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  1. 1. Oral Tolerance ðState of immunological unresponsiveness to antigen induced by feeding. It is a feature of the common mucosal immune system. 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 tolerance!
  2. 2. 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 research! suppression immune deviation anergy deletion The mucosal immune system: Consists of the gastro-intestinal tract, respiratory system, genito-urinary system, liver.
  3. 3. ðCommon lymphoid circulation ðEpithelial cells line the mucosa ðLargest area exposed to the external environment ðHeaviest antigenic load balance: Respond Don't respond Fight [ Ignore Eradicate SELF-antigens PATHOGENS FOOD Mechanisms SUPPRESSION - There has been a great deal of discussion of
  4. 4. 'suppressor cells': • Suppressor cells cannot be cloned or phenotyped. • many cells exert a suppressive effect I Bystander suppression l Antigen-specific suppression is induced by feeding l Suppression is triggered by re-encounter of antigen l Release of inhibitory cytokines will non- specifically inhibit other cells ð Transforming growth factor beta (TGFβ) non-specifically inhibits the growth of lymphocytes ð Specific immune responses can be inhibited
  5. 5. 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. 1996). II Immune Deviation % T lymphocytes are activated by antigen presenting cells (APC) µ§ Th1 cells - important in inflammatory responses (eg delayed type hypersensitivity)
  6. 6. 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. III Anergy % T lymphocyte activation requires 2 signals µ §µ § Signal Œ è T cell proliferation + Signal  (IL-2 & IL-2r) Signal Œ alone è No proliferation Eg. Some epithelial cells in the gut and lung normally express class II MHC
  7. 7. 8 research results ... ANERGY results in a specific hyporesponsiveness 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 µ§ Ref - Cobbold S & Waldmann H (1998) Infectious Tolerance. Current Opinion in Immunology 10,518-524 IV 'Infectious' tolerance Regulatory T cells have been described which
  8. 8. can bind to APC and deliver a 'negative signal' to naive T cells. However, their mechanism of action is unclear! 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 afternoon. Refer to pack provided.
  9. 9. Clinical Trials: A number of clinical trials for auto-immune disease are in progress: Disease Antigen Multiple Sclerosis Myelin Basic (MS) Protein (MPB) Rheumatoid Type II collagen Arthritis (RA) Type I Diabetes Insulin Uveitis S-antigen Organ Transplant MHC molecules Rejection
  10. 10. Human MS trial (1y double blind study) Attacks MBP 6/15 Placebo 15/15 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 centres (mg) Germany 5 0, 1, 10 12 weeks No
  11. 11. difference USA 6 0.02 -2.5 12 weeks Only at 20µg/day Investigators are finding that dose and frequency are important factors. Agents that enhance clinical tolerance are under investigation, eg other cytokines, adjuvants (cholera-toxin). Watch this space!!!