Lecture 17 Transplantation

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Lecture 17- Transplantation

• Barriers to transplantation
• Hyperacute rejection by preexisting antibodies
• ABO blood groups
• Acute rejection by alloreaction to MHC mismatch
• Chronic rejection to major and minor
  histocompatibility antigens.
• The role of MHC matching in graft acceptance
• The role for immunosuppressives
• Steroids
• Cytotoxics
• Cyclosporin
• Experimental approaches to organ transplantation

Reading Parham Chapter 12
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Figure 12-11
Transplant rejection vs. GvH
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ABO blood types
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Blood transfusion
Human RBC lack MHC antigens
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Hyperacute rejection
Endothelial cells express ABO antigens
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Transplanted organs often are stressed and
inflamed
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Hyperacute rejection of a kidney transplant
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Acute rejection is caused by an alloreactive T
cell response
Donor (graft) derived dendritic cells ("Passenger
leukocytes") can provide potent sensitization of
host alloreactive T cells.
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Acute rejection
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Time course of skin rejection
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Genetics of graft rejection
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Figure 13-39
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Direct and indirect presentation of alloantigens
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(No Transcript)
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Major inhistocompatibility vs. minor
inhistocompatibility
Figure 12.17
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What are minor histocompatibility antigens?
Figure 12.18
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Chronic rejection
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Acute kidney graft rejection
Lymphocytes surrounding an arteriole
Lymphocytes surrounding a renal tubule
T cells (CD3) surrounding a renal tubule
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Antibodies can also participate in chronic
rejection.
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Figure 12-20
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Figure 12-22
Histocompatibilty and graft survival
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Immunosuppression using corticosteroids
Natural compound
drug
metabolite
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Steroid receptors
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Activity of corticosteroids
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Cytotoxic drugs
Often used in cancer chemotherapy, they tend to
kill proliferating cells, including activated
lymphocytes.
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Effect of CsA on graft survival
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Cyclosporin A and FK506
Figure 12.27
Activation of the IL-2 gene and other genes leads
to clonal expansion of the T cell
No activation of transcription
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Figure 12-28
Effects of cyclosporin A
Cyclosporin A is the major drug used to overcome
graft rejection
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Tissue transplants
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Long term approaches to prolong graft survival

• Use of xenografts from genetically engineered
  animals (pigs). Many problems currently people
  are working on eliminating the blood group type
  hyperacute rejection barriers by modifying the
  glycosyl transferase activity. Advantage
  potentially unlimited availability of organs.
• Induction of antigen specific tolerance by
  suppressing costimulation.
• Introduction of graft-specific regulatory T
  cells.

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Previously activated, memory T cells can
stimulate unactivated APC using CD40L, leading to
the upregulation of B7 molecules. Such APC can
perpetuate T cell activation in graft rejection.
IL-12
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New techniques in the treatment of graft rejection
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An example of the experimental use of antibodies
to suppress graft rejection and to promote long
term graft tolerance.
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Concepts

• Choice of donor in transplantation is important
• ABO blood group matching prevents hyperacute
  rejection.
• MHC matching minimizes acute and chronic
  rejection.
• Several immunological barriers to transplantation
• Preexisting antibodies
• Passenger dendritic cells from graft
• Major and minor histocompatibility antigens
• Ultimately, immunosuppression is important to
  promote graft acceptance.
• Role of corticosteroids, cytotoxic compounds and
  inhibitors of calcineurin.
• There is much room for improvement in
  immunosuppressives, especially specificity and
  the ability to promote graft tolerance.

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