Oral Tolerance

Oral Tolerance

1. State of unresponsiveness existing for non-pathogenic antigens present within the gut lumen (specifically downregulated system essential for homeostasis)

2. Features

   • All proteins, heavy metals and contact sensitising agents can induce oral tolerance
     • Induced by humoral and cell-mediated immunity
       • Cell-mediated immunity is easier to tolerise (make tolerant to) than humoral responses, requires less antigen and lasts longer
         • Th1 responses easier to tolerise than Th2; IgE responses extremely sensitive to oral tolerance
         • Effector functions (igE & delayed-type hypersensitivity) are the easiest to tolerise
   • Oral tolerance induces defective lymphocyte migration and exhibits carrier specificity
   • Antigen persistence is required for maintaining oral tolerance

3. Induction and Maintenance of Oral Tolerance

   • Factors Affecting
     • Dosage & Frequency
     • Genetic Background
       • celiac disease and HLA-DQw2 locis
         • Susceptible individuals enerate IFN-y producing CD4+ T-cells in response to the protein, gluten, found in wheat
           • The resulting inflammation destroys the upper small intestine
       • Crohn's disease
     • Age
     • Intestinal Flora
     • Nutrition
       • Less oral tolerance with poor nutrition
   • Oral/ intranasal administration of appropriate antigens has been effective at preventing and even treating Type 1 diabetes mellitus in animals

4. Mechanisms of OT

   • Clonal Deletion
     • Tolerance of self-reactive T-cells with high antigen dose; very high doses induce T-cell apoptosis of responding T-cells
   • Clonal Anergy
     • Low antigen dosage (highly soluable, monomeric & lacking inflammatory signals) that is the basis of peripheral tolerance to self-antigen
       • Can be reversed (addition of IL-2 and limiting dilution analysis)
   • Treg-cells
     • CD*+ reg/suppressor cells mediate OT; induction of oral tolerance prevented with cyclophospamide
       • IL-10 and TGF-B enhanced following OT; Treg-cells secrete IL-10 and TGF-B
   • Bystander Suppression
     • Associated with low levels of Ag
       • OT cells suppress proliferation of unrelated antigen-specific cells with soluable factors (TGF-B)
       • OT Treg cells secrete non-specific cytokines following OT antigen exposure (to suppress local inflammation)
         • Autoimmune diseases have many autoantigens (i.e. MS has reactivity to MBP, PLP and MOG)

5. Role of Cells in OT

   • CD4+ T-cells
     • CD4 cell depletion prevents oral tolerance
       • CD4+ cells can transfer OT
     • In OT, T-cell subsets are preferentially upregulated: Th2 increased, Th1 decreased
       • Th1 and Th2 dependent cytokine & antibody responses can be tolerised with different regimes
     • IgE very susceptible to OT
       • IL-4 knock-outs can be tolerised
     • CD4+ Th3 cells produce IL-4 and IL-10 (like Th2) but also TGF-B
   • yd T-cells
     • Oral tolerance can be transferred with yd CD8+ T-cells but only suppresses IgE (not IgG)
       • Transfer of OT yd CD8+ T-cells prevents diabetes in NOD (non-obese diabetic) mice
     • OT prevented/taken away by depleting yd T-cells
       • OT can't be induced in TcR KO mice
     • yd T-cells may suppress conventional antigen-specific ab T-cells in an idiotypic manner (VCR region similarities)
     • OT emphasises the role of yd T-cells in intestinal homeostasis
   • Th3 cells
     • Produce IL-4, IL-10 and most importantly TGF-B
       • Transforming growth factor (TGF-B) has many immunosuppressive qualities but also switches B-cell secretion to IgA antibodies
   • Commensal Bacteria
     • Commensal bacteria stimulate local IgA production in the intestine and suppress local effector T-cell responses