Transplantation

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Transplantation

• March 27, 2001

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History of Transplantation

• 700 B.C. Hindu surgeons transferred flap from a
  patients forehead to repair amputated nose
• 15th Century Italian surgeons performed early
  rhinoplasty
• Late 1800s Skin grafting experiments became
  widespread
• 1908 First report of organ transplantation (cat
  kidney)
• 1925 Dr. S. Voronoff grafted testicles which
  were transplanted from apes to man in order to
  restore men to youth and vitality
• 1935 First human kidney transplant (mismatch
  caused immediate rejection)
• 1954 First successful human kidney transplant
• 1967 Dr. Christiaan Barnard performs first
  successful human heart transplant

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Transplantation

• The act of transferring healthy cells, tissues or
  organs from one individual (the donor) to another
  (the recipient or host).
• Barriers can include
• Technical challenges of physical transfer
• Availability of graft
• As of 7/99, 64,000 patients were on a transplant
  waiting list
• 70 needed kidneys (800 day wait)
• Graft rejection

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Types Of Grafts

• Autograft Transfer of self-tissue from one
  location in/on the body to another
• Isograft Transfer between identical
  twins/syngeneic animals (e.g. mice)
• Allograft Transfer between two individuals
  within the same species
• Xenograft Transfer between species

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Tissue Rejection Specificity and Memory
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What Mediates Graft Rejection?

• Transfer of lymphocytes, but not serum antibody
  transfers allograft immunity
• Nude (athymic) mice are incapable of allograft
  rejection
• T cells from first-set rejection mice transferred
  second-set rejection ability to unprimed
  recipient
• Conclusion T cells mediate rejection

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Which T Cells Mediate Rejection?
Conclusion Both CD4 and CD8 T cells are
involved
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What Antigens Are Involved?

• Blood group ABO blood group antigens are
  expressed on RBCs, epithelial cells and
  endothelial cells. These can be matched by blood
  typing.
• MHC Antigens Major histocompatibility antigens,
  originally identified during allograft
  experiments. These can be matched by HLA typing.
• Minor Histocompatibility Complex antigens can
  also be involved

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HLA Typing Fig. 21-4
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2-Stage Mechanism Of Graft Rejection

• Sensitization T cells (both CD4 and CD8)
  recognize alloantigens (primarily MHC antigens)
  and proliferate in response. This varies with
  type of tissue.
• Effector Stage Host immune cells mediate
  destruction of graft. This occurs by a variety
  of mechanisms (e.g. DTH, CTL activity, ADCC,
  antibody lysis), and cytokines play crucial roles
  in each case.

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Time Course Of Graft Rejection

• Hyperacute rejection Occurs within first 24
  hrs. Graft never becomes vas-cularized
  (rejection mediated by anti-bodies).
• Acute rejection Occurs after 10 days.
  Mediated primarily by T cells.
• Chronic rejection Occur after several months to
  several years. Mediated by both humoral and
  cellular immune responses. Managed (?) by
  immuno-suppressive drugs

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Immunosuppression

• General immunosuppression Nonspecific, limits
  immune response to all antigens. Agents used
  include mitotic inhibitors, corticosteroids,
  total lymphoid irradiation, and
  Cyclosporin-A/FK506/ Rapamycin.
• What is the risk of this strategy?
• Specific Immunosuppression Antigen-specific
  suppression of immune response to graft tissue
  while allowing normal immune response to other
  antigens. Strategies include monoclonal
  antibodies to T-cell components/cytokines and
  blocking costimulatory signals
• Remains to be used effectively in humans

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Graft-Versus-Host Disease (GVHD)

• Grafts which contain immunologically competent T
  cells (e.g. bone marrow transplants) can result
  in engrafted T cells responding against host
  tissues.
• GVHD can be a serious complication of BM
  transplants (50-70), and is associated with
  damage to skin, liver and intestine, as well as
  severe immunosuppression in recipient.

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Grafts In Immunopriveleged Sites

• Certain sites (anterior chamber of the eye,
  cornea, uterus, testes, brain) will not reject
  allografts.
• This is thought to be due to high levels of
  Fas-ligand expression at those sites, triggering
  apoptosis of Fas-bearing infiltrating lymphocytes

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