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10_peripheral_tolerance.ppt

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  • 1. Most T cells against self eliminated by central tolerance; but a few escape.
  • 2. LYMPHOCYTES REGOGNIZING EITHER SELF OR NONSELF MUST LIMIT THEIR RESPONSE!
  • 3.
    • DC Mediated Tolerance:
    • In absence of danger signals, DCs that have engulfed only self antigens, have no costim molecules, will “tolerize” Th cells.
    • DC cells seem to develop “tolerizing ability”
    • Causes either apoptosis of Th cell, or anergy.
  • 4. B cell tolerance
    • Since Th cells against self antigens should not exist, B cells binding self antigens cannot be activated.
      • Become anergic;
      • Eventually apoptose as do all unstimulated B cells
    • Somatic hypermutation can create B cell clones against self; but become anergic.
    • T cells don’t have somatic hypermutation.
  • 5. Treg cells generated by negative selection in thymus
    • Up regulation of Foxp3 transcription factor and then develop into Treg cells.
    • High CD4 and CD25 Once Treg binds to tolerogenic DC, becomes “anergic”, and can now block proliferation of ANY CD4 T cells, of any antigen specificity, through direct contact with the T cell.
    • This tolerance dominant, can be transferred by T cells.
    • “ NOD” [non-obese diabetic] mice injected w normal CD4+ T cells do not come down with diabetes.
    • 2-10% of CD4 T cells; CD25+
    • Depletion of these T-reg cells increases immune response to self or graft; normal mice develop diabetes.
    • Clincal uses?
  • 6. TOLERANCE INDUCING CONDITIONS:
      • High OR low doses of antigen
      • Persistance of antigen
      • I.V. or Oral introduction
      • Blocking of costim signal.
  • 7. Antigen given orally leads to tolerance
    • Mice fed insulin are protected from diabetes; MBP resistant to EAE
    • However, similar studies in humans
      • have been unsuccessful.
    • May be more successful in preventing
      • ONSET of disease than treating.
  • 8. IMMUNE PRIVILEGED SITES
    • CNS
    • Eyes
    • Testes
    • Eliminate activated T cells by Fas-L expressed in these sites.
  • 9. Maternal-Fetal Tolerance
    • HOW WOULD YOU design a system to tolerate fetal antigens on placenta?
    • Will accept graft from fetal MHC type during pregnancy; so it’s not just local.
    • Reactivity returns after birth.
    • Treg cells
    • Placenta nearly devoid of MHC-1
    • Only ‘MHC’ produced are non-polymorphic HLA-E and HLA-G, which suppress maternal NK cells.
  • 10. NEONATAL TOLERANCE
    • Lifelong tolerance if bone marrow and/or spleen cells introduced to neonates.
    • Perhaps presenting antigen in thymus?
  • 11. EXPERIMENTAL TOLERANCE
    • Can be easily induced in neonates, or adults with immune system weakened by irradiation or chemo
    • Even after immune system recovers, tolerance to new antigens maintained.
  • 12. QUESTIONS YOU SHOULD BE ABLE TO ANSWER
    • iNTRO: #1
    • A: #1-3,5
    • B.II-IV: #3
    • C: #1,2
    • D: #1-5