LEC 15 Immunopharmacology

Question 1

What do glucocorticoids do?

Answer 1

• mimic natural corticosteroids
• decrease cytokine production
• inhibit T cell proliferation
• decrease inflammation
• decrease ability of WBC (neutrophils) to migrate into tissue

Question 2

What are some examples of glucocorticoids?

Answer 2

• prednisone
• cortisol
• cortisone
• dexamethasone

Question 3

What are the negative side effects of prolonged glucocorticoid use?

Answer 3

• Cushings Syndrome (buffalo hump, metabolic syndrome, muscle wasting, bone loss, central obesity, and round “moon” facies)
• psychosis
• adrenal insufficency
• increased risk of infxn
• high blood sugar
• increased risk of DM
• osteoporosis

Question 4

What do cytostatic agents do?

Answer 4

target T cell growth and proliferation

Question 5

What are some examples of cytostatic agents?

Answer 5

• methotrexate
• cyclophosphamide
• azathioprine
• mycophenolate

Question 6

How does methotrexate work?

Answer 6

• folic acid analog
• inhibits dihydrofolate reductase which is crucial for nucleic acid production
• thus, it reduces DNA synthesis
• Indicated for RA, psoriasis, IBD, multiple cancers, and ectopic pregnancies

Question 7

How does cyclophosphamide work?

Answer 7

• cross-links DNA, suppressing DNA replication
• Indicated for pts w neoplasms, including solid tumors, leukemias, and lymphomas

Question 8

How does azathioprine work?

Answer 8

• pro-drug of 6-mercaptopurine (6-MP)
• mimics nucleotides and therfore blocks purine nucleotide synthesis and inhibits lymphocyte proliferation
• Indicated for RA, Crohn, glomerulonephritis

Question 9

How does mycophenolate work?

Answer 9

• reversibly inhibits IMP dehydrogenase which is involved in purine synthesis
• purine synthesis and thus DNA replication reduced in B and T cells
• used in organ transplants (prevention of allograft rejection) and autoimmune diseases

Question 10

What are the two calcineurin inhibitor drugs?

Answer 10

• Tacrolimus
• Cyclosporine

Question 11

What does calcineurin do?

Answer 11

• activates T-cell transcription factors that upregulate interleukin 2 (IL-2) production, specifically nuclear factor of activated T cells (NFAT)
• Without calcineurin, IL-2 levels decrease and subsequently T-cell proliferation slows

Question 12

How does Tacrolimus work?

Answer 12

• binds FK506 binding protein (FKBP)
• inhibits calcineurin and thus decreased IL-2 production and decreased T cell proliferation
• used to prevent transplant rejection
• atopic dermatitis

Question 13

How does cyclosporine work?

Answer 13

• binds cyclophilin
• inhibits calcineurin, decreased IL-2 production and decreased T cell proliferation
• used to prevent tranplant rejection
• used in severe, active RA that’s not responsive to methotrexate
• severe psoriasis

Question 14

How does Sirolimus (rapamycin) work?

Answer 14

• Binds FKBP and inhibits the mammalian target of rapamycin (mTOR)- a kinase that plays a role in regulating cellular processes
• blocks T-cell activation and B-cell differentiation by preventing a response to IL-2 (instead of preventing the production of IL-2)
• also used to prevent transplant rejection

Question 15

What are the negative side effects of calcineurin inhibitors?

Answer 15

• Highly nephrotoxic
• creatinine levels must be monitored
• Sirolimus is less nephrotoxic and may be preferred for pts w existing kidney disease

Question 16

What are the toxicities associated with Methotrexate?

Answer 16

• bone marrow suppression
• adverse effects on the skin and GI mucosa
• nephrotoxicity
• hepatotoxicity

Question 17

What are the toxicities associated with mycophenolate?

Answer 17

• Can cause birth defects
• Increased risk of infections and malignancy
• GI disturbances, pancytopenia
• High blood sugar, high cholesterol

Question 18

What toxicities are associated with azathioprine?

Answer 18

• bone marrow depression
• anemia

Question 19

How does Infliximab (Remicade) work?

Answer 19

• anti–TNF-α MAb that bind to and directly inhibit the cytokine from binding to its receptor
• Blocks induction of proinflammatory cytokines, decreases leukocyte migration, and reduces activation of neutrophils and eosinophil
• Therapeutic uses - Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis

Question 20

What toxicities are associated with Infliximab?

Answer 20

predisposition to serious infections

Question 21

How does Etanercept work?

Answer 21

• Fusion protein of TNF receptor to the Fc part of IgG1 – acts as a decoy receptor for TNFa
• FDA-approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis
• Black box warning for serious infections

Question 22

How does Tocilizumab work?

Answer 22

• MAb to human IL-6R, thereby blocking IL-6-associated inflammation
• treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome
• Also used for treatment of severe COVID-19 Acute Respiratory Distress Syndrome (ARDS)
• Adverse effects include URTI, nasopharyngitis, headache, high blood pressure

Question 23

How does Belatacept work?

Answer 23

• Fusion protein of Fc fragment of IgG1 and extracellular domain of CTLA-4
• Blocks T cell costimulation
• Alternative treatment to limit toxicity associated with calcineurin inhibitors (cyclosporine and tacrolimus)

Question 24

How do Basiliximab & Daclizumab work?

Answer 24

• Block CD25 (IL-2R)
• Basiliximab was FDA approved in 1998
• Daclizumab was discontinued for transplant patients, but was approved for treatment of relapsing multiple sclerosis in 2016