primary prevention of coeliac disease - Associazione Italiana ...

86 IMMUNOTHERAPY OF COELIAC DISEASE
hypothetical use of IL10 in the treatment of intestinal disorders, there are many
evidences both in vitro, in the fetal organ culture system, and in vivo, in a mouse model
of inflammatory colitis, that IL10 or cells producing it, such as Tr1 cells, are able to
downregulate T cell activation and to control the pathogenic process. Moreover several
reports showed that IL10 may have a central role in the development and homeostasis
of gut associated immune system (GALT). We know that in the mucosa of untreated
coeliac patients IL10 mRNA levels (and protein level) are higher than in controls, but
they face, and cannot efficiently contrast, enormously higher levels of proinflammatory
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cytokines as gamma interferon . Also the addition of further exogenous IL10 to the
organ culture of biopsies from untreated coeliac patients fail to control the
inflammatory process (Salvati et al, unpublished observations). Nonetheless, the
addition of IL10 in the organ culture system of treated coeliac mucosa challenged with
gliadin is able to downregulate the specific mucosal immune response to gliadin in
terms of reduced densities of CD25+ cells, reduced expression of CD80/CD86
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costimulatory molecules and of mRNA for inflammatory cytokines .
Moreover, preliminary evidences show that the production of g-interferon upon
gliadin stimulation is still absent 3 weeks later the isolation of T cells from biopsies
cultured with gliadin in presence of IL10. Interestingly, the effect is partially reverted
by the addition of anti-IL10 receptor and of anti-TGF b, this further suggesting the
presence of an active suppressive mechanism, maybe mediated by regulatory T cells.
In conclusion, our results showed that immunomodulation by IL10 on gliadin
reactive T cells could be a consequence of downregulation of costimulatory molecules
but also suggest that IL10 may operate through induction of Tr1 cells and inhibits the
migration into the intestine of pathogenic Th1 cells. Given that, the induction or the
expansion of specific T regulatory cells remains one of the possible
immunomodulatory strategies to implement in CD.
Mucosal tolerance
A very efficient route to induce tolerance to a specific antigen is the intravenous
administration, but the induction of tolerance via mucosae is a strategy more often
implemented in the experimental therapy of autoimmune diseases. Nevertheless, in
CD, being the small intestine the target of the disease, mucosae other than those of the
small intestine are candidate to elicit mucosal tolerance. Despite its peculiar
physicochemical properties, gliadin has been shown to be a good oral tolerogen.
We studied the potential for tolerance induction in gluten-free diet Balb/c mice by
intranasal administration of whole antigen, as it has been demonstrated that this
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strategy is effective in a variety of different experimental systems . Our results showed
that intranasal administration of native gliadin before immunization abrogated the
specific T cell response. Moreover, a marked decrease in g-interferon and IL-2 levels,
and normal levels of IL-4 expression were detected, suggesting that intranasal
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administration of gliadin can induce tolerance in Th1-cells . These data were produced
in mice parenterally immunized with gliadin: it is a model quite far from CD, but yet it
offers a series of questions, in particular concerning the ability of the nasal
administration of antigen to tolerate also gut T responses and to control a Th1 mediated
enteropathy.