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68 MECHANISMS OF ORAL TOLERANCE
types of T cell populations in the intestine.
Much has been learned about dendritic cells in recent years: some types particularly
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influence the development of Th1 cells and others Th2 cells . These dendritic
populations can be identified on the basis of expression or absence of the adhesion
molecule CD11c and also by the type of cytokines (such as IL-12) which they produce.
The heterogeneity of dendritic cells is increasingly being recognised and it is now
appreciated that the major function of some populations is to induce T cell tolerance,
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rather than a productive immune response .
As with all events in the immune system, a circular feedback system (so-called
inter-cellular cross-talk) operates between dendritic cells and the T cells which they
help stimulate (fig. 3). Thus, the cytokine products of dendritic cells influence the T cell
populations which they generate and in turn, the cytokines produced by T cells
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influence the type of dendritic cells which occupy that locale .
A further population of cells, likely to be involved in antigen presentation, which
express the macrophage scavenger receptor (CD163) has been identified by
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immunohistochemistry in the central core of individual villi . The cytokine products of
this population of macrophage-like cells, including secreted CD163, may play a role in
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down-regulation of the local immune response .
Cytokine environment of the mucosa
Virtually all cells in the mucosa, including enterocytes, produce a wide range of
cytokines and the profile of cytokines determines the net effect on the type of immune
response elicited. It is presumed that a major, final determining influence is the type of
cytokines produced by the local T helper populations. Since the principal default setting
of the mucosal immune response is towards tolerance of encountered antigen, the
cytokines which could determine tolerance have been investigated. The three cytokines
which have received most interest for their potential involvement are IL-4, IL-10 and
TGF-b.
For some time it was considered that T cell tolerance in the mucosa was achieved by
a predominant Th2 response to local antigens. Major products of Th2 cells include the
cytokines IL-4 and IL-10. However, in some animal model experiments, it was shown
that these cytokines are not required for tolerance induction. Moreover, in experimental
oral tolerance, inhibition of IgE production is a characteristic feature: the reverse would
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be predicted in an IL-4 dominant environment . Hence, it is now proposed that
tolerance in the intestine may be achieved by a further T cell population, referred to as T
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regulatory cells . The major cytokine products of these cells are IL-10 and
transforming growth factor-beta (TGF-b).
Although IL-10 is not essential in some models of oral tolerance, the importance of
this cytokine in maintaining tolerance is emphasized by the spontaneous development
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of colitis in mice when the gene for this cytokine is “knocked out” . Of great interest,
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TGF-bcan reverse the colitis . It is also known that IL-10 may be required for the
production of TGF-band that the latter cytokine inhibits the IL-12/interferon-gamma
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(IFN-g) pathway, likely to play a central role in many inflammatory diseases .
It is currently hypothesised that control of the mucosal immune system is
maintained by regulatory T cells, but at present, other than studying their cytokine