Immunosuppression for Transplantation Flashcards
What is induction therapy?
It is use of the biologic drugs within the first 2-3 months after transplantation to prevent rejection because they are very strong
What are some clinical uses for glucocorticoids?
GVHD in BM transplant, rheumatoid d/o’s, SLE, skin conditions, asthma/atopy, acute exacerbations of MS, limit allergic rxns to Ab-related immunosuppression, and *blocks first-dose cytokine storm 2/2 Muromonab-CD3 use in transplant pts
Describe the mechanism of action of glucocorticoids.
They act in the nuclei of T and B cells, binding to form the glucocorticoid-GR complex that then binds the GRE in the promoter region of inflammatory genes resulting in transcriptional repression (e.g. TNFa, IL-1, IL-2, IL-4, IL-6). They also upregulate lipocortin (suppresses arachidonic acid formation) and downregulate COX-2 – both ultimately reduce prostaglandin synthesis.
When combine with which drugs do glucocorticoids become especially diabetogenic?
Calcineurin inhibitors
When does organ rejection typically occur?
Within the first 2-3 months
Name the calcineurin inhibitors and their basic function.
Cyclosporine and Tacrolimus. They are IL-2 production inhibitors
Name the mTOR inhibitors and their basic function.
Sirolimus and Everolimus. They prevent T-cell activation and proliferation by inhibiting protein synthesis.
What does calcineurin signaling do?
It is necessary for expansion and differentiation of activated T-cells. It activates NFAT for induction of IL-2, which is responsible for expansion, activation, differentation, and maturation of T-cells.
Should you take calcineurin inhibitors with food?
No, it will delay and decrease absorption of the drug when taken with food
Describe the mechanism of action of azathioprine.
It is converted to 6-MP (purine analog) then converted to Thio-dGTP by de novo purine synthesis, then incorporated into DNA of replicating immune cells where it suppresses T and B cell proliferation
What is the primary adverse reaction associated with azathioprine?
Myelosuppression.
*Can be life-threatening when combined w/ allopurinol so decrease the azathioprine dose when using these drugs together
With what drug class should you avoid using azathioprine?
ACEIs. They potentiate azathioprine causing severe myelosuppression (ACEIs suppress EPO)
With what drug does the FDA recommend genotyping, and why?
With azathioprine. Because it is metabolized by TPMT and you need to decrease the dosage if they have an inactive TPMT allele
Describe the mechanism of action of mycophenolate mofetil.
It is a prodrug hydrolyzed to mycophenolate (IMP dehydrogenase inhibitor) in B- and T-cells, decreasing purine biosynthesis. IMPDH is key enzyme in guanine synthesis which is necessary for proliferation.
Mycophenolate mofetil preferentially inhibits what, and why do we care?
The type II isoform of IMP dehydrogenase (IMPDH) which is primarily expressed in lymphocytes. Specificity is believed to be why it’s less toxic than glucocorticoids, methotrexate, and azathioprine
