Immunopharmacology Flashcards
Describe the equilibrium of binding involving CD80/86 (B7) costimulation and inhibition
binding with CD28 (B7) provides costimulation for activation while binding with CTLA-4 has an inhibitory effect
Describe where we can intervene in the inflammatory process to stop tissue rejection. (7)
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
Name the 4 broad classes of immnosuppressive agents.
glucocoritcoids
signal transduction inhibitors (calcineurin and proliferation signal inhibitors)
purine synthesis inhibitors (cytotoxic agents)
immunosupppressive antibodies
Prednisone (Sterapred, generic)
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
Cyclosporine (Sandimmune, Neoral)
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
Tacrolimus
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
Sirolimus (Rapamune, Cypher)
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
mTOR protein has control of which other proteins in T-cells that effect the translation of selected mRNAs needed for cell cycle progression?
p70 S6 kinase and PHAS-1
Azathioprine
(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
Mycophenolate mofetil (CellCept)
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
Muromonab-CD3
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
Basiliximab
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)
Adalimumab (Humira)
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
What is belatacept?
a drug under development whose mechanism of action would be as an antibody against CD80/86 to prevent co-stimulation
Cyclophosphamide
Everolimus
Infliximab
anticancer drug
mTOR inhibitor
mouse human chimera, anti TNF-a