Immunosuppression Flashcards
What are the 6 ways we can suppress the immune response?
- Steroids
- Anti-proliferative agents
- Plasmapheresis
- Inhibit cell signalling
- Agents directed at cell surface Ag
- Agents directed at cytokines
What is the MoA of steroids?
Inhibit phospholipase A2
Phospholipase A2 converts phospholipids to arachidonic acid
Arachidonic acid is converted to inflammatory prostaglandins by COX
What effect do steroids have on phagocytes + lymphocytes?
- Phagocytes - increased number as suppressed adhesion molecule expression but don’t phagocytose
- Lymphocytes - reduced numbers (CD4 > CD8 > B) as pass into tissues but don’t function
What are the side effects of steroids?
Cushing’s syndrome, osteoporosis, adrenal suppression, avascular necrosis (therefore steroid-sparing agents favoured…)
What are the 3 main anti-proliferative agents?
Cyclophosphamide
Azathioprine
Mycophenylate Mofetil
Which cells do the anti-proliferative agents predominantly act upon?
Cyclophosphamide B > T
Azathioprine + Mycophenylate Mofetil T > B (more straight lines)
What is the main action of the anti-proliferative agents?
Inhibit DNA synthesis to stop replication of adaptive immune cells (T + B cells) by altering structure of DNA monomers. Unfortunately they also suppress replication of any rapidly replicating cell (e.g. in BM)
What are the side effects of anti-proliferative agents?
Suppressed replication of any rapidly dividing cells = BM suppression, teratogenic, infection, malignancy
Alkylates guanine
Used in multi-system CT disease with end-organ damage, cancer
Side effects: hair loss, male sterility, haemorrhagic cystitis (metabolite accumulates in urine) + bladder cancer, P jiroveci infections, gum hyperplasia
B>T
Cyclophosphamide
Indications for immunosuppression
Inflammatory diseases, e.g. CT disease, IBD
Leukaemia
Transplants
Metabolised to 6-mercaptopurine (purine analogue)
Used in transplants, IBD
BM suppression big worry - if TPMT polymorphism can’t inactivate so need to check if patient has it)
Azathioprine
Blocks guanine synthesis
Alternative to azathoprine in transplant, cyclo in CT disease
Herpes reactivation > Progressive multifocal encephalopathy (JC virus infection)
Mycophenylate Mofetil
What is plasmapheresis?
Blood passed through cell separator and Ig removed
Rest of blood replaced
What is the indication for plasmapheresis?
Really severe Ab mediated disease - mostly type III like Goodpasture’s, MG, vascular rejection
What is a risk with plasmapheresis?
Rebound Ab production
What is the MoA of cell signalling inhibitors?
Prevent cytokine PRODUCTION
Name three main types of cell signalling inhibitor
Calcineurin inhibitors (tacrolimus, cyclosporin) JAK2 inhibitors (e.g. Tofacitinib) PDE4 inhibitors (e.g. Apremilast)
How do cell signalling inhibitors vary in terms of specificity?
Calcineurin inhibitors are specific - inhibits T cell production of IL2 (requires calcineurin)
JAK2 / PDE4 are general cytokine production pathways
Inhibit T cell IL2 production
Calcineurin inhibitors e.g. tacrolimus, cyclosporin
Nephrotoxic
JAK2 inhibitor
Tofacatinib
Used in RA
PDE4 inhibitor
Apremilast
Used in psoriasis and psoriatic arthritis
What are the biologic agents?
These are agents that act on specific proteins - cytokines + antigens ~ BIND + PREVENT FUNCTION
What are the side effects of biologic agents?
Infusion reaction at site of delivery / previous site of delivery
General urticaria, wheeze, headaches after infusion
Anti-any T cell antigen
Anti-thymocyte globulin (ATG)
T cells, Allograft rejection, Daily IV
