Flashcards in Immunomodulators Deck (52)
What are the 7 classes of immunosuppressant drugs?
2) proliferation inhibitors and anti-metabolites
3) immunophilin-binding drugs (inhibitors of T cell signaling pathways)
4) antibodies for induction immunosuppression
5) misc drugs to treat relapsing remitting MS
6) passive immunization Ig
7) immune checkpoint inhibitors
Define hyperacute rejection
cause by pre-existing reactive antibodies
occurs within minutes of transplant
Define acute rejection
6-12 months post transplant
T cell mediated
Define chronic rejection
months to years
due to fibrosis causing damage to graft blood vessels
What type of rejection is targeted by immunosuppressants?
What are the two things that need to be matched prior to transplant?
1) ABO blood type compatible
2) HLA matched
What are the 4 principles of transplantation?
1) appropriate patient and donor prep and selection
2) multi-tiered approach to immunosuppression
3) potential initial immunosuppression (decreases potential toxicity of immunosuppressants)
4) drugs should be reduced or withdrawn if toxicity exceeds benefits
What is the MOA of steroids?
glucocorticoids bind to receptors in the cytoplasm and translocate to the nucleus to bind to target genes and influence their expression (INHIBIT critical immunoregulatory genes to inhibit immune response)
When are steroids indicated?
- standard immunosuppressive therapy to prevent organ graft rejection (along with others)
- high dose IV to combat acute rejection episodes and treatment of cytokine release syndrome
- treats autoimmune diseases (RA, lupus, MS, IBD, asthma, psoriasis)
What are the side effects of steroids?
hyperglycemia, hyperlipidemia, obesity
poor wound healing
mania and psychosis
Why do steroids need to be tapered?
to avoid adrenal crisis (need to teach the adrenals how to make steroids again)
What percentage of transplant patients stay on steroids after 1 year post transplant?
What are the 2 proliferation inhibitors and anti-metabolites?
What does azathioprine do?
inhibit lymphocyte proliferation
What activates azathioprine?
glutathione (converts it from prodrug to 6-mercaptopurine)
What 3 things can azathioprine affect?
1) inhibits de novo purine biosynth
2) leads to apoptosis
3) inhibits T cell and CD28/Rac1 costimulation
What are 2 indications for azathioprine?
1) prophylactic prevention of graft rejection post organ transplant
2) autoimmune diseases (RA, Crohn's, MS)
What are the adverse effects of azathioprine
diarrhea, leukopenia, hepatotox
What are the important drug interactions for azathioprine?
allopurinol and febuxostat (xanthine oxidase inhibitors used to treat gout)
due to increased levels of 6-MP
What is the MOA of mycophenolate mofetil (MMF)?
reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II which is used to make purine nucleotides
IMPDH is selectively expressed in lymphocytes so MMF selectively blocks lymphocyte prolif
What are the indications of MMF?
on label: prevent graft rejection
off label: autoimmune disorders
What is a potentially very dangerous adverse effect of MMF?
progressive multifocal leukoencephalopathy (caused by reactivation of JC virus)
What are the contraindications of MMF?
pregnancy or fertile patients
In addition to MMF and azathioprine, what are 3 other anti proliferative drugs for immunosuppression?
1) methotrexate (treat RA)
2) cyclophosphamide (treat most severe diseases)
What are the immunophilin binding drugs/inhibitors of T cell signaling pathways?
calcineurin inhibitors (cyclosporin and tacrolimus)
mTOR inhibitors (sirolimus and everolimus)
What are 3 indications of calcineurin inhibitors?
1) prevent solid organ rejection (heart, kidney, liver, lungs)
2) prevent graft vs host in bone marrow transplant
3) treat autoimmune disease (severe psoriasis, severe RA, SLE, IBD, nephrotic syndrome)
What is the MOA of immunophilins? cyclosporin binds to _________ while tacrolimus binds to _________
What are cyclophilin and FKBP?
peptidyleprolyl isomerases but the biologic activity of these drugs is independent of that activity
instead the drug enzyme complex binds and inhibits calcineurin
What does calcineurin do?
helps activate NFAT which is a TF responsible for expression of many genes including T cell growth factor IL2