Immunomodulators

Question 1

Glucocorticoids: MOA

Answer 1

Activates the glucocorticoid receptor
      transcription factor
Modifies expression of cytokine and 
      other immunoregulatory genes
Suppresses active immune responses

Question 2

Glucocorticoids: Indications

Answer 2

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of  Cytokine-release Syndrome
Treatment of a wide variety of autoimmune and inflammatory diseases

Question 3

Glucocorticoids: adv.

Answer 3

Many Adverse effects
Hyperglycemia
Hypertension
Hyperlipidemia
Obesity
Diabetes
Poor wound healing
Mania & Psychosis
Inc. Risk infections

Question 4

How to discontinue GC’s

Answer 4

Glucocorticoid dose must be gradually reduced to minimize adverse effects

Question 5

Azathioprine: MOA

Answer 5

Prodrug
Converted to 6-MP by HGPRT
Inhibits de novo purine synthesis
Incorporated into DNA & causes SSB
     base mispairing, leading to apoptosis
Inhibits CD28 co-stimulation

Question 6

Indications for azathioprine, mycophenolate

mofetil, and calcineurin inhibitors

Answer 6

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
      diseases

Question 7

Azathioprine: adverse effects

Answer 7

Leukopenia/thrombocytopenia
Hepatotoxicity
Inc. Risk infections and malignancy

Question 8

Notable interactions for azathioprine

Answer 8

Interacts with anti-gout drugs (Allopurinol &; Febuxostat), leading to Azathioprine toxicity, because inhibiting xanthine oxidase leads to increased levels of 6-mercaptopurine as well

Question 9

Mycophenolate Mofetil: MOA

Answer 9

Prodrug
Converted to mycophenolic acid
Inhibits inosine monophosphate
dehydrogenase II (IMPDH2
- selectively expressed in lymphocytes, leading to Inhibition of purine nucleotide synthesis
- no salvage pathway in lymphocytes

Question 10

Mycophenolate Mofetil: adv effects

Answer 10

Leukopenia/anemia
Teratogenic for both male and female
Inc. Risk infections, malignancy
***RARE- Risk of Progressive multifocal leukoencepalopathy (PML), a fatal viral disease caused by reactivation of JC virus

Question 11

Mycophenolate Mofetil: counterindications

Answer 11

Men and women who wish to become parents

Question 12

Calcineurin inhibitors: tacrolimus and cyclosporine, MOA

Answer 12

Cyclosporin and tacrolimus bind
cyclophilin and FKBP, respectively
to form inhibitory complexes
Cyclophilin/cyclosporin and
FKBP/tacrolimis complexes inhibit the
calcium-regulated phosphatase, calcineurin
Inhibition of calcineurin inhibits the activation
of the NFAT transcription factor, which is involved
in regulating the expression of IL-2 and multiple
other immunoregulatory genes
Potently inhibit the T cell immune response by
inhibiting Signal 1

Question 13

Calcineurin inhibitors: adverse effects

Answer 13

Nephrotoxicity****

Hypertension***

Question 14

Calcineurin inhibitors: Interactions

Answer 14

Metabolized by CYP3A4

3A4 inhibitors inc. risk of toxicity
3A4 inducers inc. risk of risk graft rejection

Question 15

mTor inhibitors: sirolimus, everolimus, MOA

Answer 15

Drugs form complex with FBKP
FKBP/drug complexs inhibits:
IL-2 mediated activation of mTor kinase
(T cell signal 2)
IL-2 stimulated protein synthesis,
Cell proliferation and survival

Question 16

mTor inhibitors: indication

Answer 16

Immunosuppression
To prevent graft rejection
           - NOT LUNG
           - NOT LIVER
To prevent GvHD
Included in arterial stents to inhibit re-stenosis

Question 17

mTor inhibitors: adv.

Answer 17

Hypertriglyceridemia
Hypercholesterolemia
Inc. Lung disease
Inc. Risk of diabetes
Anemia, thrombocytopenia, 
       & leukopenia
Dec. Wound healing
Teratogenic
Inc. Risk infections, malignancy

Question 18

mTor inhibitors: Contraindications

Answer 18

Contraindicated in Pregnancy
NOT RECOMMENDED
- Lung transplantation (risk anastomotic dehiscence)
- Liver transplantation (risk hepatic artery thrombosis)

Question 19

mTor inhibitors: Interactions

Answer 19

CYP 3A4!!!

Question 20

Ipilimumab MOA

Answer 20

Antibody specific for CTLA4
Antagonizes the negative regulatory CTLA4 protein
responsible for downregulating activated T cells
Enhances T cell responses

Question 21

Immune checkpoint inhibitors (Ipilimumab and Pembrolizumab/Nivolumab) adverse effects

Answer 21

Potential for RARE
Autoimmune response
(can be fatal)

Question 22

Immune checkpoint inhibitors (Ipilimumab and Pembrolizumab/Nivolumab) adverse effects

Answer 22

Potential for RARE Autoimmune response (can be fatal)

Ipili: Inflammation of Skin, GI tract, liver, nerves and adrenal glands

Pem/Niv: e.g. lung, liver, colon, kidney, skin, pituitary, thyroid & pancreas

Question 23

Pembrolizumab/Nivolumab MOA

Answer 23

Antibody specific for the PD1 protein, which is a negative regulatory receptor expressed on activated T cells that is responsible for downregulating T cell responses
The PD1 ligand PD-L1 is expressed on tumor cells, so they can avoid the immune response
Antibody drugs block PD1/PD1-L1 interactions, blocking the inhibitory signal and leading to enhanced tumor immune responses

Question 24

Counterindications for immune checkpoint inhibitors

Answer 24

PREGNANCY

Question 25

Which drugs treat relapsing/remitting MS?

Answer 25

Fingolimod Natalizumab IFN-beta Glatiramer Acetate

Question 26

Adverse effects of natalizumab

Answer 26

Increased risk of progressive multifocal leukoencephalopathy - especially if: - prior use of immunosuppression - seropositive for JC virus - chronic treatment

Question 27

Adverse effects of fingolimod

Answer 27

Bradyarrhythmia Atrioventricular block Chickenpox infection Malignancy

Question 28

Anti-thymocyte globuline, Alemtuzumab adverse effects

Answer 28

Cytokine release syndrome

Question 29

IVIG - MOA, indications

Answer 29

Pooled Ig from healthy individuals Provides patient with Ig from healthy immunized donors to provide immunity to common pathogens

Question 30

Rhogam - when is it given

Answer 30

Given to Rh- mother at 28 weeks & 72 hr post pregnancy to deplete any fetal RBC in maternal blood

Question 31

Glatiramer acetate - MOA

Answer 31

Promotes production of specific suppressor T cells that migrate to the brain and produce bystander suppression at sites of inflammation

Question 32

Indications of Induction agents (Rabbit Anti-thymoycyte Globulins (rTAG), Alemtuzumab, Basiliximab)

Answer 32

Lymphocyte depletion intra-operatively and 3-7 days post-op

Question 33

MOA of rTAG

Answer 33

Reacts with proteins expressed on lymphocyte surface- CD2, CD3, CD4, CD8, CD11a etc Actively depletes lymphocytes from the blood and lymphoid organs - Fc receptor-mediated/complement-dependent lysis and opsonization After injection recovery of immune system takes several months

Question 34

Best tolerated lymphocyte depletion induction therapy?

Answer 34

Well tolerated, although more rejection than with depleting agents

Question 35

Maintentance therapy?

Answer 35

Glucocorticoid + either cyclosporin or tacrolimus + an anti-proliferative drug - Sirolimus/everolimus are sometimes used in place of either cyclosporin/tacrolimus or the anti-proliferative drug