Immunopharmacology

Question 1

Describe the equilibrium of binding involving CD80/86 (B7) costimulation and inhibition

Answer 1

binding with CD28 (B7) provides costimulation for activation while binding with CTLA-4 has an inhibitory effect

Question 2

Describe where we can intervene in the inflammatory process to stop tissue rejection. (7)

Answer 2

gene transcription
cytotoxic agents to deplete T-cells
inhibit intracellular signaling (IL-2)
neutralize cytokines (with antibodies)
use antibodies to deplete T-cells
inhibit costimulation to cause anergy
inhibit lymphoctye adhesion molecules

Question 3

Name the 4 broad classes of immnosuppressive agents.

Answer 3

glucocoritcoids
signal transduction inhibitors (calcineurin and proliferation signal inhibitors)
purine synthesis inhibitors (cytotoxic agents)
immunosupppressive antibodies

Question 4

Prednisone (Sterapred, generic)

Answer 4

activated to prenisolone for its anti-inflammatory properties through COX-2 inhibition only; indirectly inhibits PLA-2 metabolism through increasing transcription of annexin; decreases mediators inflammation throughout COX inflammation pathway

Question 5

Cyclosporine (Sandimmune, Neoral)

Answer 5

fungal metabolite used in organ rejection prevention (also used as an anti-inflammatory)

mechanism: cycloporine bind to cyclophilin; the complex binds to calcinuerin to inhibit its activity (dephosphorylates NF-AT transcription factor that stimulates cytokine gene expression)

metabolism by 3A4 can lead to drug interactions

problems with nephrotoxicity, requires therapeutic monitoring as therapeutic window is very small

possible hypertension, hirsutism, gingival hyperplasia, tremor, ocular burning by ***hyperglycemia is fairly rare

Question 6

Tacrolimus

Answer 6

calcineurin inhibitor for organ transplant and derm concerns

mechanism: calcineurin complex binds to FK binding proteinm inhibiting the phosphatase activity of calcineurin and preventing dephospho rylation and translocation of NF-AT

50-100x more potent than cycloporin, 3A4 metabolism, concentrated in the pancreas and may inhibit pancreatic insulin secretion

nephrotoxicity, hyperglycemia considerable and requires therapeutic drug monitoring

Question 7

Sirolimus (Rapamune, Cypher)

Answer 7

used to prevent rejection after renal transplant, not recommended for liver or lung transplant; drug also used with placement of vessel stent to reduce acute phase cell proliferation and clotting

mechanism: drug and FK binding protein complex and bind to mTOR which down regulates cell growth and proliferation in Tcells

drug has long half life, risk of myelosupression, lipid disregulation, electrolyte imbalance and edema, still some nephrotoxicity (still monitor drug levels

Question 8

mTOR protein has control of which other proteins in T-cells that effect the translation of selected mRNAs needed for cell cycle progression?

Answer 8

p70 S6 kinase and PHAS-1

Question 9

Azathioprine

Answer 9

(first immusuppresent for transplantation) is metabolized to active form 6-mercatopurine, used in kidney transplant, with excessive immune function and as a an anti leukemia agent

mechanism: drug metabolites are incorporated into DNA and RNA and impair function as well as interfere with several de novo purine biosynthetic pathways (decreased ATP and GTP)

some genotype variation in metabolism, myelosuppression is possible, possibly sever leukopenia

do not treat with allopurinol, is class D

Question 10

Mycophenolate mofetil (CellCept)

Answer 10

given as a prodrug, is selective for lymphocytes

metabolism: is a reversible inhibitor of inosine monophosphate dehydrogenase, inhibits denovo pathway of guanosine biosynthesis (blunted T and B cell responses)

relatively high dose (1.5g) with numerous adverse reactions; caution with low GFR (mostly excreted through the urine) and a class D drug

Question 11

Muromonab-CD3

Answer 11

murine monoclonal antibody against CD3, used to block acute rejection of heart, liver, kidney and to deplete T cells for bone marrow donation

mechanism: does bind to Tcell receptor (initial activation and cytokine release) followed by blockade and apoptosis (T cell depletion occurs quickly ~minutes)

can trigger cytokine release syndrome (pretreatment with glucocort, acetamin,or diphenhydramine)

rare but possibly data anaphylaxis rxn; care with allergy to mouse proteins

Question 12

Basiliximab

Answer 12

non-depleting immunosuppressive agent; anti CD25 antibody; prevents activation by IL-2 in cells that have been activated

is a human/mouse chimera, given IV in two doses during the acute phase

adverse effects less severe and less frequent than muromonabCD3 although similar; long half life (7days)

Question 13

Adalimumab (Humira)

Answer 13

fully humanized monoclonal antibody, suppressive agains TNF-a used for rheumatoid arthritis, Chron’s, ankylosing spondyliis and psoriasis

mechanism: binds to TNF-a and prevents it interactions with p55 and p75 cell surface receptors resulting in reduced IL-1 and IL-6, less leukocyte migration, less activation of neutrophils and eosinophils, decrease fibroblast prolix, less prostaglandins, less matrix metalloproteinases

admin via subcutaneous injection every 2 weeks

has a very long half life (10-20 days) danger of TB infection, with mild hypertension, hyperlipidemia reactions

Question 14

What is belatacept?

Answer 14

a drug under development whose mechanism of action would be as an antibody against CD80/86 to prevent co-stimulation

Question 15

Cyclophosphamide
Everolimus
Infliximab

Answer 15

anticancer drug
mTOR inhibitor
mouse human chimera, anti TNF-a

Question 16

Explain the following drug suffices:

• mab
• u-
• xi-

Answer 16

(mab) monoclonal antibody
(u) humanized
(xi) chimera