I assume you are thinking about the clinical trial of ImmusanT that had the goal to re-educate gluten-reactive T cells. Yes, you are right this trial was stopped last summer after an interim analysis as it became clear that the drug was not effective.

Such setbacks are not unusual in drug development. In fact, it is considered that only one out of ten candidate drugs become a real drug for treatment of patients.

There are many other drugs for coeliac disease in the pipeline. Hopefully, one or more of these will make it so that a non-dietary treatment alternative becomes a reality for coeliac disease. 

Actually, not much is known as to why some people react more strongly to gluten exposure than others, but the amount of signal substances from T cells correlates with the degree of severity of symptoms. It is not very likely that this release of signal substances from T cells correlates with other consequences of coeliac disease.   

No, not much research now. We suspect the dental problems in coeliac disease are under-reported. There used to be some dentists working with clinical studies on this.  

Yes, there is research on both, in particular refractory coeliac disease II with malignant cells.

Basic science studies and a very few drug trials have been done or are ongoing. refractory coeliac disease I is tricky. It is for sure a mixed bag where inadvertent, continuous gluten exposure is a frequent cause.

In many other cases, the patient is clinically well, but the gut takes a long time to heal.   

For some patients, recovery to a normal mucosa (no villous blunting) can take several years on a gluten free diet. A few patients also fail to recover despite a strict gluten free diet. We do not really know yet why this is, but in most cases very small amounts of gluten are the cause, as some patients respond stronger to small amounts of gluten than others. However, clinical symptoms may still disappear despite the presence of villous blunting.  

Our current understanding of the disease mechanism in coeliac disease is way better than for other immune mediated diseases like type 1 diabetes or rheumatoid arthritis. Yet, there is still a lot we do not understand. For instance, as you mention, why not everybody who carries the genes for HLA-DQ2 or HLA-DQ8 does not develop the disease. We know that genes other than the HLA genes are implicated in the development of coeliac disease.

Many people who carry the HLA-DQ2/DQ8 do not develop coeliac disease and so it’s most likely they lack some of these other non-HLA susceptibility genes. In addition, we strongly believe that environmental factors other than gluten, for instance diarrheal viruses, are involved in coeliac disease development.

Some HLA-DQ2/DQ8 carriers who do not develop coeliac disease may have avoided a critical viral infection.

There is much to learn. The ultimate goal, and what hopefully can be achieved with even better insight, is prevention of coeliac disease.

No, not yet.

No drugs are accepted as non-dietary treatment. We all have hopes that such drugs will come to the market. They may be used for accidental exposure, and maybe as a cure.   

For the HLA-DQ:gluten tetramer test to become available in clinical practise, production of the test must be industrialised (that means, manufactured for sale).

This process is ongoing and will hopefully be successful. In addition, the test must be validated for its performance when samples are sent in from many patients from different doctors to the analysing laboratories. All this will take some time, maybe a year or two if everything goes well. 

T cells are special cells that are part of our immune system. They protect us against pathogens.

In individuals with coeliac disease, some of these T cells will go crazy when they meet gluten. This causes inflammation in the intestine when you eat gluten. The diagnosis of coeliac disease is relatively easy to achieve compared to many other gastrointestinal disorders, and all of those tests should be available from your local GP. 

Yes, such a drop can often be seen when the patient is fully compliant with a gluten free diet.   

I think it is quite infrequent. But some patients have several immune disorders at the same time, unfortunately.  

Transglutaminase 2 (TG2) is a wound healing enzyme, and its natural role is to crosslink proteins in the body. We cannot remove TG2 but we can inhibit the enzymatic activity of TG2. This would prevent TG2 from modifying gluten peptides in the gut. Because the T cells that respond to gluten in coeliac disease depend on this modification, we think that inhibition of TG2 activity should prevent the activation of gluten specific T cells.

A drug that does exactly that, a TG2 inhibitor, is currently tested in patients with coeliac disease (clinical trial by Dr. Falk Pharma). This is a good example of observations from the clinic (antibodies to TG2, and gluten specific T cells from gut biopsies) that were studied in the lab and where the discovered mechanisms have led to development of therapy. 

By chance as many other things in life. 

I was a medical student and wanted to do research. In the medical school curriculum, cellular immunology had fascinated me. I thus contacted immunology professor Per Brandtzaeg to ask whether there was an option to take a gap year and get involved in research. Per had just supervised a doctor (Helge Scott) together with another immunology professor Erik Thorsby. The PhD thesis of Helge was on the topic of immunology of coeliac disease. Per and Erik suggested I should follow the paths of Helge as this would also include studies of T cells. I thought this was a good suggestion and started.

After several backlashes and a feeling of being completely useless, I made progress. I took another leave from medical school and during this period I made the discovery of HLA-DQ2 being a culprit molecule in coeliac disease. I was utterly fascinated and absorbed by science and after medical school and completing service to become a licensed doctor, I went back to the lab. I have more or less worked there since.   

This is what is listed on ClinicalTrials at the moment.

Professor Sanders in Sheffield took part in the gluten degrading enzyme trial sponsored by Alvine Pharmaceuticals. There are no UK centres in the ongoing (recruitment completed) trial with transglutaminase 2 inhibitor by Dr. Falk Pharma.

The UK should be a good place to do studies, and there are several trials coming.    

Yes, we hope so.

Stephanie has looked at certain markers on the gluten specific T cells and how quickly they appear in response to gluten. If we include this marker with the HLA-DQ:gluten tetramer test, we may be able to say something about whether patients have eaten gluten recently or not. We need to perform further validation of this phenomenon before we can use it in a clinical setting. 

Not yet, but we hope that such distinctions can be made in the future.

At the moment it is not clear whether refractory coeliac disease (RCD) type I is mechanistically similar to or different from untreated coleiac disease, even though we know that RCD I patients have little or no effect of a gluten free diet. We have not yet studied RCD samples by our protein analysis approach, but we plan to do so in near future. 

The study was published last year.

The primary endpoint was not met, unfortunately, but some effect was seen. Some patients benefitted from the treatment, but their problems were not solved overall. The drug may be developed further, but many of us were a bit disappointed by the result.    

The short answer is that we believe it is more difficult to make immune (T-cell) responses to gluten proteins of oats than to gluten proteins of the other cereals. 

Coeliacs have T cells responding to certain peptides (what immunologists call epitopes) of wheat, barley and rye. (BTW: all peptides have to be modified by transglutaminase 2 in the body before T cells will recognise them). Some epitopes are shared between different grain types, some are specific for a certain type of grain. What initiates the response to a given epitope and the expansion of specific T cell clones that follows, we believe is related to how much of an epitope will survive gut digestion. After an initial sensitisation to an epitope, the immune system becomes very sensitive to this epitope requiring very little to get fired up. The epitopes of oats that some very few coeliacs mount responses to, are part of cereal proteins that are not very resistant to digestion by the gut digestive enzymes. This is in contrast to most other gluten epitopes of wheat, barley and rye. Thus, it is less of a chance to get sensitised to oats.

The biggest question is whether the treatment with removal of gluten-specific T cells will be sufficiently effective.

It is possible that if a few gluten-reactive T cells remain. These cells can expand on a new contact with gluten - and then the problem is back. It is also possible that there will be sensitisation of naive T cells that have not seen gluten before.

Basically, the initiation of coeliac disease from the beginning might again happen. This latter scenario we consider to be less of a problem though. 

Individuals with coeliac disease are not considered at higher risk of catching the flu or other viral or bacterial infectious diseases than non-coeliac individuals unless they have hyposplenism (a small spleen with reduced function). There is an increased risk of hyposlenism in people with coeliac disease compared with the general population, but risk is small.

Why hyposplenism develops in some people, we do not know. Coeliac disease in the absence of hyposplenism does not affect the overall immune system. In the disease process driven by gluten exposure, only a small fraction of all your immune cells get involved. While this immune response makes it very uncomfortable to eat gluten, it is unlikely to have an overall effect on the immune system unless the person has hyposplenisms. As it is unlikely to be tested for hyposplenism, people with coeliac disease are recommended to take certain vaccines.  

Actually the same enzyme is already on the market as Tolerase G in the US and with other trade names in Europe. It works during brewing of beer and also in human stomachs, but has not been tested properly as a treatment in coeliac disease. And it probably won’t work if for instance you drink milk with the enzyme.  

Probably, the ambition is this treatment will replace the gluten free diet (but this will be for the company to decide).

This trial was unsuccessful due to what is called a trial effect. All the participants in this trial whether they received the drug or placebo (the dummy drug) got better so it was impossible to conclude whether the drug was effective or not.

We do not expect that this should have any effect on the immune system in general as the gluten specific T cells are only a small population in the total T cell population. Therefore it should be completely safe to remove the gluten specific T cells if we can target them specifically. 

Addison’s disease also has an HLA association with the DR3-DQ2 and DR4-DQ8 haplotypes (some of the genes that predispose people to developing coeliac disease also predispose to Addison’s disease). Addison’s disease is a rare disorder so screening all people with coeliac disease for Addison’s disease would probably not be advised.

The short answer is no. The Sheffield group is doing very nice studies in the UK - very difficult to compete with them!

Yes, probably but not yet proven. It has not been well studied so far. Our centre is entering this field, but mainly on the B cell side.  

Yes, they are. The genes encoding for DQ2 are involved in many autoimmune diseases (type 1 diabetes, Graves’ disease, Myasthenia gravis, Addison’s disease etc) and the genes encoding for DQ8 are involved in some diseases, for instance type 1 diabetes. In coeliac disease these HLA molecules present gluten peptides to T cells. In the other diseases we do not know which peptides they are presenting, but it is very unlikely that they are gluten derived peptides.  

Well, it depends a bit on which antibody test you refer to. The most frequently used is IgA against transglutaminase 2 (TG2). If that has been negative and now is positive, it indicates you are exposed to gluten. Are you well clinically? Have you had a repeat biopsy?     

Not at the moment, but we are several individuals with the DQ2 or DQ8 HLA types and several of us have close relatives with coeliac disease.

This is a hard one to reply to as an adult gastroenterologist.

It is very good your son is doing better. I (Knut Lundin) have had that question several times and actually it seems that some people have persistent antibody levels. Why that happens and what to do about it is uncertain. In some cases it does turn out to be ongoing exposure to gluten. A test for gluten peptides in urine and faeces has been developed, but is not yet widely used, mainly in research.

We are exploring these tests in our Coeliac clinic and we do have some people with a positive test indicating exposure to gluten, although they consider themselves to be adhering to a strict gluten free diet.    

No, probably not every potential coeliac will go on to develop the 'full-blown' disease. An issue here will be how long the individuals are followed up. 

We also have evidence from studies of children that some who are positive for IgA anti-transglutaminase 2 antibodies in the blood, become negative for these antibodies. In these children we believe that they are on the way to develop disease, but then the disease process for some reason reverts. Whether the same can be the case in adults, it is not known. If so, it is probably not very common.