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PHAR 301 > Immunosuppression > Flashcards

Immunosuppression Flashcards

1
Q

what is innate immunity?

A

non-specific immunity –> does not require priming

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2
Q

what are 6 components of innate immunity?

A
  1. complement
  2. granulocytes
  3. monocytes/macrophages
  4. NK cells
  5. mast cells
  6. basophils
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3
Q

what is acquired immunity?

A

learned immunity –> depends on antigen exposure or priming

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4
Q

what are the 2 types of effector cells for acquired immunity?

A
  1. B cells
  2. T cells
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5
Q

Th1 is responsible for which type of adaptive response?

A

cell-mediated

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6
Q

What does Th1 produce?

A

Produce IL-2

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7
Q

how are CTLs activated and what is their activity?

A

APCs activate CTLs by themselves OR with the help of Th1 (cross-presentation)

IL-2 is produced to induce proliferation

activated CTL can recognize and kill tumour cells

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8
Q

describe T cell activation

A

multiple ways that T cells interact with APCs to stimulate response

SIGNAL 1: APC presents antigen to TCR
SIGNAL 2: co-stimulatory molecules are expressed

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9
Q

what type of T cell causes a humoral response?

A

Th2

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10
Q

what is the goal of the immune response?

A

to discriminate self from non-self

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11
Q

what is immunosuppression?

A

minimize impact of exaggerated/inappropriate immune response

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12
Q

what are 4 uses of immunosuppressive agents?

A
  1. autoimmune disease
  2. isoimmune disease (Rh hemolytic disease)
  3. organ transplant
  4. prevention of cell proliferation (stents)
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13
Q

approx how many ppl in USA suffer from autoimmune disease?

A

23.5 million ppl in USA

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14
Q

describe Rh hemolytic disease of the newborn

A

FIRST BABY Rh+ and Rh- mother
- when blood mixes during birth, mother’s immune system will detect Rh as foreign and make antibodies against Rh

SECOND BABY Rh+ and Rh- mother
- mother’s blood has Ab against Rh
- RBC will lyse –> bad for baby

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15
Q

why are there complications with organ transplants?

A

many possible MHC –> diff combos of HLA

recipient reacts to non-self MHC

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16
Q

what are 3 targets for immunosuppressive drugs? which has the lowest selectivity? which has the highest selectivity?

A
  1. cell proliferation (low selectivity)
  2. T cell function
  3. Ab approaches: Ag recognition (high selectivity)
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17
Q

describe 2 actions of glucocorticoids

A

inhibit transcription of pro-inflammatory genes
OR
increase transcription of anti-inflammatory genes

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18
Q

what are 3 pro-inflammatory genes that are inhibited with glucocorticoids?

A
  1. IL-1
  2. IL-2
  3. IL-6
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19
Q

what are the results of glucocorticoid action? (3)

A
  • reduced inflammation
  • reduced immune cell signaling and proliferation
  • immunosuppression
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20
Q

Describe innate immune signaling during COVID infection

A

CYTOKINE STORM
- cytokines and inflammation everywhere

PANOPTISIS
- killing cells in many ways

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21
Q

Describe the use of dexamethasone for hospitalized COVID patients

A

Different recommendations based on severity of COVID

Dexamethasone may be recommended for COVID patients who require supplemental O2

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22
Q

What is the purpose of cytotoxic drugs?

A

To kill cells

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23
Q

What are 4 examples of cytotoxic drugs?

A
  1. Cyclophosphamide
  2. Azathioprine
  3. Mycophenolate Mofetil (MMF)
  4. Methotrexate
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24
Q

What type of agent is cyclophosphamide?

A

DNA alkylating agent

(Nitrogen mustard-like drug)

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25
Q

What is cyclophosphamide used for?

A

Anti-cancer drug and immunosuppressant

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26
Q

What does cyclophosphamide cause?

A

Covalently binds DNA
- irreversible until NER
- produces INTERSTRAND DNA crosslinks

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27
Q

What is azathioprine metabolized into?

A

Azathioprine metabolized to 6-mercaptopurine

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28
Q

What does Azathioprine do?

A

Inhibits purine synthesis —> ultimately blocks DNA/RNA synthesis

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29
Q

What does mycophenolate mofetil (MMF) do?

A

Inhibits inosine monophosphate dehydrogenase —> blocks DE NOVO purine synthesis

This inhibits T and B cell proliferation

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30
Q

Why does mycophenolate motefil inhibit T and B cell proliferation?

A

T and B cell proliferation requires de novo purine synthesis and MMF blocks de novo synthesis

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31
Q

which cytotoxic drug is most specific? why?

A

MYCOPHENOLATE MOFETIL

It is more specific for immune cells

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32
Q

Describe the action of methotrexate

A

Similar to DHF so it tightly binds DHF reductase and blocks THF production

Therefore, blocks methyl transfer reactions so thymidine is not available

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33
Q

What are the 3 drugs that target T cells?

A
  1. Cyclosporine
  2. Tacrolimus
  3. Sirolimus
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34
Q

Which 2 drugs are Calcineurin inhibitors?

A
  1. Cyclosporine
  2. Tacrolimus
35
Q

What type of molecules are cyclosporine and tacrolimus?

A

Large, complex molecules

36
Q

what do calcineurin inhibitors do in general?

A

block calcineurin to inhibit T cell response

37
Q

what does cyclosporin do?

A

binds cyclophilin to remove phosphate group from TF to inhibit IL-2 transcription

38
Q

what does tacrolimus do?

A

binds FKBP to remove phosphate group from TF to allow IL-2 transcription

39
Q

what does sirolimus do?

A

blocks mTOR which is involved in cell cycle for G1 to S phase transition

this inhibits Cdk2 to prevent activated IL-2R from causing its effects –> no T cell proliferation

40
Q

what is an example of polyclonal Ab?

A

Anti-thymocyte globulin (ATG)

41
Q

what does anti-thymocyte globulin do?

A

rapidly kills peripheral T cells –> prevents initial graft rejection

42
Q

why are polyclonal Ab less beneficial than monoclonal Ab?

A

monoclonal Ab are more targeted

43
Q

what are the 4 types of monoclonal antibodies and their suffixes?

A
  1. human (-umab)
  2. murine (-momab)
  3. chimeric (-ximab)
  4. humanized (-zumab)
44
Q

what is an advantage and disadvantage of using human monoclonal antibodies?

A

advantage: person won’t reject it
disadvantage: less practical to produce

45
Q

what is the disadvantage of using murine monoclonal antibodies?

A

person will reject the mouse antibody

46
Q

what are chimeric monoclonal antibodies?

A

some mouse, some human

47
Q

what is the rejection risk of chimeric monoclonal antibodies?

A

small rejection risk

48
Q

what are humanized monoclonal antibodies

A

all human, just a bit mouse

49
Q

what is the rejection risk of humanized monoclonal antibodies?

A

may or may not reject

50
Q

what type of monoclonal Ab is Muromonab (OKT3)

A

Murine

51
Q

what does Muromonab (OKT3) do?

A
  • anti-CD3 –> blocks CD3 on TCR
  • induces internalization to block antigen rejection
  • reduces CD3+ cells
52
Q

what was Muromonab (OKT3) used for?

A

to reverse acute allograft rejection

53
Q

why is Muromonab (OKT3) no longer on the market?

A

murine monoclonal antibody –> caused side effect

54
Q

what is the role of Basiliximab?

A

binds CD25 (IL-2Ra) to block IL-2 mediated T cell activation

55
Q

what type of drug is Basiliximab typically used with?

A

used with calcineurin inhibitors

56
Q

why is Basiliximab used with calcineurin inhibitors?

A

prevents acute organ rejection

57
Q

what type of molecule is Belatacept?

A

a fusion protein

58
Q

what does Belatacept do?

A

binds CD80/86 on APCs to block co-stimulation and prevent T cell activation

59
Q

what type of monoclonal antibody is Infliximab?

A

chimeric IgG1 mAb

60
Q

what is the role of Infliximab?

A

anti-TNF alpha

61
Q

why is Infliximab unique?

A

interacts with immune response, not T cells that mediates the response

62
Q

what 2 diseases are Infliximab used for?

A
  • Rheumatoid arthritis
  • Crohn’s disease
63
Q

what is the first line of drugs used for autoimmune disease?

A

STEROIDS –> prednisone, dexamethasone

64
Q

what is the second line of drugs used for autoimmune disease?

A

CYTOTOXIC DRUGS –> cyclophosphamide, azathioprine, MMF, methotrexate

65
Q

what is the third line of drugs used for autoimmune disease?

A

ANTIBODIES –> Anti-IL-1, Anti-IL-6, Anti-TNF

66
Q

how to decide which drugs are used for autoimmune diseases?

A

start with more simple/standard drugs first, if those don’t work then use more complex drugs

67
Q

what drug is used to prevent Rh hemolytic disease of the newborn?

A

RhD IgG with a high titer to RhD Ag

68
Q

what does RhD IgG do?

A

binds Rh antigen from FIRST BABY so the mother cannot develop anti-Rh antibodies and SECOND BABY does not get Rh hemolytic disease

69
Q

when is RhD IgG administered?

A

at 28 weeks gestation and/or within 72h of birth of 1st baby

70
Q

what is the general approach to organ transplantation therapy?

A
  1. select best available ABO blood type-compatible HLA match for organ donation
  2. give multiple immunosuppressive agents, each with different targets
71
Q

what is an example regimen for a kidney transplant recipient? (3 drugs)

A
  1. tacrolimus
  2. MMF
  3. Prednisone
72
Q

how long do organ transplant recipients have to take immunosuppressive drugs? why?

A

forever –> always will have foreign proteins present

73
Q

why is it problematic that immunosuppressive drugs must be taken forever?

A

some of the drugs can be toxic

74
Q

why was cyclosporin replaced by tacrolimus?

A

tacrolimus is less toxic

75
Q

what drug is used in drug-eluting coronary stents?

A

sirolimus

76
Q

what are 2 unwanted effects of immunosuppressive agents?

A
  1. increased risk of infections
  2. increased risk of lymphomas and secondary malignancies
77
Q

CYCLOPHOSPHAMIDE

A

like nitrogen mustard

for cancer and immunosuppression

DNA alkylating agent –> covalently binds DNA
Produces interstrand DNA crosslinks
Irreversible until NER

78
Q

AZATHIOPRINE

A

becomes 6-mercaptopurine
inhibits purine synthesis
inhibits DNA/RNA synthesis

79
Q

MYCOPHENOLATE MIFETIL (MMF)

A

inhibits inosine monophosphate dehydrogenase
blocks DE NOVO purine synthesis
inhibits T and B cell proliferation and function

*more specific for immune cells than cyclophosphamide and azathioprine

80
Q

METHOTREXATE

A

similar to DHF

binds DHF reductase
cannot make THF/thymidine
inhibits methyl transfer reactions

glutamated in cells –> cannot leave

81
Q

MUROMONAB

A

murine

binds CD3 on TCR
induces internalization
blocks antigen recognition
depletes CD3+ cells

was used to to reverse acute allograft rejection but no longer on market bc of side effects

82
Q

BASILIXIMAB

A

humanized

binds IL2Ra (CD25) to block IL-2 induced proliferation

use with calcineurin inhibitors to prevent acute organ rejection

83
Q

BELATACEPT

A

fusion protein

binds CD80/86 on APC to block costimulation
cannot activate T cells

84
Q

INFLIXIMAB

A

chimeric

anti TNF alpha
(affects immune response instead of directly interfering with TCR/T cell)

for Crohn’s and Rheumatoid Arthritis

PHAR 301 (11 decks)

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