Immunosuppressive Drugs

Question 1

describe induction therapy of transplantation therapy

Answer 1

2 groups of antibodies are used:
1. depleting agents - destruction of active lymphocytes
2. immune modulators - suppression

intensify initial immunosuppressive therapy in high risk patients (repeat transplant, African-Americans, pediatric)

want to delay the use of nephrotoxic calcineurin inhibitors

Question 2

during induction therapy of transplantation…
1. antihymocyte globulin and Muromonab (CD3 mAb) are used as ______
2. Daclizumab (anti-IL-2R) and Muromonab (CD3 mAb) are used as _____

Answer 2

1. antihymocyte globulin and Muromonab (CD3 mAb) are used as DEPLETING AGENTS
2. Daclizumab (anti-IL-2R) and Muromonab (CD3 mAb) are used as IMMUNE MODULATORS

Question 3

how is Daclizumab used in transplantion

Answer 3

Daclizumab: anti-IL-2R, used as immune modulator during induction therapy

humanized anti-CD25 mAb (CD25 is on IL-2R on activated T cells)

used against acute rejection in renal recipients by competitive antagonism of IL-2 induced T cell proliferation

Question 4

describe maintenance therapy of transplantation

Answer 4

use multiple drugs to achieve synergic effects and minimize toxicities - drugs should have distinct mechanisms

typical combination includes calcineurin inhibitor (nephrotoxic), glucocorticoids, mycophenolate mofetil (cytotoxic) —> needs careful modification and surveillance of toxicity

Question 5

what are 5 types of immunosuppressive drugs?

Answer 5

1. calcineurin inhibitors: cyclosporine, tacrolimus (FK506)
2. cytotoxic drugs: azathioprine, mycophenolate mofetil
3. glucocorticoids
4. mTOR inhibitors: sirolimus (Rapamycin), everolimus
5. antibodies: antihymocyte globulin, muromonab-CD3, daclizumab

Question 6

what are two kinds of calcineurin inhibitors and what is their use?

Answer 6

1. cyclosporine - produced by a fungus
2. tacrolimus (FK506) - produced by bacterium (new drug, more potent)

used for prevention and treatment of transplant rejection, typically used at maintenance dose (because of nephrotoxicity)

useful for autoimmune disorders (psoriasis, RA)

Question 7

Cyclosporine and tacrolimus (FK506) are calcineurin inhibitors used in transplant immunosuppressive therapy. What does calcineurin do?

Answer 7

1. MHC:Antigen-TCR engagement
2. calcium influx
3. calcineurin activated by calmodulin
4. calcineurin dephosphorylates NFAT
5. NFAT migrates into nucleus, binds promoter for IL-2

IL-2 expression triggers immune response

so by blocking calcineurin, cyclosporine and tacrolimus block downstream IL-2 expression and immune response

Question 8

what is the major toxicity of calcineurin inhibitors?

what drug should not be administered at the same time, as it enhances this type of toxicity?

Answer 8

renal toxicity (most patients experience this)
sirolimus reduces metabolism by p450 - this drug should be administered at a separate time (enhances renal toxicity)

others: HTN, diabetes (esp. when used with glucocorticoids), tremor, hirsutism

increased risk of malignancy and infections (common for immunosuppressed patients)

Question 9

What are 2 kinds of mTOR inhibitors used in transplant immunosuppressive therapy? What is their mechanism of action?

Answer 9

1. sirolimus - bacterially produced
2. everolimus - derivative of sirolimus

mTOR is important for IL-2 receptor mediated growth signaling to stimulate proliferation of immune cells

so sirolimus and everolimus block downstream immune cell proliferation

Question 10

what are the toxicities and drug interactions of mTOR inhibitors used in transplant immunosuppression?

Answer 10

mTOR inhibitors: sirolimus, everolimus

toxicities: increase serum cholesterol/triglycerides, possible anemia/ leukopenia/infections

drug interactions: be careful with co-administration of drugs that affect activity of CYP34A and P-glycoprotein

mTOR inhibitors enhance renal toxicity of calcineurin inhibitors - concurrent use should be avoided

Question 11

azathioprine

Answer 11

cytotoxic drug used in transplant immunosuppression

azathioprine is prodrug - intermediate form inhibits de novo purine biosynthesis, final product is incorporated into DNA and prevents replication

azathioprine therefore suppresses immune cell proliferation

Question 12

provide the clinical uses, side effects, and drug-drug interactions of azathioprine

Answer 12

clinical use: cytotoxic drug for transplant immunosuppression - used as adjunct for preventing kidney rejection, treatment of severe RA (and other autoimmune)

side effects: bone marrow suppression, increased risk of neoplasia/ infections

drug-drug interactions: mainly metabolized by xanthine oxidase, interacts with allopurinol

Question 13

mycophenolate mofetil

Answer 13

cytotoxic drug used in transplant immunosuppression

inhibits inosine monophosphate dehydrogenase - enzyme needed for de novo purine synthesis

remember that B/T cells lack purine salvage pathway - so mycophenolate selectively suppresses lymphocyte proliferation

Question 14

how are anti-lymphocyte/thymocyte antibodies obtained and what are they used for?

Answer 14

obtained by injection of human thymic lymphocyte into animal

act on circulation lymphocytes, also deplete thymus-dependent lymphocytes (if administered continuously)

used for induction therapy in transplantation

Question 15

muromonab-CD3

Answer 15

murine mAb raised against CD3 subunit of TCR —> causes destruction of T cells

uses: prevent acute rejection (heart, liver, kidney), depleting T-cells from donor bone marrow prior to transplant

adverse effects: cytokine release syndrome, acute hypersensitivity, infections

Question 16

how can cytokine release syndrome be avoided when administering muromonab-CD3 (causes destruction of T cells) during transplant immunosuppression?

Answer 16

cytokine release syndrome - engagement of TCR causes release of cytokines like TNFa

glucocorticoids should be administered before injection of muromonab-CD3

Question 17

natural and synthetic steroid hormones

Answer 17

glucocorticoids

GLUCOse + CORTex + sterOID

*synthetic are made to be more potent

Question 18

dexamethasone is an example of

Answer 18

glucocorticoid

(as well as cortisol/hydrocortisone)

Question 19

what is the mechanism of action of glucocorticoids, their therapeutic uses, and adverse effects?

Answer 19

mechanism: inhibit expression of cytokines (IL-1, IL-2, IL-6, IFN, TNFa), inhibit T-cell proliferation (and therefore T-cell dependent immunity)

uses: prevent organ transplant rejection, autoimmunity (RA, SLE, psoriasis), allergic reactions (asthma), leukemia/other hematopoietic malignancies, shock, adrenocortical dysfunction

adverse effects: growth retardation, osteoporosis, infections, skin ulcers, obesity, hyperglycemia, HTN, cachexia (muscle wasting)