L65 Flashcards
What are the 3 signals required for activation of T cells by APCs?
APC gets antigen -> draining LN 1. MHC2 + TCR (CD4) MHC 1 + Tc (CD8) 2. Costim B7 on APC + CD28 on T cell 3. T cell produce IL2 that act paracrine to turn it on
What is the purpose of induction chemotherapy for transplant?
Reduce acute rejection
Deplete T cell so can’t respond to the donor antigens
What are the 2 induction agents that deplete T cells?
ATG = anti-thymocyte globulin
Alemtuzumab
What is the induction agent that does not deplete T cells?
Basiliximab - Ab vs IL 2 receptor
No signal 3 for T cell activation
What are the 2 toxicities of ATG therapy?
TCP
Leukopenia
AKA drop platelets and T cells… duh… common SE to all these drugs
So you’re watching for infection - prophylactic antibiotics
What are your 2 drugs of choice for initial immuno-suppression in setting of transplant?
Calcineurin inhibitors
1. Cyclosporine
2. Tacrolimus
Mechanism = prevent IL 2 transcription
Toxicity of both calcineurin inhibitors
Nephrotox - if use this for immune suppression in transplant of other organs, develop CKD over time
↑K
↓Mg + PO4
Thrombotic microangiopathy
2 SE tacrolimus
Alopecia - can’t tack on that lost hair!
**Post-transplant diabetes
SE cyclosporine
Gingival hyperplasia
↑ hair - male pattern
What is the normal fxn of calcineurin?
TCR gets bound - activates calcineurin to turn NFAT-P = NFAT
NFAT required for IL2 transcription
Architecture changes to kidney on calcineurin inhibitors
Stripes of fibrosis
Mechanism of anti-metabolite agents
Inhibit T cell prolif by blocking nucleotide synthesis
Aka stop G1 -> S progression (after IL2 binds - activates TOR - then would normally undergo cell cycle)
What are the 2 anti-metabolites you need to know? What is the difference in their mechanism?
Azathioprine = “azothio-purine” = X purine recycling/synthesis
vs
Mycophenolate mofetil = MMF = inhibits de novo purine synthesis
Why do you avoid azathioprine in gout patients?
Azathioprine is broken down by xanthine oxidase
Your gout pt is probably on ALLOPURINOL = xanthine oxidase inhibitor to ↓uric acid levels
Gout pts can’t breakdown azathiprine = ↑SEs
Biggest SE/concern with azathioprine
Sensitize to UV radiation
↑↑risk skin cancer
Mechanism of glucocorticoids for immune suppression
XNfKB - X IL2
↓T + B cell production
SE glucocorticoids
**Osteoporosis
**Diabetes (hyperglycemia)
AVN
Cushing features: central obesity, muscle breakdown
Cataracts
HTN
What is steroid withdrawl vs avoidance?
It is easier to pull pts off steroids who have been on them short term
If you have long term users, higher change of rejection if take off glucocorticoids
What is the mechanism of mTOR inhibitors?
Block T cell response to binding IL 2 (aka progressing into cell cycle)
2 mTOR inhibitors
Sirolimus = rapamycin
Everolimus
SE sirolimus
**Delayed wound healing - not right after OR
Insulin resistance
↑Cholesterol
TCP, leukopenia, anemia…
Mechanism of belatacept
Block costim via CD28 (2nd signal)
SE belatacept
↑post-transplant lymphoma - esp CNS lymphoma
Not going to give to a sero-neg EBV pt
Initial immune suppression regimen in adult kidney transplant pts
Tacrolimus = calcineurin I
+
MMR = mTOR block
Induction agent used at time of kidney transplant
T cell depleters: ATG or Alemtuzumab
How are the calcineurin Is broken down - which enzyme? Which drugs would ↑ vs ↓ their metabolism?
Tacrolimus + cyclosporine via CYP3A4 in liver Drugs that ↓enzyme = ↑immune suppression 1. CCBs = dilitizaem, verapamil 2. Azoles 3. Antibiotics - mycins Drugs that ↑enzyme = ↓IS *worry about rejection* 1. Rifampin (rifle) 2. Phenytoin (seizures) 3. Phenobarbital (barbituate) 4. St. John's Wart
How treat rejection?
Intensify IS:
+ Prednisone
Thymoglobulin
IVIg if Ab mediated rejection
Treat transplant pt with CMV infection
Present w/ flu-like symptoms
Stop anti-prolif agent
Immune system will take care of it
Treat BK/JC virus in transplant pt
Presentation of BK is asymptomatic - watch Cr for ↑
Prevention = monitoring
↓IS
Which drugs do you use in pregnancy for IS?
Cyclosporine/tacrolimus
Azathiprine
Prednisone
Drug that causes pneumonitis
Sirolimus (X mTOR)
Drug that causes vision changes
Cataracts = glucocorticoids
Drug class most likely to cause neutropenia/leukopenia
All but esp anti-metabolites
- Azathiopurine
Drug that causes proteinuria + oral ulcers
Sirolimus (X mTOR)
