primary prevention of coeliac disease - Associazione Italiana ...

THE BASIS OF COELIAC DISEASE
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interactions between mesenchymal cells and epithelial cells during the migration of
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epithelial cells and fibroblasts from the crypts to the tips of the villi . Moreover, the
tTG antibodies may modulate the deamidating activity of tTG either in an inhibiting or
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promoting fashion . Further research will tell us what role these antibodies play.
Translation of the new knowledge into therapy
The increasing insight into the molecular and cellular basis of CD should give
benefits to the patients. The knowledge on which gluten epitopes are recognized by gut
T cells should allow the methods by which gluten free foods are assessed to be
improved. Moreover, the new knowledge should uncover novel targets for therapy.
There are already some attractive possibilities. Activation of CD4+ gluten specific T
cells appears to be a critical checkpoint in the development of CD, and interference with
this step in the pathogenesis should be an effective way to control the disease. One
possibility, which is basically an extension of today's treatment with a gluten free diet, is
to produce wheat that is devoid of T cell epitopes, either by breeding programs or
transgenic technology. Success by use of classical breeding already seems unlikely as
epitopes are found in both a-gliadins and g-gliadins which are encoded by the Gli-1 and
Gli-2 loci located on chromosomes 1 and 6, respectively. The classical breeding
approach is further complicated by the hexaploid nature of wheat. tTG is a target for
intervention because of its critical role in generating gluten T cell epitopes. Inhibitors of
tTG activity exist and likely inhibitors suitable as drugs can be developed. The biggest
problem with this approach is that tTG inhibitors may have unacceptable side effects.
tTG is involved in many different physiological processes including programmed cell
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death . Another strategy would be to aim at the gluten specific T cells. If coeliacs have a
normal oral tolerance to native gluten proteins, but a broken tolerance to deamidated
gluten peptides, exposing the gut immune system to already deamidated peptides may
establish oral tolerance to these deamidated gluten peptides as well. This approach will
utilize the body's own mechanism to silence T cells. Alternatively, one could try to
directly silence gluten specific T cell by using soluble dimers of HLA/ peptide
complexes, which have been demonstrated to induce antigen specific apoptosis
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because of inappropriate T cell stimulation . The central role of DQ2 and DQ8 in
presenting gluten peptides offers yet another target for intervention. Blocking the
binding-sites of these HLA molecules would prevent presentation of disease inducing
gluten peptides. The challenge with this approach will be to find an efficient way to
target and block the binding sites of DQ molecules, which are continuously synthesized
by antigen presenting cells. This approach, blocking of peptide presentation, has also
been suggested as therapy for other HLA associated diseases. CD should be better
suited to this approach than many other HLA associated diseases because drug delivery
in the gut is easy compared for example to joints in rheumatoid arthritis or islet cells in
type 1 diabetes.
Whatever new therapeutic modality is introduced in CD, it will have to prove better
than the current gluten free diet regime, also when coming to its long-term safety. This
fact must be taken into consideration when devising new treatments. Although there are
already interesting therapeutic principles with a good, rational basis that can be tested, it
may for this reason take some years before a new treatment becomes reality.