2: Lecture 5 Flashcards
Why need immunosuppression
To minimize impact of exaggerated or inappropriate immune responses like with autoimmune diseases (2x more in women than men), isoimmune diseases, and organ transplantation
Also with insertion of stents to prevent proliferation of cells around said stent
What is Rheumatoid arthritis
Autoimmune disease where body reacts against its own cartilage and joints
What is Rh hemolytic disease of newborns
When mother is Rh- but fetus is Rh+ (father is most likely Rh+), mother lacks Rh antigen so attacks fetus
First baby is ok but is second baby is also Rh+, mother’s body will recognize antigen and start an immune response against it lysing the fetus’ red blood cells
What is a drug-eluting coronary stent
Stent inserted with immunosuppressant agents (sirolimus) to prevent cells from accumulating/proliferating around them
Used in patients with blocked arteries
Targets for immunosuppressive drugs (low–>high selectivity)
Cell proliferation (glucocorticoid receptor agonists and cytotoxic drugs)
T cell function
Antibody approaches
Main action of glucocorticoid receptor agonists
ex. Prednisone, hydrocortisone, dexamethasone
Interact with glucocorticoid receptor to regulate gene expression (such as pro-inflammatory genes: IL-1, IL-2, IL-6)
Glucocorticoids can lead to increased transcription of anti-inflammatory genes
Overall decrease in immune cell signaling and proliferation (dampening entire immune response)
When to use Glucocorticoids
ex. prednisone, hydrocortisone, dexamethasone
For adrenal insufficiency, suppression of allergic, inflammatory, and autoimmune disorders, asthma, prevent acute transplant rejection, treat graft versus host disease
Main action of Cytotoxic drugs
ex. Cyclophosphamide, Azathioprine, Mycophenolate mofetil (MMF), methotrexate
Target cell proliferation (not very selective)
Mechanism of Cyclophosphamide (cytotoxic drug)
A DNA alkylating agent with 2 active chloroethyl groups that can crosslink DNA (hard to repair these crosslinks)
Kills fast proliferating cells more selectively
Mechanism of Azathioprine (cytotoxic drug)
Purine analog that metabolizes into 6-mercaptopurine that inhibits purine synthesis in immune cells (due to its sulfhydryl group)
Used as an anticancer drug an immunosuppressant
Mechanism of Mycophenolate mofetil (MMF) (cytotoxic drug)
More specific immunosuppressant
Inhibits conversion of inosine monophosphate to guanine monophosphate (IMP–>GMP) by inhibiting inosine monophosphate dehydrogenase that catalyzes conversion
Blocks de novo purine synthesis (that T and B cells depend on hence being more selective)
Mechanism of Methotrexate (cytotoxic drug)
Folic acid analog
Blocks dihydrofolate (DHF) reductase and thymidylate synthase
Starves cells of thymidine
What are 3 T cell targets
1) Calcineurin inhibitors
2) Sirolimus
3) Antibodies
Main action of Calcineurin inhibitors
ex. Tacrolimus, cyclosporine
Blocks T cell activation and calcineurin and reduces IL-2 transcription
Block synthesis of IL-2
Cyclosporine–>binds cyclophilin
Tacrolimus–> binds FKBP
Mechanism of Calcineurin Inhibitors
ex. Tacrolimus, cyclosporine
Binds to form complex that inhibits calcineurin (phosphatase)–>Calcineurin dephosphorylates NFAT (transcription factor) (no calcineurin= no dephosphorylation of NFAT)–>NFAT DOES NOT translocate to nucleus and binds to DNA–>decrease NFAT–>decreases transcription of IL-2
Happens in T cell
