Immunosuppressant Therapy Flashcards
Induction therapy
Given at time of transplant. Very Potent, prolonged use is toxic. May include donor specific transfusion or irradiation as drug alternatives.
Maintenance Therapy
Lower potency, tolerable in chronic doses
Rescue Therapy
Intense, applied inresponse to rejection episode. Chronically intolerable
Describe typical Maintenance Therapy
Involves three drugs that work at different levels of the inflammatory cascade:
Calcineurin Inhibitor, anti-proliferative, steroid
What does anti-cd3 therapy accomplish?
Blocks T-Cell activation
What does Calcineurin usually do?
Controls nuclear access of NFAT (Nuclear factor of activated transcription)
What do you gain by inhibiting Calcineurin?
NFAT can’t access the nucleus and mediate IL-2 transcription
What cell surface receptor does IL-2 normally interact with?
CD-25
Guess what you can use to keep adjacent T-cells from becoming activated by IL-2
Monoclonal abs for CD-25
What does inhibition of mTOR accomplish
Prevents IL-2 from having an effect on cells. It can bind but nothing happens
What do drugs that block cell cycle accomplish
Prevent proliferation of T cells.
Anti-CD52 drugs?
CD-52 expressed on surfact of mature lymphocytes. Binding of a mab to these identifies the cell for lysis.
How do you target an individual T Cell for lysis
Polyclonal IgG against human T-cells derived from horses (Atgam) or rabbitts (thymoglobulin). Targets cells for complement opsonization and lysis.
What are the major risks associated with immunosuppressants?
- ) Patients are immuno depressed and should receive prophylactic therapy against opportunistic infections
- ) Secondary malignancy or Lymphoproliferative disorder
- ) Cytokine release syndrome
What are the major calcineurin inhibitors?
Cyclosporin and tacrolimus (tacrolimus is much more powerful).
What is the major tocxicity associated with calcineurin inhibitors?
Renal (which blows because they are used with kidney transplants. It is often difficult to tell transplant rejection apart from CNI toxicity.
Some other CNI toxicities:
Cardiovascular, Neurological, gengival hyperplasia, hypertrychosis (no idea what that is, secondary malignancy
How do corticosteroids work?
Bind to GR and GR can inhibit inflammatory gene transrption directly by binding to HAT or can recruit HDAC2 and cause it to deacetylate genes leading to suppression of active inflammatory genes
Toxicities of corticosteroids?
Neutrophilia, eosinopenia, monocytopenia, poor healing (protein metabolism), cushings syndrome, depression etc…
Name an mTor inhibitor
Sirolimus
What does Sirolimus do?
Inhibits 2nd phase of T cell activation. Prevents B cell differentiation into plasma cells.
What are the major toxicities of Sirolimes
Fatal hepatic necrosis, Can affect cells outside the immune system as well
Name the Cell Cycle disruptors
Mycofenolate Mofetil, Axathioprine, Cyclophoshamide, Methotrexate.
Most common sideeffects of mycofenolate mofetil?
GI stuff
Most common sideeffects of Azathioprine?
Birth defect risk
Cyclophosphamide
Pro drug
Methotrexate does what?
Inhibits S phase of cell cycle
What tissues are most sensitive to Methotrexate?
Those that are dividing at a high rate
