ðState of immunological unresponsiveness to
antigen induced by feeding.
It is a feature of the common mucosal immune
General properties of mucosal tolerance:
l Antigen specific.
l Often partial (eg. antibodies inhibited, but
T cell responses may remain).
l Not complete (eg. may be a quantitative
reduction in antibody levels).
l Wanes with time.
l Easier to abrogate a response than reduce
and established response.
l Good immunogens are better at inducing
l Dose and route dependent.
How does it work?
Central tolerance ð deletion of self-reactive T
cells in the thymus
Peripheral tolerance ð an area of very active
The mucosal immune system:
Consists of the gastro-intestinal tract,
respiratory system, genito-urinary system,
ðCommon lymphoid circulation
ðEpithelial cells line the mucosa
ðLargest area exposed to the external
ðHeaviest antigenic load
Respond Don't respond
Fight [ Ignore
- There has been a great deal of discussion of
• Suppressor cells cannot be cloned or
• many cells exert a suppressive effect
I Bystander suppression
l Antigen-specific suppression is induced by
l Suppression is triggered by re-encounter of
l Release of inhibitory cytokines will non-
specifically inhibit other cells
ð Transforming growth factor beta (TGFβ)
non-specifically inhibits the growth of
ð Specific immune responses can be inhibited
by IL-4 and IL-10
ðSome populations of T lymphocytes (both
CD4 and CD8) can consume
IL-2, the T cell growth factor. Surrounding
cells therefore fail to grow.
& Feeding oral insulin to mice prevents virus
induced insulin-dependent diabetes in a mouse
model. IL-4 and IL-10 were generated which
inhibited a specific immune response.
(Von Herrath et al., J Clin Invest 98, 1324.
II Immune Deviation
% T lymphocytes are activated by antigen
presenting cells (APC)
Th1 cells - important in inflammatory
responses (eg delayed type hypersensitivity)
Th2 cells - important in helping antibody
responses. Suppress Th1 cells (IL-4, IL-10).
ðTherefore Th1 immune responses may be
inhibited if Th2 cells are stimulated instead.
% T lymphocyte activation requires 2 signals
µ §µ §
Signal è T cell proliferation
+ Signal (IL-2 & IL-2r)
Signal alone è No proliferation
Eg. Some epithelial cells in the gut and lung
normally express class II MHC
8 research results ...
ANERGY results in a specific
l Anergic cells do not respond to specific
MHC+peptide plus costimulation
l Anergic cells may then block APC - and
inhibit immune responses
l Anergic cells may consume IL-2
l Anergic cells are more susceptible to
programmed cell death (apoptosis)
∴ anergy ðdeletion
Ref - Cobbold S & Waldmann H (1998) Infectious Tolerance. Current Opinion in Immunology
IV 'Infectious' tolerance
Regulatory T cells have been described which
can bind to APC and deliver a 'negative
signal' to naive T cells.
However, their mechanism of action is
Multiple models of oral tolerance have been
proposed (Weiner, 1997).
Animal models which investigate the
induction of oral tolerance for the treatment
of auto-immune disease will be discussed this
Refer to pack provided.
A number of clinical trials for auto-immune
disease are in progress:
Multiple Sclerosis Myelin Basic
(MS) Protein (MPB)
Rheumatoid Type II collagen
Type I Diabetes Insulin
Organ Transplant MHC molecules
Human MS trial (1y double blind study)
Those individuals fed myelin had a higher
frequency of TGFβ producing cells (Fukuara et
al., 1996. J Clin Invest 98, 70).
Several studies have investigated the effect of
feeding type II collagen to RA patients.
Study No of Dose Time Result
Germany 5 0, 1, 10 12 weeks No
USA 6 0.02 -2.5 12 weeks Only at
Investigators are finding that dose and
frequency are important factors.
Agents that enhance clinical tolerance are
under investigation, eg other cytokines,
Watch this space!!!