primary prevention of coeliac disease - Associazione Italiana ...

IMMUNOTHERAPY OF COELIAC DISEASE
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immune response to antigenic peptide, altering the peptide structure . Peptides could
be enginereed so that they would bind HLA molecules but not TCR, or bind TCR with
the result of a switching from a proinflammatory Th1 to a Th2 or protective Th3
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responses . Of course, the possibility of using peptides in immunotherapy and chances
of success depend on the identification of immunodominat epitopes.
Regarding CD, a number of gluten peptides have been implicated in the
pathogenesis of the disease. At least five different antigenic peptides, three of them
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obtained from a-gliadin , one from g-gliadin , and one from glutenin have been
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identified so far. Three peptides are DQ2-restricted , two are DQ8-restricted . It is
noteworthy to mention that the complexity of the gluten antigens, the variability of the
responses of CD patients to the identified epitopes and the role of each peptide in the CD
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pathogenesis make the available data difficult to interpret .
Nevertheless, the possible therapeutic use of such peptides is hampered by many
unsolved problems, that are not only technical, as the poor bioavailability of synthetic
peptides and the choice of the administration route. First of all, it is still undefined the
number of such epitopes: how many they are and which are the immunodominant ones.
Moreover, among the different peptides it is also difficult to identify those which are
primarily disease eliciting and those which are created by antigen spreading.
Furthermore, it is possible that different groups of patients show different pattern of
reactivity. To this respect, differences have been hypothesized between adults and
children with CD. Again, Dq8- and DQ2-positive coeliac patients may recognize
different sets of peptides. We have recently examined in the organ culture system one of
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the epitopes characterized in Dr Koning's laboratory as one DQ8-restricted peptides .
It was clearly recognized in vitro only by DQ8 positive coeliac patients. Biopsy
fragments from DQ8 positive, but not from DQ2 positive coeliac patients, showed a
significant increment of CD25 positive cells in the presence of such peptide, while both
groups of patients reacted to the whole mixture of gliadin peptides. As a matter of fact,
one of the problem with gliadin peptides is the posttranslational modifications they
undergo. Although many evidences have been produced on the importance of
deamidation of some peptides by tissue transglutaminase, it remains to be defined the
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extent of such phenomenon . Incidentally, we found that both native and deamidated
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forms of the peptide were equally recognised .
Finally, and this is probably the most important issue, it is still unclear if structures
reacting with T cell receptors are really the ones which trigger the disease; in other term,
the relationship between toxicity and immunogenicity is still to be clarified. As already
mentioned, in vitro and in vivo challenge studies have pointed to peptides (e.g. A-
gliadin 31-43 sequence), which instead have shown a scarce if any reactivity with
mucosal T cells.
IL10 and regulatory T cells
Among cytokines with regulatory properties, there is no doubt that IL10 is a
molecule with a strong immunomodulatory activity. IL10 is a potent immunoregulatory
cytokine that has been found to suppress T cell-mediated immune response by either
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inhibiting the expression of costimulatory molecules on antigen presenting cells or
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directly inducing a long term unresponsiveness of specific T cells . Regarding the