Immunological Tolerance


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Immunological Tolerance

  1. 1. Immunology 2008 Lecture 21 Immunological Tolerance 4 November
  2. 2. TODAY Immunological Tolerance, Chapter 19 Autoimmunity, Chapter 20
  3. 3. Note: “Peripheral” vs. “Central” Tolerance, anatomical distinction… TOLERANCE
  4. 4. Central Problem of Tolerance: Random generation of diversity (G.O.D.) is dangerous . How to deal with self-reactive receptors??
  5. 5. No formation of isoantibodies Stable chimeras Shared placenta, exchange of hemopoietic stem cells Tolerance in dizygotic cattle twins Owen, 1942 No rejection of tissue grafts.
  6. 6. <ul><li>Souter et al. (2003) A Report of Dizygous Monochorionic Twins. N. Eng. J. Med . 349:154 </li></ul><ul><li>Sex-discordant twins </li></ul><ul><li>Monochorionic, shared fetal circulation </li></ul><ul><li>Blood chimerism (many allelic DNA markers) </li></ul><ul><li>Product of in vitro fertilization (relevant?) </li></ul>Human dizygotic twins, unlike cattle, do not normally share a common placenta. However… These siblings should display the same mutual tolerance shown by Owen’s cattle twin chimeras – but not yet examined.
  7. 7. Hypothesis: Tolerance develops to antigens present during development of immune system Burnet, “Clonal Selection” hypothesis – Clonal deletion of self-reactive cells occurs during the development of immunocompetent cells. Medawar experiments - Induction of tolerance to skin grafts can be induced by inoculation of F1 spleen cells into parental inbred newborn mice. Burnet & Medawar shared the Nobel Prize in 1960
  8. 8. Three mechanisms for maintenance of tolerance Clonal deletion Suppression Receptor blockade *
  9. 9. Clonal Deletion of Self-Reactive AFCPs
  10. 10. T-Cell diversity poses a special problem T-Cells require the ability to recognize self-MHC – how to prevent this from becoming autoreactive?? Positive & Negative Selection during intrathymic development
  11. 11. = clonal deletion “ death by neglect” Intrathymic T-cell maturation: Two ways to die ~3-5%
  12. 12. <ul><li>Experimental Model of Clonal Deletion: </li></ul><ul><li>Cytoxan-Induced Tolerance </li></ul><ul><li>Antigen followed by cytoxan </li></ul><ul><li>Proliferating cells are selectively killed </li></ul><ul><li>Short-term tolerance </li></ul><ul><li>(compare with Mishell/Dutton 3 HTdR experiments) </li></ul>… in Humans? Not yet.
  13. 13. Three mechanisms for maintenance of tolerance Clonal deletion Suppression Receptor blockade *
  14. 14. Prediction : If tolerance is maintained by clonal deletion, then the tolerant state should not be transferable .
  15. 15. Clonal deletion cannot account for all models of tolerance Must hypothesize active “suppression”, T Reg cells
  16. 16. <ul><li>Graca et al. (2002) Identification of Regulatory T Cells in Tolerated Allografts . J. Exp. Med. 195:1641 </li></ul><ul><li>Mouse skin graft model </li></ul><ul><li>Induce tolerance to allogeneic grafts </li></ul><ul><li>Transfer tolerance with tolerated skin grafts </li></ul><ul><li>Grafts are colonized by CD4 + regulatory T-cells </li></ul><ul><li>which can emigrate in a new recipient and </li></ul><ul><li>establish a permanent state of tolerance </li></ul>
  17. 17. DaVeroelen, Brand and Claas (2004) Pretransplant Blood Transfusions Revisited: A Role for CD4+ Regulatory? Transplantation 77, S26–S28 It has long been observed that multiple blood transfusions prior to grafting increase the survival of human kidney transplants. Recent findings reviewed in this publication suggest that this effect may be due to the presence of CD4 + suppressor cells in the transfusions .
  18. 18. Three mechanisms for maintenance of tolerance Clonal deletion Suppression Receptor blockade *
  19. 19. T/B Cooperation in Primary Response 1 2
  20. 20. No Signal 1
  21. 21. Ag excess – no cross-linking
  22. 22. Significant mechanism for maintaining tolerance to serum proteins (soluble and abundant) No Signal 1 No Signal 2 (…for B M )
  23. 23. Three mechanisms for maintenance of tolerance Clonal deletion Suppression Receptor blockade “ CENTRAL” TOLERANCE “ PERIPHERAL” TOLERANCE
  24. 24. Immune Reactions: Balance between Immunity and Tolerance
  25. 25. Immunity vs. Tolerance
  26. 26. Fin