Oral Tolerance (OT)- term used to refer to state of unresponsiveness that exists for non-pathogen...

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Oral Tolerance (OT)- term used to refer to state of unresponsiveness that exists for non-pathogenic antigens present within gut lumen by Mind Map: Oral Tolerance (OT)- term used to refer to state of unresponsiveness that exists for non-pathogenic antigens present within gut lumen

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

14. Brings problems when developing oral Vaccines

14.1. Oral vaccines against mucosal pathogens are desirable as they direct immune response where needed

14.2. No need for expensive and painful needles

14.3. Development of recombinant vaccines could be incorporated into transgenic plants