New study is first strong sign immune system could be trained to tolerate gluten
By Amy Ratner, Medical and Science News Analyst
In a recent study, researchers took tiny of fragments of gluten, encapsulated them in nanoparticles made from the same material as absorbable stitches and gave them to study participants with celiac disease. Next, the participants were given a hefty gluten challenge. The study, which is still in early stages, found that the nanoparticle treatment could potentially prevent gluten from triggering the damaging immune reaction in celiac disease.
Research into the nanoparticle approach to treating celiac disease started in the laboratory of Stephen Miller, PHD, director of the Interdepartmental Immunobiology Center at Northwestern University and a member of the Beyond Celiac scientific advisory council. Miller’s work formed the basis of a recently completed small Phase 2a clinical trial that was preliminarily presented at a European gastroenterology conference.
Takeda Pharmaceuticals recently obtained the exclusive global license of the celiac disease immunotherapy developed by Miller through Cour Pharmaceuticals. Miller will now focus on multiple sclerosis, type 1 diabetes and peanut allergies that could benefit from a nanoparticle therapy. But he says his interest in celiac disease remains. He would like to explore whether celiac disease patients produce self-antigens, which originate inside the body as a secondary response to gluten, and how immune reactions might be turned off.
Miller talked recently with Beyond Celiac about what the clinical trial found, though he noted that he did not work directly with the patients who participated in the study. Here’s how he answered some questions raised by people with celiac disease after news of the trial results were widely reported.
Q: Is this treatment designed to protect against cross-contact while maintaining a gluten-free diet or would it mean the end of the need for a gluten-free diet?
A: Only further studies that Takeda plans to carry out in future clinical testing are going find that out. Hopefully it’s going to mean the end of having to adhere to a gluten-free diet.
As a matter of fact, a gluten-containing diet might help the therapy in the long run because the infusion of the nanoparticles containing gluten ends up inducing immune cells, called regulatory cells, that shut off the immune response against gluten. In order to maintain those gluten-specific regulatory cells, being exposed to gluten fairly regularly would be helpful in maintaining the number and functional activity of those regulatory cells.
Q: Is it likely that after the clinical trials, if and when the drug becomes available to patients, that it would initially be used along with the gluten-free diet and perhaps eventually replace the diet?
A: I am not a clinician, but I would say probably initially it would be the treatment and then gluten would be introduced at low amounts every once in a while, and then try to build that up.
Q: How would the treatment be likely to be administered? Would it be done in a doctor’s office? How often?
A: It won’t be something that a patient can do at home. Whether it’s going to require multiple treatments — monthly, every six months, every year –only future clinical testing will tell. But I can tell you that in animal models of autoimmune diseases, including celiac disease, multiple sclerosis, type 1 diabetes and allergies to peanuts, one infusion is enough to give very long protection. In humans, it may be different and that is going to have to be tested. We are hoping it’s not going to be more than every six months or a year or something like that.
Q: Three people in the group that got the treatment quit due to gluten-related symptoms, the same number as in the group a did not get the treatment. What did that show about protection from the nanoparticles?
A: Like everything, people are going to respond to therapy differently. Overall, people in the treatment group did better than the people who got the placebo. There are, of course, going to be outliers on each side of that. So that’s why you do a group that’s big enough, and you can then do accurate statistical analysis.
My understanding is that no one had any symptoms that were the result of the treatment itself, which was given in two shots, seven days apart. Then seven days later all the study participants were given a gluten challenge, which was quite robust, 12 grams of pure gluten in a capsule for three days, followed by 6 grams for 11 days. A small number of people developed some symptoms after they started the challenge. This was a level of gluten they probably had not seen for years. But the fact that the symptoms were reduced in the treatment I find encouraging.
Q: Some people with celiac disease worry about any treatment that involves altering the immune system, in particular suppressing it. How is the immune system affected with this treatment?
A: The point of this treatment is that it is only going to suppress the part of your immune system that’s making an immune response against gluten. That’s what immune tolerance means, which is what we’re trying to accomplish. The opposite of that would be a case where someone got a heart transplant or a kidney transplant and is then put on a series of what we call immunosuppressive drugs.
Those drugs are going to suppress your ability to make immune responses against anything. They have no specificity so you might end up becoming more susceptible to infections and increased rates of cancer. We are trying to specifically target only that part of the immune system that’s causing the symptoms of celiac disease.
The real beauty of the technology is that it theoretically has the possibility to treat any autoimmune or allergic diseases as long as we have you know a good understanding of what the antigen is.
Q: A measurement of the damage to the intestine, called the villous height-to -crypt depth, was included in the study. It concluded there was a trend toward protecting the small intestine. What does that mean?
A: In the placebo group that underwent the gluten food challenge, their villous-height-to-crypt ratio decreased, as you would expect because when that decreases it measures increased damage to the intestine. In patients who got treatment, their ratio did not significantly decrease as a result of challenge. Patients who got the treatment did not have a significant decrease [meaning they were not showing more damage}.
The clinical trial was set up to measure the difference between pre-challenge biopsy and post challenge biopsy in each group. The placebo group had significant change. The treated group was not significantly different from before the challenge to after the challenge, but it just missed significance.
I look at it that the treated patients did not get significant shortening of the villi, in other words did not get further damage. You can look at it like an optimist or a pessimist.
People were given the challenge only a week after the treatment. Future studies will determine what dose should be given; how many doses should be given. Future trials might find that the effect of the treatment will be more protective [as seen in the villi] in two weeks or a month after you treat rather than a week. It is encouraging that we saw a huge protection against the immune response against gluten, which was the primary outcome measure and was highly significant.
Q: The measurements of tissue transglutaminase (TTG) antibodies is a way of evaluating a reaction to gluten exposure. This study measures interferon gamma. What is that and why is it a significant measurement in this study?
A: Celiac disease is dependent on immune cells called T-cells responding against gluten. And those T-cells then talk to other immune cells called B-cells that make the antibodies that you are talking about. T-cells are the starting point of the disease and the level of antibodies follows along later in the process.
Interferon gamma measures T-cell activity in response to gluten. By measuring the T-cell response we thought we were looking at what I would call the most upstream immune reactivity. And based on everything we know from all other autoimmune diseases, if we knocked a T-cell response down by 90 percent like we did in this study, eventually the antibody response will be suppressed at least that level. It will probably take longer to see antibodies go down compared to T-cells.
Q: One of the conclusions of the study was that the treatment caused less inflammatory response to gluten. Can you explain?
A: That was referring predominantly to the very profound decrease in interferon gamma, the inflammatory cytokines. The inflammation was also measured quantitatively in the biopsy. By both measures the inflammation was reduced in the treated group.
That shortening of the height-to-crypt depth seen in the placebo is a read out for gut inflammation Something is going on. That was mitigated, largely but not totally, in the treated patients, which meant their inflammatory response was decreased.
Q: What do you think is the most important thing that the patient community should know about this potential new treatment.
A: I think they should know that this is the first really strong indication in any autoimmune disease that you could induce tolerance in humans. Without question that’s demonstrated here. Second, this bodes well for this technology being improved for the future treatment of celiac patients, but theoretically the same nanoparticle carrier could be used to treat any auto immune or allergic diseases simply by switching the antigen inside these particles.
This interview was edited for length and clarity.