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Pharmacotherapy I > Exam 4 Pharmacology of Immunosuppressants > Flashcards

Exam 4 Pharmacology of Immunosuppressants Flashcards

1
Q

What immune system components are responsible for the hyper acute rejection?

A

Pre-existing antibodies in the host for donor antigens. Mostly for ABO groups, sometimes HLA antigens if patient had previous transplantation.

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2
Q

What type of rejection are we preventing with lifelong immunosuppressive drugs?

A

The acute rejection.

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3
Q

What occurs in the direct pathway of acute rejection?

A

Recipient CD8+ and CD4+ T cells recognize MHCI and MHCII on donor APCs like dendritic cells and cause apoptosis of these donor cells.

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4
Q

What occurs in the direct pathway of rejection?

A

Recipient CD8+ and CD4+ T cells recognize MHCI and MHCII on donor APCs like dendritic cells and cause apoptosis of these donor cells.

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5
Q

What occurs in the indirect pathway of rejection?

A

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.

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6
Q

Which mechanism of allorecognition is largely responsible for chronic rejection?

A

Indirect pathway

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7
Q

What occurs in chronic rejection?

A

The host mounts an immune response against the vasculature of the donor organ >1 year after transplantation.

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8
Q

What do induction agents do?

A

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.

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9
Q

What type of drugs are all the induction agents?

A

Antibodies given IV

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10
Q

What type of drugs are all the induction agents?

A

Antibodies given IV. They either deplete immune cells or prevent their proliferation/survival.

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11
Q

What type of drugs are all the induction agents?

A

Antibodies given IV. They either deplete immune cells or prevent their proliferation/survival.

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12
Q

What kind of antibody is thymoglobulin?

A

Rabbit anti-thymocyte globulin, a collection of polyclonal antibodies. ATGAM is the same only from horses.

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13
Q

What major side effect do we worry about with thymoglobulin and ATGAM?

A

Cytokine release syndrome. (also serum sickness from foreign proteins, worst infusion reaction of induction agents).

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14
Q

What receptor does alemtuzemab target?

A

CD52, present on most lymphocytes but not precursors. FDA approved for tumors (leukemia), not induction agent.

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15
Q

What type of side effects are especially concerning with alemtuzemab?

A

Low levels of certain cells like neutrophils, platelets, and RBCs (neutropenia, thrombocytopenia, and anemia)

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16
Q

What type of antibody is alemtuzemab?

A

A humanized monoclonal antibody against CD52.

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17
Q

What type of antibody is alemtuzemab?

A

A humanized monoclonal antibody against CD52.

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18
Q

What two induction agents work by antagonizing IL-2 on activated T cells rather than by killing off immune cells?

A

Basiliximab (Simulect) and daclizumab (Zenapax–now withdrawn)

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19
Q

Differentiate basiliximab and daclizumab. Which antibody is chimeric? Which one is humanized?

A

Basiliximab is chimeric (some mouse some human); daclizumab is humanized (only very small mouse portion).

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20
Q

What class of maintenance immunosuppressive agents works by inhibiting the expression of inflammatory genes such as cytokines?

A

Glucocorticoids

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21
Q

What class of maintenance immunosuppressive agents works by inhibiting the expression of inflammatory genes such as cytokines?

A

Glucocorticoids

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22
Q

What major intracellular target do glucocorticoids inhibit from entering the nucleus?

A

NFkB

23
Q

APC MHC with antigen binds to the TCR on the T cell, causing increased levels of calcium. What protein does this activate?

A

Calcineurin

24
Q

What nuclear transcription factor is activated by MHC-TCR binding? What protein is produced when transcription is activated this way?

A

NFAT; IL-2 is produced.

25
Q

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?

A

mTOR

26
Q

What is the intracellular target of cyclosporine and tacrolimus?

A

Calcineurin

27
Q

What calcineurin inhibitor is also a macrolide antibiotic?

A

Tacrolimus

28
Q

APC MHC with antigen binds to the TCR on the T cell, causing increased levels of calcium. What phosphatase does this activate?

A

Calcineurin

29
Q

What nuclear transcription factor is activated by dephospho rylation by calcineurin? What protein is produced when transcription is activated this way?

A

NFAT; IL-2 is produced.

30
Q

What calcineurin inhibitor is also a macrolide antibiotic?

A

Tacrolimus

31
Q

What does cyclosporine do once it reaches the cell cytoplasm?

A

It binds to cyclophylin, which then binds to and blocks calcineurin.

32
Q

What does tacrolimus do once it reaches the cell cytoplasm?

A

It binds to FKBP12 (a different immunophilin), forming a complex which then binds to and blocks calcineurin

33
Q

What odd side effect can be caused by cyclosporine?

A

Abnormal hair growth (gum hyperplasia also acceptable)

34
Q

What distinguishing side effect can be caused by tacrolimus but not cyclosporine?

A

Diabetes

35
Q

Along with the more unique side effects, what other side effects can both calcineurin inhibitors cause?

A

Infection, hypertension, abnormal renal function, acne

36
Q

Along with the more unique side effects, what other side effects can both calcineurin inhibitors cause?

A

Infection, hypertension, abnormal renal function, acne

37
Q

What do sirolimus and everolimus bind to within the cell?

A

FKBP12 (just like tacrolimus) but this complex inhibits mTOR instead of calcineurin

38
Q

What toxicity concerns us with sirolimus (Rapamycin) and everolimus, so much that we totally avoid them in one type of organ transplant?

A

Lung toxicity. Dont give in lung or heart transplants.

39
Q

What toxicity concerns us with sirolimus (Rapamycin) and everolimus, so much that we totally avoid them in one type of organ transplant?

A

Lung toxicity. Dont give in lung or heart transplants.

40
Q

What is the target of mycophenolate mofetil (CellCept)?

A

Inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo synthesis of guanosine nucleotides.

41
Q

How does inhibition of inosine monophosphate (mycophenolate) lead to immune suppression?

A

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.

42
Q

What anti-proliferative long-term immunomodulator is a prodrug?

A

Azathioprine

43
Q

What is the target of azathioprine?

A

Inhibition of de novo purine biosynthesis – TIMP

44
Q

What is the target of azathioprine?

A

Inhibition of de novo purine biosynthesis – TIMP

45
Q

What is the target of azathioprine?

A

Inhibition of de novo purine biosynthesis – TIMP

46
Q

What do cyclophosphamide, methotrexate, and leflunomide all have in common?

A

They are anti-cancer agents used off-label for immunosuppression.

47
Q

What entirely synthetic protein is used to block T cell costimulation?

A

Belatacept (Nulojix)

48
Q

What type of cell does belatacept bind to? Why?

A

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.

49
Q

What do we do to prevent hyperacute rejection?

A

Crossmatch tests to identify pre-existing antibodies against HLA or ABO blood group antigens.

50
Q

What is being done to overcome hyperacute rejection when donor and recipient have conflicting ABO or HLA groups in light of donor shortages?

A

Pretransplant desensitization – plasmapheresis + IV immunoglobulin + anti-CD20 mab (rituximab) or splenectomy + antirejection drugs.

51
Q

What is being done to overcome hyperacute rejection when donor and recipient have conflicting ABO or HLA groups in light of donor shortages?

A

Pretransplant desensitization – plasmapheresis + IV immunoglobulin + anti-CD20 mab (rituximab) or splenectomy + antirejection drugs.

52
Q

What is the clinical use for ribuximab (Rituxan)?

A

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.

53
Q

What is the clinical use for eculizumab?

A

Paroxysmal nocturnal hemoglobinuria (?), experimentally to block antibody-mediated rejection. Antibody for C5 protein blocks antibody-mediated tissue damage during rejection.

54
Q

What is the idea behind donor cell chimerism?

A

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.

Pharmacotherapy I (15 decks)

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