IL-15 is an important cytokine (immune system protein) involved in celiac disease. In those of us with celiac, ingestion of gluten triggers the release of IL-15 by cells in the lining of our small intestines. IL-15 stimulates the production of intraepithelial lymphocytes (IELs) which are unique immune cells found in the lining of the small intestine—these are often seen on our intestinal biopsies when we are first diagnosed with celiac disease.
Based on the work of Dr. Jabri and colleagues at the University of Chicago, we know that IL-15 has 4 major roles in celiac disease. It is involved in all of the following:
- Loss of tolerance to gluten.
- Loss of immune system regulation.
- Epithelial cell destruction in the small intestines.
- Promotion of the growth of aberrant, or abnormal, IELs.
IL-15 is involved in the development of both non-responsive celiac disease and refractory celiac disease. Non-responsive celiac disease (NRCD) is diagnosed when one has persistent symptoms, elevated celiac antibodies (i.e. TTG-IgA) and/or small intestinal damage after at least 6 to 12 months on the GF diet. Although most cases of NRCD are due to accidental ingestion of gluten, a small percentage of cases are due to refractory celiac disease, which involves persistent symptoms, antibodies and intestinal damage in the presence of abnormal IELs. Refractory celiac disease, which can associated with the development of lymphoma, is difficult to treat as it does not respond to the gluten-free diet.
AMG-714 is a monoclonal antibody that blocks IL-15. I was given the opportunity last month to interview Dr. Francisco Leon, MD, PhD, the CEO and CMO of Celimmune, a company that is investigating the use of AMG-714 as a treatment for celiac disease. According to Dr. Leon, Celimmune has two Phase IIb clinical trials of AMG-714 in the works. The first, which will take place in European centers, will be targeting subjects with non-responsive celiac disease. It will involve subcutaneous injections of AMG 714 every 2 to 4 weeks. The second trial, which will be centered in the U.S. (New York and San Diego), will involve the intravenous dosing of AMG 714 to subjects with refractory celiac disease. They aim to recruit 24 subjects with refractory celiac disease, starting in March 2016, for the U.S. trial. Please see clinicaltrials.gov in upcoming months for more information on study design, enrollment criteria, etc.
The bottom line, from my discussion with Dr. Leon, is that help is on the way for those with persistent symptoms despite being on strict gluten free diets and that we will soon be able to tailor our management of celiac disease to our specific needs and lifestyles.
For more information on IL-15, AMG 714, and other celiac therapeutic agents in development, please see Dr. Leon’s recent article (reference #3 below).
Rubio-Tapia, A, Hill, ID, Kelly, CP, et al. American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013; 108: 656-76.
Leon, F and Llewellyn, B. Experimental therapeutics for celiac disease and refractory celiac disease. Drug Discovery World. Spring 2015. 73-78.