2012-08-07 20:01:19 UTC

Celiac Disease: Future Therapies

Aug. 7, 2012

NAME

Carol E. Semrad, MD

Professor of Medicine, The University of Chicago Medicine, GI Section, IL

 

Celiac disease is a common T-cell mediated inflammatory disease of the small bowel that has an environmental and genetic component. In the U.S. and other countries, its estimated prevalence is 1 percent of the Caucasian population. As diseases go, celiac disease is not a bad disease to have. Why? Because unlike most inflammatory bowel diseases, the trigger — gluten present in wheat, barley and rye — is known. Take gluten out of the diet and small bowel inflammation resolves in most.

So why is there a need for future therapies? Wheat is ubiquitous in the Western diet and not easily excluded, particularly when dining out or traveling. Some individuals with celiac disease are exquisitely sensitive to trace amounts of gluten in the diet. Histological recovery is not always complete, even in those on a strict gluten-free diet with uncertain clinical consequences. Alternative therapies that are adjuvant to a gluten-free diet, promote gluten tolerance or prevent disease development have the potential to improve the quality of life of celiac patients and prevent complications.

Celiac disease is a model disease to teach medical students the pathophysiology of small-bowel inflammation and villous atrophy. The early knowledge that wheat triggers intestinal villous atrophy has led to intensive investigation into toxic epitope(s) of gluten, genetic susceptibility and the inflammatory steps that lead to damage. Gluten provides the elastic (chewy) quality to breads, and over millenniums, wheat grain has been cultivated to contain ever higher amounts. Unfortunately, gluten contains stretches of the amino acids glutamine and proline that are poorly cleaved by human digestive enzymes.1 Undigested gluten peptides are capable of crossing the intestinal epithelium into the lamina propria. Toxic gluten peptides alone, or when converted to a more potent negatively charged form (glutamine to glutamic acid) by tissue transglutaminase (TG2), trigger intestinal inflammation in genetically susceptible hosts. The genetics of celiac disease is not simple. The highest gene association is the HLA DQ2 and DQ8 alleles A1:05, B1:02 and B1:0302. However, other genes are involved in disease development.

There are a number of targets in the pathogenesis of celiac disease that may render new therapies (view figure below)

  • Grain detoxification. Genetic engineering of grains to remove toxic epitopes in gluten would be difficult, due to the large number of peptides identified that are capable of triggering an immune response in celiac disease.
  • Oral enzyme therapy. Endoprolylpeptidases from bacteria, barley grain or yeast are capable of cleaving toxic gluten peptides into inactive fragments.2 How much gluten in the diet can be detoxified by oral enzyme therapy? Clinical studies are in progress.
  • Barrier modulators. A barrier modulator, AT-1001, has been developed that increases epithelial barrier function. However, clinical trials failed to show a significant change in intestinal permeability in celiac subjects ingesting drug plus gluten when compared to placebo.
  • Vaccination for tolerance or prevention. There are many gluten peptides capable of triggering an immune response in celiac disease. With careful mapping of these peptides and responses, three HLA DQ2 immunodominant epitopes have been identified that may protect against all other peptides.3 Based on these three peptides, a vaccine — Nexvax2® — has been created to provoke tolerance to gluten in HLA DQ2-positive celiac individuals; clinical studies are underway. A vaccination at birth in high-risk infants may prevent disease development.
  • Specific inhibitors
    • Blockade of gluten peptides across the intestinal epithelium awaits further studies to define the paracellular or transcellular transport mechanism.
    • TG2 inhibitors may prevent conversion of gluten peptides to their more negatively charged, potent form. As TG2 deamidates other biological processes, inhibitors may have unwanted cellular consequences.
    • Inhibitors of the positively charged pocket of HLA DQ2 and DQ8. Like TG2 inhibitors, this may have other unwanted immunologic consequences.
    • IL-15 production is unique to the innate inflammatory response generated in celiac disease4 and refractory sprue. If IL-15 is predominantly responsible for the downstream consequences of villous atrophy, inhibition may be effective in preserving epithelial cells for absorption.

In conclusion, there has been great progress in defining the pathogenesis of celiac disease with predictions that new therapies will be available in the next five years. This offers celiac patients hope for an adjunct therapy to the gluten-free diet or to allow gluten tolerance.

Dr. Semrad is a clinical investigator on a multi-center celiac disease patient-reported study conducted by Alvine Pharmaceuticals, Inc.

References

1. Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in coeliac sprue. Science 2002;297:2275-2279.

2. Sollid LM and C Khosla. Novel therapies for coeliac disease. J Intern Med 2011;269:604-613.

3. Camarca A, Anderson RP, Mamone G, et al. Intestinal T cell responses to gluten peptides are largely heterogeneous: Implications for a peptide-based therapy in celiac disease. The Journal of Immunology 2009;182:4158-4166.

4. DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 2011;471:220-224.

More on Celiac Disease

Spotlight on Fellow-Led Quality Improvement Projects

Oct. 3, 2017

These 19 projects presented at DDW® 2017 showcase the extensive work being done by fellows to improve the quality of care provided to GI patients.

Avoidance of Cow's Milk–Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial

Oct. 1, 2017

Increased cow's milk antibody titers before the appearance of anti-TG2A and celiac disease indicates that subjects with celiac disease might have increased intestinal permeability in early life.

Can You Name the Top Five Products with Gluten?

Sept. 20, 2017

This month’s CGH patient education section provides you with top talking points for your celiac disease patients.