Apr6 M2-Immunosuppression Flashcards
4 situations where IS agents can be used
- autoimmune disease
- isoimmune disease (Rh hemolytic disease of the newborn)
- organ transplant
- preventional of cell prolif (as with coronary stents)
2 common autoimmune disorders
RA and lupus
Rh hemolytic disease of the newborn (isoimmune disease) def
- mom Rh-, dad Rh+
- baby has Rh Ag
- mother recognizes Rh Ag of baby as foreign, makes an Ab against it
who’s affected by Rh hemolytic disease of the newborn (isoimmune disease)
- first child is OK
- second child, IF ALSO RH+, may have this hemolytic disease of the newborn, hemolyzing their cells
lowest to highest lvl of selectivity in terms of targets of IS
- target cell proliferation (discussed in chemo lec)
- target T cell function
- specific Abs to target specific things
different drugs in terms of diff levels of selectivity as IS targets
- target cell prolif = glucocorticoids like prednisone + cytotoxic drugs (azathioprine, mycophenolate mofetil, mtx)
- target T cell fct = calcineurin inhibitors (cyclosporine, tacrolimus, sirolimus)
- Antibodies
glucocorticoids action
- bind CS-R and CS-R binds coactivator proteins (ones present can be diff at diff times)
- CS-R + coactivator prots increase or decrease expression of certain genes
specific examples of gene transcription effects of glucocorticoids
prednisone will lead to
- inhibition of transcr of pro-inflam genes like IL-1 and IL-2
- increased transcr of anti-inflam genes
- net result = decrease in signaling and proliferation of immune cells, less comm between them*
effect of blocking IL-2 signaling with glucocorticoids
- blocking many places where it serves as communication
- blocking humoral and cellular response therefore
azathioprine (cytotoxic drug) effect
- converted to mercapopurine
- it blocks a step in the synthesis of purines (A and G)
- kills cells in the S phase (like mtx) + ALSO affects gene expression
mycophenolate mofetil (MMF) (cytotoxic drug) effect
- inhibits iosine monophosphate dehydrogenase
- it’s an enzyme needed in DE NOVO PURINE (A and G) SYNTHESIS
- *T and B cells depend on de novo purine synthesis more than other cells so MMF is more specific**
mtx effect
- folic acid analog
- binds dihydrofolate reductase to inhibit thymidine synthesis
- inhibits DNA synthesis at S phase
- mtx
mtx use in cancer vs immunosuppression
cancer = intermittent high dose tx
immunosuppression: more constant lower dose
T cell targeting drugs block what process exactly
- block T cell activation
- act on IL-2 signaling process, required after the APC-T cell interaction (with MHC2+peptide and TCR)
effect of cyclosporine and tacrolimus (T cell targeting drugs)
- cyclosporine binds cyclophilin in the T cell
- tacrolimus binds FKBP in the T cell
- these binding complexes inhibit calcineurin
what happens when cyclosporine and tacrolimus (T cell targeting drugs) inhibit calcineurin
- calcineurin important to activate nuclear factor (a TF) in activated T cells (NFAT), NFAT = a TF
- NFAT turns on IL-2 expression (for IL signaling)
- no more IL-2 signaling
what kind of protein calcineurin is exactly
- phosphatase. removes PO4 from NFAT, a TF
- NFAT enters the nucleus to turn on IL-2 synthesis
- calcineurin inhibited = don’t remove PO4 from NFAT. NFAT stays in cyto. doesn’t turn on IL-2 synthesis
sirolimus (rapamycin) effect (T targeting drug)
- binds FKBP like tacrolimus
- affects mTOR activity, which affects cell cycle progression
- cell is blocked at GI to S phase (at this transition step)
sirolimus exact effect
- binds FPBK like tacrolimus
- blocks mTOR
- inhibits cell cycle regulator cdk2. no more cell prolif
- ALSO this blocks the action of IL-2 R
- ALSO blocks prod and transcription of IL-2 like tacro and cyclosporine
- *so sirolimus acts on both IL-2 AND IL-2 R
non specific Ab used in initial response to a graft (to avoid rejection) and how it works
- anti-thymocyte globulin (ATG) or anti-lymphocyte Ab
- polyclonal Ab that DEPLETES PERIPHERAL LYMPHOCYTES that interact with initial graft rejection
Ab used to reverse an ACUTE graft rejection (not prevent it like ATG)
- muromonab (OKT3)
- anti-CD3. causes internalization of TCR and kills cytotoxic T cells
Ab used in combination with calcineurin to avoid an acute organ rejection (like ATG)
-daclizumab (anti-IL2 R’s CD25 portion. CD25 is the alpha chain of IL-2)
(IMPORTANT) summary of the IL-2 targeting drugs discussed
- glucorticoids (prednisone): decrease IL-2 (and IL-1) expression
- calcineurin inhibitors
- cyclosporin (binds cyclophilin) and tacrolimus (binds FKBP) inhibit IL-2 synthesis
- sirolimus (rapamycin) (binds FKBP) inhibits IL-2 synthesis AND blocks the IL-2 R action - daclizumab (anti-CD25, so anti-IL-2R bc CD25 is alpha chain of IL-2R). blocks IL-2 signaling
Abs used for Crohn’s disease and rheumatoid arthritis
infliximab (anti-TNFa)
-blocks TNF (or TNF-R). TNF has a role in mediating the inflam response
