Research at the Celiac Center
Updated May 2009
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:
Monique Martin
Office of Development
330 Brookline Avenue (BR)
Boston, MA 02215
Phone: 617-667-7330
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
Research Study Opportunity:
The Celiac Center at Beth Israel Deaconess Medical Center is now enrolling participants in a study to address the absence of an accurate method to monitor celiac disease and to look at early changes in protein levels in the blood which occur with gluten exposure. This research may help to develop tests to determine if a patient has active celiac disease and to find better ways to test potential new treatments for celiac disease. This study involves eating gluten for two weeks and making a total of 6 visits to the research center over a 6 week period. These visits will include collection of blood and urine specimens, a computer based test of attention, and completing short questionnaires. On 3 of the visits we will be obtaining small intestinal biopsies using a pediatric mini-endoscope. This procedure will take less than 10 minutes and no sedation other than throat spray is necessary. You will be compensated for your time and parking.
For more information, please contact:
Dr. Ciaran Kelly
The Celiac Center
Beth Israel Deaconess Medical Center
Phone: 617.667.8397
celiac@bidmc.harvard.edu
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.
Recent Abstracts
The following abstracts were presented at the International Celiac Conference in Amsterdam, The Netherlands in April 2009. All three will also be presented at the Digestive Disease Week in Chicago at the end of 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:
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, 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.
Gluten-sensitive enteropathy can be induced in mice after adoptive transfer of gliadin-primed CD4+CD45RBlowCD25- T cells
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)
- Celiac Center, Division of Gastroenterology,Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
- Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215;
- Immunopathology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Abstract:
Background & Aims: Celiac disease (cd) is a common small intestinal inflammatory disorder that results from abrogation of T cell tolerance to dietary gluten proteins. We aimed to develop a mouse model of cd that could be used to test novel non-dietary therapies. Methods: T cell fractions depleted of (tolerogenic) regulatory T cells (FACS) were adoptively transferred into lymphopenic mice that were then challenged with oral gluten. Results: Rag1-/- recipients of gliadin-presensitized CD4+CD45RBlowCD25- effector/memory T cells (but not control-presensitized effector/memory or naïve CD4+CD45RBhigh T cells) failed to gain weight and suffered from exacerbation of duodenitis only when challenged with oral gluten. This was accompanied by deterioration of mucosal histological features characteristic of cd (mononuclear cell infiltration, crypt hyperplasia, villus atrophy), as well as increased Th1 cell polarization in the small intestine. Splenocytes produced high levels of IFN? in response to gliadin restimulation in vitro. Moreover, B cell-competent nude recipients of gliadin-presensitized effector/memory T cells produced high levels of serum anti-gliadin IgA, IgG1 and IgG2c only when challenged with oral gluten. Conclusions: Adoptive transfer of gluten-reactive effector/memory T cells, but not naïve T cells, leads to a breach of tolerance to gluten in the intestine of lymphopenic recipients. Gliadin-primed CD4+ T cells can cause gluten-sensitive enteropathy in the mouse, which should be highly useful for testing novel non-dietary therapies for cd.
Detlef Schuppan, MD, and his research team have studied a novel role of gluten 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 celiac disease. On the other hand, the innate response to gluten likely increases T cell immunity in celiacs.
This work is supported by NIH grant # 1R21AI078385A1-01 to D.S.
Abstract:
Gliadin elicits innate immune responses in vitro and in vivo via the MyD88 pathway.
Yvonne Junker (1), Herbert Wieser (2), Daniel Leffler (1), Ciaran Kelly (1), Detlef Schuppan (1)
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, USA;
- German Research Center of Food Chemistry and Hans-Dieter-Belitz-Institute for Cereal Grain Research, Garching, Germany
Background: Celiac disease is a small intestinal enteropathy caused by certain gluten peptides that bind to HLA-DQ2 or -DQ8 which results in TH1 T cell activation and mucosal destruction. However, only 2-5% of individuals who express DQ2 or DQ8 develop celiac disease, indicating that additional mechanisms such as an innate immune response to gluten are necessary to trigger and potentiate adaptive immunity. However, the specificity and nature of this response remains controversial.
Methods: Wheat gliadin was digested with a combination of pepsin and trypsin. Digested zein, a family of maize proteins that resemble gliadin in structure and amino acid composition but which lack stimulatory capacity in celiac patients, was used as negative control. Human monocytic cell lines (HL-60, THP-1, U-937) and mouse peritoneal macrophages were stimulated with digests of gliadin and zein for 16 hours and cytokine levels of IL-8, TNF-α and MCP-1 in culture supernatants were measured by ELISA. In addition, cells were stimulated with gliadin synthetic peptide alpha p31-43 that was previously implicated in innate immune responses, and a scrambled control peptide. To test their stimulatory capacity in vivo gliadin, zein and LPS were injected i.p. in C57BL/6 mice. Serum was taken 2h after injection and chemokine levels were measured by ELISA.
Results: Upon stimulation with the peptic tryptic digest of gliadin but not zein all tested cell lines secreted high amounts of IL-8, MCP-1 and TNF-α. This effect was not due to lipopolysaccharide (LPS) or lipopeptide contamination, since proteinase K digestion abrogated the stimulatory effect of gliadin peptides but not of purified LPS or Pam3CSK4. Synthetic alpha gliadin peptide p31-43 did not trigger chemokine/cytokine secretion. Peritoneal macrophages isolated from MyD88 gene deleted mice or C3H/HeJ mice that lack the TLR-4 did not show innate immune responses upon gliadin stimulation as compared to macrophages from wild type mice. Furthermore, intraperitoneal injection of gliadin into C57BL/6 mice lead to an increase in TNF-alpha and KC (IL-8) serum levels comparable to effects triggered by LPS injection.
Conclusion: Gliadin peptides elicit an innate immune response in vitro and in vivo and TLR-4 seems to be the signal transducer of these reactions. Since the previously described peptide p31-43 was not confirmed as innate immune trigger in our systems, other gliadin peptides with stimulatory capacity must be implicated.
Correspondence should be addressed to: Detlef Schuppan, 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:
Elli L, Bergamini CM, Bardella MT, Schuppan D. Transglutaminases in
inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver
Dis. 2009 Feb 3. [Epub ahead of print] PubMed PMID: 19195940.
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 Apr 15;29(8):898-905. PubMed PMID: 19183153.
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 Jan;29(1):29-37. Epub 2008 Aug
12. PubMed PMID: 18696220.
Schuppan D, Kelly CP. Is duodenal biopsy required in all patients with
suspected celiac disease?. Nat Clin Pract Gastroenterol Hepatol. 2008
Feb;5(2):70-1. Epub 2007 Nov 27. PubMed PMID: 18043590.
Schuppan D, Junker Y. Turning swords into plowshares: transglutaminase to
detoxify gluten. Gastroenterology. 2007 Sep;133(3):1025-8. PubMed PMID: 17854603.
Dieterich W, Schuppan D. Is gliadin harmful from the first morsel?. Dig Liver
Dis. 2007 Oct;39(10):917-21. Epub 2007 Aug 27. Review. PubMed PMID: 17720638.
