By Amy Ratner, Beyond Celiac Medical and Science News Analyst
A blood test that can detect the earliest effects of gluten could mean that those already on the gluten-free diet would only have to eat gluten one time in order to be accurately tested for celiac disease.
As a result, these patients could avoid the intestinal injury they risk when going through the typical 6-week gluten challenge currently needed for accurate diagnosis.
The test could also speed up the search for a new treatment for celiac disease because it could enable researchers to more quickly determine whether a drug being studied is working to prevent gluten from triggering a response.
A single exposure to gluten results in early changes in the levels of cytokines in the blood of those who have celiac disease and are on a gluten-free diet, according to data presented at the recent International Celiac Disease Symposium by ImmusanT, a Massachusetts biotechnology company. The test being developed by the company measures carefully-timed cytokine levels combined with a specific amount of gluten in a gluten challenge.
Cytokines: small secreted proteins released by cells that have a specific effect on the interactions and communications between cells. There are both pro-inflammatory and anti-inflammatory cytokines.
Leslie Williams, ImmusanT president and chief executive officer, said that while the test is promising for both diagnosis and research, she is most excited by the way the data related to it explains what happens when patients eat gluten and why they get symptoms. The cytokine changes are seen in celiac disease patients, but not those who have gluten sensitivity.
“What’s new is that we have advanced dramatically the understanding of the disease from a structural and functional standpoint and can translate that into therapeutics and diagnostics,” she said. “The data that we’ve generated really opens up the differentiation between celiac disease and non-celiac gluten sensitivity in a way that much more objective than it has been.”
Immunologists who attended the international symposium took note of this new understanding, Williams said. “The reason leading immunologists were so excited by our findings is that it really simplified the understanding of how celiac disease operates on a molecular level,” Robert Anderson, M.D., ImmusanT chief scientific officer, added.
“The real take home is the celiac disease is an adaptive immune response driven by the CD4 T-cell and there’s no question that that is what drives the disease,” Williams said.
T-cells: White blood cells that function as the body’s disease fighting soldiers. In the case of celiac disease, they are incorrectly turned on to attack when the gluten peptides are detected.
Diagnosis after going gluten-free
ImmusanT research showed celiac disease patients had up to a ten-fold increase in cytokines after a gluten challenge, while gluten sensitive patients had no response.
The cytokines increased as early as two hours, and up to eight hours, after the gluten challenge. The earliest and most prominent cytokine released was interleukin (IL)-2, which is released by activated T-cells. This was the first time an increase within two hours of gluten consumption was demonstrated.
“We know that these cytokines are being released and they’re the ones that orchestrate the damage,” Anderson said. “This is probably the earliest point anyone has been able to get evidence of the effect of gluten.”
Over the past 30 years, cytokines have been measured in other ways, but not in a “real life” scenario in patients who ate gluten and then had their blood tested, he noted.
Cytokine changes were evident in many celiac disease patients even though symptoms were mild or absent. ImmusanT researchers also found that higher levels of cytokines were associated with more severe symptoms in celiac disease patients within 6 hours after consuming gluten. Anderson said the studies will increase researchers' interest in trying to understand how cytokines, T-cells and digestive symptoms are linked.
Symptoms don’t consistently line up with either the anti-tissue transglutaminase immunoglobulin A (tTG IGA) blood test used for diagnosis or the biopsy considered to be the gold standard in the United States. Some patients have no symptoms but positive blood tests or damage discovered through the biopsy.
Currently, there is no specific test for gluten sensitivity because no bio-marker for the disease has been found. Consequently, gluten sensitivity is a diagnosis of exclusion after celiac disease has been ruled out. The tTG test is used to diagnose those who’ve already adopted the gluten-free diet, but it requires at least several weeks of gluten consumption to be accurate. Patients who have gone on the gluten-free diet to relieve symptoms without a celiac disease diagnosis are often reluctant to go off the diet and potentially become ill again.
Some patients think an official diagnosis does not matter since the gluten-free diet it the only treatment for both conditions but the recent review of five years of evidence concluded that getting the correct diagnosis is important, especially since gluten sensitivity might not require a lifelong gluten-free diet as opposed to celiac disease, which does.
“With approximately 80 percent of people living with celiac disease undiagnosed, and no current treatment available, these data demonstrate the potential for a simple, highly sensitive diagnostic tool to improve patient health,” Williams said.
ImmusanT is looking to collaborate with a diagnostic company to make the test widely available but expects it would take at least until the end of 2018 before that can happen.
Researchers studying celiac disease need a way to measure how effective any potential treatment is. ImmusanT is investigating development of a test for scientists based on their findings related to cytokine levels.
“This could be a helpful tool in clinical trials because you would no longer necessarily need a biopsy to see how a treatment was working,” Anderson said. “If you have a treatment and you are trying to change the way the t-cell activation occurs, this is a very simple way of knowing how that has changed. It’s telling you how responsive the immune system is to gluten exposure.”
He said cytokine measurement could lead to a “rapid test” to assess whether a study participants response to gluten has been affected by treatment.
ImmusanT is using measurement of cytokine levels in development of NexVax 2, a therapeutic vaccine to treat celiac disease.
Broader use of the test in clinical studies would take several steps, including validation by independent bodies.
Nexvax2 is designed to protect against the effect of gluten in those who have celiac disease and the gene most commonly associated with it, HLA-DQ2.5. This includes about 90 percent of celiac disease patients in the United States. Nexvax2 would target T-cells that react to gluten and turn off the response in those who have celiac disease and the requisite gene. Initially, it would be used along with the gluten-free diet to protect against unintentional gluten consumption, mainly through cross-contact when eating outside the home. But as a second step, ImmusanT is looking to launch a vaccine that would eliminate the need for the diet.
Previous studies have shown that the same T-cells respond to gluten and Nexvax2 by releasing cytokines, with a single high dose having the same effects as a one-time gluten challenge. When the vaccine was given twice weekly over eight weeks, patients demonstrated no intestinal damage, excess symptoms or elevated cytokines. Additionally, blood tests for an immune response to damaging gluten peptides had become negative in almost all patients. Nexvax2 this year will begin Phase 2 clinical testing, during which a dosing regimen will be studied.
The ImmusanT research presented at the recent celiac disease symposium in India was included in poster presentations.
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