Block 2 Lecture 6/7 -- Transplant Flashcards
MoA of OKT3
Anti-TCR (anti-CD3)
MoA of CTLA4-Ig
anti-costimulatory
MoA of basiliximab
anti-IL-2R
MoA of daclizumab
anti-IL-2R
MoA of rapamycin
interferes with mTOR signaling
– reduces proliferation
MoA of cyclosporine
inhibits calcineurin
– interferes with NF-AT mediated cytokine transcription (IL-2)
MoA of FK506/tacrolimus
inhibits calcineurin
– interferes with NF-AT mediated cytokine transcription (IL-2)
MoA of azathioprine
anti-proliferator blocks B/T cell synthesis
MoA of mycophenolate
anti-proliferator blocks B/T cell synthesis
MoA of corticosteroids
1) anti-inflammatory: inhibit m0 cytokine synthesis
2) blocks T cell activation
MoA of thymoglobulin
anti-tcr
MoA of atgam
anti-tcr
What agents are used in induction immunosuppression?
1) anti-TCR
2) anti-IL-2R
3) alemtuzumab
MoA of alemtuzumab
targets CD52
What drugs are used in maintenance immunosuppression?
1) calcineurin inhibitors
2) anti-proliferators
3) +/- corticosteroids
How is hyperacute rejection mediated?
self-Ab-mediated (against blood or graft)
How is acute rejection mediated?
allo-Ag-specific CD4/8 T-cell-mediated
How is chronic rejection mediated?
CD4-cytokine mediated
endothelium recognizes cytokines
Results of hyperacute rejection:
1) complement activation
2) endothelial damage
3) inflammation
4) thrombosis
Results of acute rejection:
1) parenchymal cell damage
2) interstitial inflammation
3) endothelialitis
Results of chronic rejection:
1) chronic inflammatory reaction in vasculature walls
2) intimal smooth muscle cell proliferation
3) vessel occlusion
What is direct antigen presentation?
allo/donor-APC presents self-Ag to T-cell
– T cell recognizes allo-MHC as foreign
What is indirect antigen presentation?
self-APC presents peptide of donor-MHC as Ag to T cell
How does sensitization occur?
direct- or indirect-antigen recognition
What is the role of T-cells in rejection?
1) sensitization
2) IL-2 release
3) rejection
What occurs in the rejection phase after sensitization?
effector CD4/8’s migrate to periphery
What are the reagents in mixed lymphocyte reaction?
donor and recipient’s mononuclear leukocytes
- (DCs, NK, B, T)
- one set may be inactivated
What are the reagents in cross matching test?
- recipient serum + donor lymphocytes
- - add complement
What is measured in the MLR?
B/T proliferation
What is measured in cross-matching?
cell lysis
What are the reagents in a PRA test?
1) fluorescent-MHC-labeled coated beads
2) patient’s serum
What is measured in a PRA?
% of MHC bound by patient’s MHC
What does the PRA result represent?
risk for hyperacute and acute rejection
How might MHC-Abs be pre-formed?
1) past transfusion
2) past transplant
3) pregnancy
How many HLA alleles must be matched for a “perfect match”?
6
Where are HLA alleles located?
chromosome 6
Why are PRA’s performed multiple times?
serum titers change over time
What are tests run to determine pre-formed Abs and HLA matching?
PRA
cross-matching
MLR
What backbone is common to all blood antigens?
4-sugar backbone
1) galactose
2) NAG (glucosamine)
3) galactose
4) fucose
Describe A blood Ag structure
backbone + N-acetyl-galactosamine
Describe B blood Ag structure
backbone + galactose
Describe O blood Ag structure
backbone only
What is the result of IL-2 production in sensitization?
1) T-cell proliferation
2) clonal expansion
3) cytokine production
What is the signaling cascade of the IL-2R?
1) production of mTOR
results in proliferation
What is the signaling cascade of the TCR?
1) calcineurin activation
2) NFAT activation
- - results in IL-2 production
3) also produces mTOR
- - results in proliferation
What is the signaling cascade of CD28?
results in IL-2 production
What interactions are involved in the immunological synapse?
1) pMHC - TCR
2) B7 - CD28
3) IL2 - IL2R
What are the goals of immunosuppressive therapy?
prevent acute rejection and minimize toxicity
What are non-T-cell depleting induction agents?
1) anti-IL2R
2) basiliximab
What are T-cell depleting induction agents?
1) antithymocyte globulin
2) alemtuzumab
What is the role of CD52?
on T-cells, leads to ADCC
How is cytokine release syndrome prevented?
1) APAP
2) benadryl
3) methylprednisolone
What agent is prone to provoking cytokine release syndrome?
OKT3
What is the induction cocktail?
1) T-cell depleting/non-depleting
2) cytokine prophylaxis
3) steroid taper
MoA of sirolimus
mTOR inhibitor
MoA of everolimus
mTOR inhibitor
What is the immunosuppressive maintenance cocktail?
2-3 meds from different classes +/- steroids
- calcineurin
- mTOR inhibitors
- antiproliferatives
