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Flashcards in Immunomodulators Deck (52)
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1

What are the 7 classes of immunosuppressant drugs?

1) glucocorticoids/steroids
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

2

Define hyperacute rejection

cause by pre-existing reactive antibodies
occurs within minutes of transplant

3

Define acute rejection

6-12 months post transplant
T cell mediated

4

Define chronic rejection

months to years
due to fibrosis causing damage to graft blood vessels

5

What type of rejection is targeted by immunosuppressants?

acute

6

What are the two things that need to be matched prior to transplant?

1) ABO blood type compatible
2) HLA matched

7

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4) drugs should be reduced or withdrawn if toxicity exceeds benefits

8

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)

9

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)

10

What are the side effects of steroids?

hyperglycemia, hyperlipidemia, obesity
developing diabetes
osteopenia
cataracts
poor wound healing
mania and psychosis

11

Why do steroids need to be tapered?

to avoid adrenal crisis (need to teach the adrenals how to make steroids again)

12

What percentage of transplant patients stay on steroids after 1 year post transplant?

80%

13

What are the 2 proliferation inhibitors and anti-metabolites?

azathioprine
mycophenolate mofetil

14

What does azathioprine do?

inhibit lymphocyte proliferation

15

What activates azathioprine?

glutathione (converts it from prodrug to 6-mercaptopurine)

16

What 3 things can azathioprine affect?

1) inhibits de novo purine biosynth
2) leads to apoptosis
3) inhibits T cell and CD28/Rac1 costimulation

17

What are 2 indications for azathioprine?

1) prophylactic prevention of graft rejection post organ transplant
2) autoimmune diseases (RA, Crohn's, MS)

18

What are the adverse effects of azathioprine

diarrhea, leukopenia, hepatotox

19

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

20

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

21

What are the indications of MMF?

on label: prevent graft rejection
off label: autoimmune disorders

22

What is a potentially very dangerous adverse effect of MMF?

progressive multifocal leukoencephalopathy (caused by reactivation of JC virus)

23

What are the contraindications of MMF?

pregnancy or fertile patients

24

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)
3) chlorambucil

25

What are the immunophilin binding drugs/inhibitors of T cell signaling pathways?

calcineurin inhibitors (cyclosporin and tacrolimus)

mTOR inhibitors (sirolimus and everolimus)

26

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)

27

What is the MOA of immunophilins? cyclosporin binds to _________ while tacrolimus binds to _________

cyclophilin
FKBP

28

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

29

What does calcineurin do?

helps activate NFAT which is a TF responsible for expression of many genes including T cell growth factor IL2

30

Cyclosporine inhibits or activates NFAT?

INHIBITS