48.
Schuppan D. Celiac sprue. Encyclopedia of Molecular Mechanisms of Disease. Lang F, ed. Springer, New York; 2008. p.168-70.
