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Transplant rejection
Lecture 6
14
Pharmacology
Professional
10/28/2012

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Term
What are the different types of transplants?
Definition
- Orthotopic - in a normal location
- Heterotopic - Different location
- Autologous - graft comes from yourself
- Syngeneic - graft comes from a genetically identical individual
- Allogeneic - Different individuals of the same species
- Xenogeneic - Different species
**Last 2 need rejection drugs.
Term
Where does antigen recognition and T cell differentiation take place?
Definition
The lymph nodes
Term
What is the function of B cells in humoral immunity
Definition
Recognition of an antigen and secretion of antibodies
Antibodies then label for opsonization, activate complement, or attract NK cells.
Term
What are the 3 signals for T cell activation?
Definition
1) Antigen + MHC - CD4 binds to MHC, CD3 is a drug target
2) Adhesion molecules - B7 + CD28. CTLA4 will block. LFA1/ICAM are also for adhesion
3) Release of IL-2
Term
What pathways for T cell activation have drug targets?
Definition
- IP3/Calcineurin pathway - NF-AT
- NFkB signalling pathway
**Both lead to formation of IL-2
Term
What reactions are involved in rejection?
Definition
- Hyperacute
- Humoral - antibodies
- Acute cellular
- Chronic
Term
How do glucocorticoids help prevent rejection of transplants?
Definition
Inhibition of the NFkB pathway by either upregulating the IkB inhibitor or preventing transcription directly on the DNA
Term
What drugs are immunophilin-binding agents and how do they work?
Definition
- Tacrolimus/Prograf - inhibits Calcineurin
- Sirolimus/Rapamune - inhibits mTOR --> in IL-2 step. IL-2 cannot stimulate mTOR, a necessary step.
- Cyclosporin/Sandimmune or Neoral - also inhibits calcineurin --> NF-AT
Term
What drugs are purine antagonists and how do they work for transplant rejection?
Definition
- Azathioprine/Imuran
- Mycophenolate/Cellcept
Inhibit the synthesis of purines and thus DNA and RNA
Term
What polyclonal antibodies are used for transplant rejection, and how do they work?a
Definition
- ATGAM - LFA1, CD3, CD4, CD2
- Thymglobulin - IL2-R, CD44, MHC, CD2, CD45
**Bind to MULTIPLE surface antigens, depleting lymphocytes and blocking replications. TCR NOT INVOLVED!
Term
What monoclonal antibodies are used for transplant rejection, and how do they work?a
Definition
- OKT3/Orthoclone - binds to CD3 during first step. T cells redistributed to bone marrow
- Daclizumab/Zenapax - binds to IL-2 receptors. Humanized
- Basiliximab/Simulect - binds to IL-2 receptors. Chimeric. Binds only to ALPHA subunit of ACTIVATED t-cells
Term
How does Alemtuzumab/Campath work for transplant rejection?
Definition
Binds to CD52 on B cells, Tcells neutralize B cells.
Term
What drug for transplantation has affinity for B7?
Definition
-Belatacept/Nulojix
Soluble CTLA4 binds to B7, preventing 2nd signal
Term
How does Bortezomid/Velcade work for transplant rejection?
Definition
NOT an antibody!!
Proteosome inhibitor - buildup of proteins induces apoptosis. Degrades ubiquinated proteins, preventing protein destruction
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