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Bloc F - Defense > Apr6 M2-Immunosuppression > Flashcards

Apr6 M2-Immunosuppression Flashcards

1
Q

4 situations where IS agents can be used

A
  • autoimmune disease
  • isoimmune disease (Rh hemolytic disease of the newborn)
  • organ transplant
  • preventional of cell prolif (as with coronary stents)
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2
Q

2 common autoimmune disorders

A

RA and lupus

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3
Q

Rh hemolytic disease of the newborn (isoimmune disease) def

A
  • mom Rh-, dad Rh+
  • baby has Rh Ag
  • mother recognizes Rh Ag of baby as foreign, makes an Ab against it
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4
Q

who’s affected by Rh hemolytic disease of the newborn (isoimmune disease)

A
  • first child is OK

- second child, IF ALSO RH+, may have this hemolytic disease of the newborn, hemolyzing their cells

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5
Q

lowest to highest lvl of selectivity in terms of targets of IS

A
  1. target cell proliferation (discussed in chemo lec)
  2. target T cell function
  3. specific Abs to target specific things
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6
Q

different drugs in terms of diff levels of selectivity as IS targets

A
  1. target cell prolif = glucocorticoids like prednisone + cytotoxic drugs (azathioprine, mycophenolate mofetil, mtx)
  2. target T cell fct = calcineurin inhibitors (cyclosporine, tacrolimus, sirolimus)
  3. Antibodies
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7
Q

glucocorticoids action

A
  • 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
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8
Q

specific examples of gene transcription effects of glucocorticoids

A

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*
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9
Q

effect of blocking IL-2 signaling with glucocorticoids

A
  • blocking many places where it serves as communication

- blocking humoral and cellular response therefore

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10
Q

azathioprine (cytotoxic drug) effect

A
  • 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
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11
Q

mycophenolate mofetil (MMF) (cytotoxic drug) effect

A
  • 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**
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12
Q

mtx effect

A
  • folic acid analog
  • binds dihydrofolate reductase to inhibit thymidine synthesis
  • inhibits DNA synthesis at S phase
  • mtx
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13
Q

mtx use in cancer vs immunosuppression

A

cancer = intermittent high dose tx

immunosuppression: more constant lower dose

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14
Q

T cell targeting drugs block what process exactly

A
  • block T cell activation

- act on IL-2 signaling process, required after the APC-T cell interaction (with MHC2+peptide and TCR)

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15
Q

effect of cyclosporine and tacrolimus (T cell targeting drugs)

A
  • cyclosporine binds cyclophilin in the T cell
  • tacrolimus binds FKBP in the T cell
  • these binding complexes inhibit calcineurin
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16
Q

what happens when cyclosporine and tacrolimus (T cell targeting drugs) inhibit calcineurin

A
  • 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
17
Q

what kind of protein calcineurin is exactly

A
  • 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
18
Q

sirolimus (rapamycin) effect (T targeting drug)

A
  • binds FKBP like tacrolimus
  • affects mTOR activity, which affects cell cycle progression
  • cell is blocked at GI to S phase (at this transition step)
19
Q

sirolimus exact effect

A
  • 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
20
Q

non specific Ab used in initial response to a graft (to avoid rejection) and how it works

A
  • anti-thymocyte globulin (ATG) or anti-lymphocyte Ab

- polyclonal Ab that DEPLETES PERIPHERAL LYMPHOCYTES that interact with initial graft rejection

21
Q

Ab used to reverse an ACUTE graft rejection (not prevent it like ATG)

A
  • muromonab (OKT3)

- anti-CD3. causes internalization of TCR and kills cytotoxic T cells

22
Q

Ab used in combination with calcineurin to avoid an acute organ rejection (like ATG)

A

-daclizumab (anti-IL2 R’s CD25 portion. CD25 is the alpha chain of IL-2)

23
Q

(IMPORTANT) summary of the IL-2 targeting drugs discussed

A
  1. glucorticoids (prednisone): decrease IL-2 (and IL-1) expression
  2. 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
  3. daclizumab (anti-CD25, so anti-IL-2R bc CD25 is alpha chain of IL-2R). blocks IL-2 signaling
24
Q

Abs used for Crohn’s disease and rheumatoid arthritis

A

infliximab (anti-TNFa)

-blocks TNF (or TNF-R). TNF has a role in mediating the inflam response

25
Q

Ab used as medication in MS (multiple sclerosis)

A

sphingosine 1 phosphate R modulator (fingolimod)

  • blocks migration of T cells in CNS
  • decreases amount of inflam and T cell response in CNS (which is what causes CNS damage related to MS)
26
Q

summary of treatment of autoimmune disorders

A
  • glucocorticoid (prednisone)
  • cytotoxic drugs, anti cell prolif (azathioprine, mtx)
  • Interferons:
  • TNFa-R antagonists (infliximab)
  • IL-2 R antagonist (daclizumab)
  • S1P R modulator (fingolimod)
27
Q

treatment used for Rh hemotylic disorder of the newborn

A
  • an RhD IgG Ab that is given at 28 weeks during the first pregnancy. binds Rh of newborn so never seen by mother
  • mother won’t develop a memory response to Rh Ag if ever 2nd child is also Rh+
28
Q

immunosuppression principles to prevent organ transplant rejection

A
  • intensive induction with biological agents (ATG, muromonab, daclizumab)
  • lower dose maintenance (tacrolimus, prednisone, MMF)
29
Q

drug added on stents to avoid cell proliferation around the stent (called drug-eluting coronary stents)

A

sirolimus. binds FKBP, blocks mTOC, blocks cdk2. blocks IL-2 synthesis and IL-2 R action

30
Q

unwanted effects of immunosuppressive agents

A

higher risk of
-infections
-lymphoma and secondary malignancies
(for ex, mtx is not a friendly drug, blocks immune surveillance)

31
Q

important concept in transplant to avoid the unwanted effects of immunosuppressive agents

A
  • Abs only given SHORT TERM

- calcineurin inhibitors LONG TERM

Bloc F - Defense (57 decks)

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