Oral Tolerance (OT)- term used to refer to state of unresponsiveness that exists for non-pathogen...
Oral Tolerance (OT)- term used to refer to state of unresponsiveness that exists for non-pathogenic antigens present within gut lumen
by Ewan Murphy
1. Clonal Deletion
1.1. High antigen dose
1.2. Mechanism of tolerance of self-reactive T cells
1.3. Uncommon after peripheral tolerance
1.4. High doses can induce apoptosis of responding T cells
2. Clonal Anergy
2.1. Low dose of antigen
2.2. Lacks inflammatory signals
2.3. Basic of peripheral tolerance to many self Ag
2.4. Can be reversed by addition of Il-2 and limiting dilution analysis
3. Role of gamma delta cells in OT
3.1. OT can be trasferred gamma delta CD8+ T cells
3.2. Only suppresses IgE and not IgG
3.3. Diabetes in non-obese diabetic mice can be prevented by transfer of tolerised CD8 gamma delta T cells
3.4. Can be prevented or abrogated by depleting gamma delta T cells
3.5. cannot be induced in d TcR KO mice
3.6. gamma delta T cells may suppress conventional Ag specific alpha beta T cells in an idiotype specific manner
4. Reg T Cells
4.1. IL-10 and TGF-B enhanced following OT
4.2. Blocking TGF-B blocks oral tolerance
4.3. Treg cells secrete IL-10 and TGF-B
5. Bystander Suppression
5.1. Associated with feeding of low doses of Ag
5.2. OT cells suppress proliferation of unrelated Ag-specific cells factor is soluble, TGF-B1
5.3. Factor is soluble, TGF-B1
5.4. Regulatory cells induced by OT secrete Ag non-specific cytokines following challenge by OT Ag
5.5. Suppress inflammation locally
6. Role of CD4+ T Cells
6.1. Depletion of CD4 prevents OT
6.2. Tolerance can be transferred by CD4 cells
6.3. Preferential upregulation of T cell subsets
6.3.1. Q2Th2, increased, Th1 decreased
6.4. Th1 and Th2 dependent cytokine and antibody responses can be tolerised by different regimes
6.5. IgE is very susceptible to OT but IL-4 KO can be tolerised
6.6. CD4 Th3 cells, like Th2 cells produce Il-4 and Il-10 but also produce TGF-B
7. OT Mechanisms
8. Oral Tolerance Features
8.1. Can be induced to both humoral and cell mediated immunity (CMI)
8.1.1. CMI is easier to tolerise than humoral responses and requires less antigen and lasts longer
8.2. All proteins can induce OT
8.3. Th1 responses are easier to tolerise than Th2 responses
8.4. Induces defective lymphocyte migration
8.5. Exhibits carrier specificity
8.5.1. Tolerance of antibody production can be broken if the defectie Th cells are bypassed with an unrelated carrier or LPS
8.6. Can be induced as quickly as 1-2 days after feeding and last +/- 18 months
8.7. Antigen persistence is required for maintenance
8.8. Effector functions (IgE and DTH) most associated with pathology are easisest to olerise
9. Result of innapropriate antigen presentation
9.1. Antigen-specific cytokine production in the absence of cell proliferation occurs
9.2. OT can be induced with peptides, enhanced availability of antigen to antigen presenting cell
9.3. OT is prevented if APC functions are activated
9.4. Presentation of antigen by non-costimulatory APC
9.5. Epithelial cells
9.5.1. express MHC class II but have low levels of CD80 and ICAM-1
9.5.2. May selectively present antigen to CD8 regulatory cells
9.5.3. May take up antigen and doesn't induce co-stimulatory molecules to induce immune response
9.6. Local presentation of antigen would induce local tolerance
9.7. Unusual population of APC in lipopolysaccharide and PP induce tolerance in naive recipients
9.8. Antigen-loaded dendritic cells Found in efferent intestinal lymph after feeding, expansion of DC enhances OT
10. Gut Processing antigen in particular manner
10.1. Intestinal processing generates tolerogenic protein
10.2. Intact protein is absorbed from gut
10.3. Serum taken 1 hour after feeding can trasfer OT and inhibit delayed type hypersensitivty
10.4. Serum taken following antigen administration via routes cannot transfer tolerance
10.5. Tolerogenic material can't be transferred following feeding to SCID or irradiated mice
10.6. Intestinal filtration results in deaggregated monomers that are tolerogenic in other systems
10.7. Alterations in antigenic structure may be required, inhibition of pancreatic enzymes inhibits OT
11. Switching Th response
11.1. OT can be induced normally in anti-IL-4 treated or IL-4 KO mice
11.2. OT normal in IL-5 and IL-6 KO mice
11.3. IL-10 can restore tolerance to microflora
11.4. IL-10 KO mice develop IBD
11.5. IL-10 and IL-4 up-regulated following OT
11.6. Interferon gamma suppressed by OT, preceded by Ag-specific IFN-y response
12. Induction of Treg cells ( production of TGF-beta)
12.1. TFG-beta is abundant in gut
12.1.1. mediator of epithelial cell differentiation
12.1.2. Immunosuppresive
12.1.3. IgA class switching
12.2. Bystander suppression dependent on TGF-beta
12.3. TGF- beta Associated with prevention of colitis
12.4. TGF-beta Secreting CD4 and CD8 isolated from Peyers patch and mesenteric lymph nodes
12.5. TGF-beta Produced by TH3 Treg cells, macrophages,enterocytes
13. Modulation of OT
13.1. Augmentas (enhances tolerance)
13.1.1. IL-2, IL4/IL10
13.1.2. Anti IL-12
13.1.3. Cholera toxin B subunit
13.1.4. LPS
13.1.5. IFN-beta
13.1.6. Multiple emulsions
13.2. Decreases
13.2.1. IFN-gamma
13.2.2. IL-12
13.2.3. Cholera toxin
13.2.4. Anti-MCP-1
13.2.5. Anti-gamma delta
13.2.6. Cyclophosphamide
13.2.7. Graft versus host disease
13.2.8. Parasite Infection