primary prevention of coeliac disease - Associazione Italiana ...

84
IMMUNOTHERAPY OF COELIAC DISEASE
CD shares several immunological features with other less benign conditions, for
example, insulin dependent diabetes or multiple sclerosis, for which
immunomodulatory strategies have been studied and found to ameliorate the disease.
When devising immunomodulatory strategies it is of fundamental importance to have
systems where to test the success of the strategy implemented. Most of the attempts
done so far have been realized using the in vitro organ culture system, which represents
the only available tool since an animal model of CD is at moment still lacking.
The organ culture system of the treated coeliac mucosa is an experimental system to
explore the immunological events triggered by the contact of the antigen gliadin with
the jejunal mucosa. Changes suggesting an activation of T cell immunity have been
shown at the lamina propria level, including increased density of monuclear cells
expressing IL2 receptor or enhanced expression of costimulatory molecules or
adhesion molecules. The epithelium is also involved becoming infiltrated by
4-5
lymphocytes and expressing Fas molecules . As far as cytokines are concerned, a
6
strong enhancement of mRNA expression for g- interferon and IL2 has been observed .
Block of costimulation
B7/CD28 is one of major costimulatory pathways for the T cell activation providing
important signals for complete T cell activation; in fact, as in the absence of
costimulation T cells become unresponsive (anergic), the blockage of CD28/B7
7
costimulation represents a potential target for immunotherapeutic strategies . In
addition, the inhibition of costimulation has been reported to block specific antibody
response, to prolong transplants survival and to inhibit animal model of autoimmune
8
diseases .
CTLA4 (CD152) is a CD28 homologue that binds to CD80/CD86 with higher
affinity. CTLA-4 is expressed on activated T cells and down-regulates T cell activation,
9
providing a feedback negative signal . Recently, Maiuri and co-workers observed that a
fusion protein of CTLA-4 (CTLA-4-Ig) specifically blocked gliadin-induced immune
10
activation in the treated coeliac mucosa challenged with gliadin . They observed that
the addition of CTLA4-Ig in the organ culture system of treated mucosa, had a clear
effects on T cell activation in terms of decreased percentage of CD25 positive cells and
reduced expression of ICAM-1 on mononuclear cells after 24 hours of culture.
Interestingly, they found that almost 10% of lamina propria mononuclear cells showed
apoptotic phenomena. Nonetheless, two other features, such as T cell infiltration and
FAS expression by epithelial cells, were not affected. As a whole, these data suggest
that not all phenomena triggered by gliadin in the mucosa are the result of T cell
activation, and warn us that probably not everything may be modulated by affecting T
cell activity.
Gliadin peptides as tolerogens
The identification of gliadin epitopes has a crucial importance to understand the
mechanism leading to CD mucosal damage, but also to offer an important tool for a
strictly focused immunomodulatory strategy based on the modification of the structure
of antigenic peptide. In fact, it has been reported that is possible to modulate the specific