Exam 4 Pharmacology of Immunosuppressants Flashcards
What immune system components are responsible for the hyper acute rejection?
Pre-existing antibodies in the host for donor antigens. Mostly for ABO groups, sometimes HLA antigens if patient had previous transplantation.
What type of rejection are we preventing with lifelong immunosuppressive drugs?
The acute rejection.
What occurs in the direct pathway of acute rejection?
Recipient CD8+ and CD4+ T cells recognize MHCI and MHCII on donor APCs like dendritic cells and cause apoptosis of these donor cells.
What occurs in the direct pathway of rejection?
Recipient CD8+ and CD4+ T cells recognize MHCI and MHCII on donor APCs like dendritic cells and cause apoptosis of these donor cells.
What occurs in the indirect pathway of rejection?
Recipient APCs take up dead donor cell material and present it on their MHCII. Recipient CD4+ T cells then mount a humoral response to the donor antigens.
Which mechanism of allorecognition is largely responsible for chronic rejection?
Indirect pathway
What occurs in chronic rejection?
The host mounts an immune response against the vasculature of the donor organ >1 year after transplantation.
What do induction agents do?
They disable the immune system for a short period of time in the weeks right before and after the transplantation surgery to prevent early acute rejection.
What type of drugs are all the induction agents?
Antibodies given IV
What type of drugs are all the induction agents?
Antibodies given IV. They either deplete immune cells or prevent their proliferation/survival.
What type of drugs are all the induction agents?
Antibodies given IV. They either deplete immune cells or prevent their proliferation/survival.
What kind of antibody is thymoglobulin?
Rabbit anti-thymocyte globulin, a collection of polyclonal antibodies. ATGAM is the same only from horses.
What major side effect do we worry about with thymoglobulin and ATGAM?
Cytokine release syndrome. (also serum sickness from foreign proteins, worst infusion reaction of induction agents).
What receptor does alemtuzemab target?
CD52, present on most lymphocytes but not precursors. FDA approved for tumors (leukemia), not induction agent.
What type of side effects are especially concerning with alemtuzemab?
Low levels of certain cells like neutrophils, platelets, and RBCs (neutropenia, thrombocytopenia, and anemia)
What type of antibody is alemtuzemab?
A humanized monoclonal antibody against CD52.
What type of antibody is alemtuzemab?
A humanized monoclonal antibody against CD52.
What two induction agents work by antagonizing IL-2 on activated T cells rather than by killing off immune cells?
Basiliximab (Simulect) and daclizumab (Zenapax–now withdrawn)
Differentiate basiliximab and daclizumab. Which antibody is chimeric? Which one is humanized?
Basiliximab is chimeric (some mouse some human); daclizumab is humanized (only very small mouse portion).
What class of maintenance immunosuppressive agents works by inhibiting the expression of inflammatory genes such as cytokines?
Glucocorticoids
What class of maintenance immunosuppressive agents works by inhibiting the expression of inflammatory genes such as cytokines?
Glucocorticoids
What major intracellular target do glucocorticoids inhibit from entering the nucleus?
NFkB
APC MHC with antigen binds to the TCR on the T cell, causing increased levels of calcium. What protein does this activate?
Calcineurin
What nuclear transcription factor is activated by MHC-TCR binding? What protein is produced when transcription is activated this way?
NFAT; IL-2 is produced.
IL-2 is a major inflammatory cytokine that lets immune cells activate each other. What protein is required for IL-2 to cause cell proliferation?
mTOR
What is the intracellular target of cyclosporine and tacrolimus?
Calcineurin
What calcineurin inhibitor is also a macrolide antibiotic?
Tacrolimus
APC MHC with antigen binds to the TCR on the T cell, causing increased levels of calcium. What phosphatase does this activate?
Calcineurin
What nuclear transcription factor is activated by dephospho rylation by calcineurin? What protein is produced when transcription is activated this way?
NFAT; IL-2 is produced.
What calcineurin inhibitor is also a macrolide antibiotic?
Tacrolimus
What does cyclosporine do once it reaches the cell cytoplasm?
It binds to cyclophylin, which then binds to and blocks calcineurin.
What does tacrolimus do once it reaches the cell cytoplasm?
It binds to FKBP12 (a different immunophilin), forming a complex which then binds to and blocks calcineurin
What odd side effect can be caused by cyclosporine?
Abnormal hair growth (gum hyperplasia also acceptable)
What distinguishing side effect can be caused by tacrolimus but not cyclosporine?
Diabetes
Along with the more unique side effects, what other side effects can both calcineurin inhibitors cause?
Infection, hypertension, abnormal renal function, acne
Along with the more unique side effects, what other side effects can both calcineurin inhibitors cause?
Infection, hypertension, abnormal renal function, acne
What do sirolimus and everolimus bind to within the cell?
FKBP12 (just like tacrolimus) but this complex inhibits mTOR instead of calcineurin
What toxicity concerns us with sirolimus (Rapamycin) and everolimus, so much that we totally avoid them in one type of organ transplant?
Lung toxicity. Dont give in lung or heart transplants.
What toxicity concerns us with sirolimus (Rapamycin) and everolimus, so much that we totally avoid them in one type of organ transplant?
Lung toxicity. Dont give in lung or heart transplants.
What is the target of mycophenolate mofetil (CellCept)?
Inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo synthesis of guanosine nucleotides.
How does inhibition of inosine monophosphate (mycophenolate) lead to immune suppression?
T and B cells are highly depending on de novo nucleotide synthesis, and have Type 2 IMPDH so blocking this enzyme impairs B and T cell proliferation and induces apoptosis, but doesnt affect other cells (type 1 IMPDH) as much.
What anti-proliferative long-term immunomodulator is a prodrug?
Azathioprine
What is the target of azathioprine?
Inhibition of de novo purine biosynthesis – TIMP
What is the target of azathioprine?
Inhibition of de novo purine biosynthesis – TIMP
What is the target of azathioprine?
Inhibition of de novo purine biosynthesis – TIMP
What do cyclophosphamide, methotrexate, and leflunomide all have in common?
They are anti-cancer agents used off-label for immunosuppression.
What entirely synthetic protein is used to block T cell costimulation?
Belatacept (Nulojix)
What type of cell does belatacept bind to? Why?
APCs, because belatacept is composed of IgG1 fragment and CTLA-4, which binds to the CD80 on the APC surface. This prevents the APC from interacting with a T cell.
What do we do to prevent hyperacute rejection?
Crossmatch tests to identify pre-existing antibodies against HLA or ABO blood group antigens.
What is being done to overcome hyperacute rejection when donor and recipient have conflicting ABO or HLA groups in light of donor shortages?
Pretransplant desensitization – plasmapheresis + IV immunoglobulin + anti-CD20 mab (rituximab) or splenectomy + antirejection drugs.
What is being done to overcome hyperacute rejection when donor and recipient have conflicting ABO or HLA groups in light of donor shortages?
Pretransplant desensitization – plasmapheresis + IV immunoglobulin + anti-CD20 mab (rituximab) or splenectomy + antirejection drugs.
What is the clinical use for ribuximab (Rituxan)?
Used pre-operatively to eliminate B cells because it binds CD20 on B cells and makes them get phagocytized or apoptosed.
Also used for antibody-mediated rejection.
What is the clinical use for eculizumab?
Paroxysmal nocturnal hemoglobinuria (?), experimentally to block antibody-mediated rejection. Antibody for C5 protein blocks antibody-mediated tissue damage during rejection.
What is the idea behind donor cell chimerism?
Do a partial bone marrow transplant from the donor at the same time as the other transplant to try to generate a “chimeric” immune system that is tolerant of both donor and recipient antigens. Want to transplant naive immune cells.
