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PHAR 301 > Immunosuppression > Flashcards

Immunosuppression Flashcards

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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
What is cyclophosphamide used for?
Anti-cancer drug and immunosuppressant
26
What does cyclophosphamide cause?
Covalently binds DNA - irreversible until NER - produces INTERSTRAND DNA crosslinks
27
What is azathioprine metabolized into?
Azathioprine metabolized to 6-mercaptopurine
28
What does Azathioprine do?
Inhibits purine synthesis —> ultimately blocks DNA/RNA synthesis
29
What does mycophenolate mofetil (MMF) do?
Inhibits inosine monophosphate dehydrogenase —> blocks DE NOVO purine synthesis This inhibits T and B cell proliferation
30
Why does mycophenolate motefil inhibit T and B cell proliferation?
T and B cell proliferation requires de novo purine synthesis and MMF blocks de novo synthesis
31
which cytotoxic drug is most specific? why?
MYCOPHENOLATE MOFETIL It is more specific for immune cells
32
Describe the action of methotrexate
Similar to DHF so it tightly binds DHF reductase and blocks THF production Therefore, blocks methyl transfer reactions so thymidine is not available
33
What are the 3 drugs that target T cells?
1. Cyclosporine 2. Tacrolimus 3. Sirolimus
34
Which 2 drugs are Calcineurin inhibitors?
1. Cyclosporine 2. Tacrolimus
35
What type of molecules are cyclosporine and tacrolimus?
Large, complex molecules
36
what do calcineurin inhibitors do in general?
block calcineurin to inhibit T cell response
37
what does cyclosporin do?
binds cyclophilin to remove phosphate group from TF to inhibit IL-2 transcription
38
what does tacrolimus do?
binds FKBP to remove phosphate group from TF to allow IL-2 transcription
39
what does sirolimus do?
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
what is an example of polyclonal Ab?
Anti-thymocyte globulin (ATG)
41
what does anti-thymocyte globulin do?
rapidly kills peripheral T cells --> prevents initial graft rejection
42
why are polyclonal Ab less beneficial than monoclonal Ab?
monoclonal Ab are more targeted
43
what are the 4 types of monoclonal antibodies and their suffixes?
1. human (-umab) 2. murine (-momab) 3. chimeric (-ximab) 4. humanized (-zumab)
44
what is an advantage and disadvantage of using human monoclonal antibodies?
advantage: person won't reject it disadvantage: less practical to produce
45
what is the disadvantage of using murine monoclonal antibodies?
person will reject the mouse antibody
46
what are chimeric monoclonal antibodies?
some mouse, some human
47
what is the rejection risk of chimeric monoclonal antibodies?
small rejection risk
48
what are humanized monoclonal antibodies
all human, just a bit mouse
49
what is the rejection risk of humanized monoclonal antibodies?
may or may not reject
50
what type of monoclonal Ab is Muromonab (OKT3)
Murine
51
what does Muromonab (OKT3) do?
- anti-CD3 --> blocks CD3 on TCR - induces internalization to block antigen rejection - reduces CD3+ cells
52
what was Muromonab (OKT3) used for?
to reverse acute allograft rejection
53
why is Muromonab (OKT3) no longer on the market?
murine monoclonal antibody --> caused side effect
54
what is the role of Basiliximab?
binds CD25 (IL-2Ra) to block IL-2 mediated T cell activation
55
what type of drug is Basiliximab typically used with?
used with calcineurin inhibitors
56
why is Basiliximab used with calcineurin inhibitors?
prevents acute organ rejection
57
what type of molecule is Belatacept?
a fusion protein
58
what does Belatacept do?
binds CD80/86 on APCs to block co-stimulation and prevent T cell activation
59
what type of monoclonal antibody is Infliximab?
chimeric IgG1 mAb
60
what is the role of Infliximab?
anti-TNF alpha
61
why is Infliximab unique?
interacts with immune response, not T cells that mediates the response
62
what 2 diseases are Infliximab used for?
- Rheumatoid arthritis - Crohn's disease
63
what is the first line of drugs used for autoimmune disease?
STEROIDS --> prednisone, dexamethasone
64
what is the second line of drugs used for autoimmune disease?
CYTOTOXIC DRUGS --> cyclophosphamide, azathioprine, MMF, methotrexate
65
what is the third line of drugs used for autoimmune disease?
ANTIBODIES --> Anti-IL-1, Anti-IL-6, Anti-TNF
66
how to decide which drugs are used for autoimmune diseases?
start with more simple/standard drugs first, if those don't work then use more complex drugs
67
what drug is used to prevent Rh hemolytic disease of the newborn?
RhD IgG with a high titer to RhD Ag
68
what does RhD IgG do?
binds Rh antigen from FIRST BABY so the mother cannot develop anti-Rh antibodies and SECOND BABY does not get Rh hemolytic disease
69
when is RhD IgG administered?
at 28 weeks gestation and/or within 72h of birth of 1st baby
70
what is the general approach to organ transplantation therapy?
1. select best available ABO blood type-compatible HLA match for organ donation 2. give multiple immunosuppressive agents, each with different targets
71
what is an example regimen for a kidney transplant recipient? (3 drugs)
1. tacrolimus 2. MMF 3. Prednisone
72
how long do organ transplant recipients have to take immunosuppressive drugs? why?
forever --> always will have foreign proteins present
73
why is it problematic that immunosuppressive drugs must be taken forever?
some of the drugs can be toxic
74
why was cyclosporin replaced by tacrolimus?
tacrolimus is less toxic
75
what drug is used in drug-eluting coronary stents?
sirolimus
76
what are 2 unwanted effects of immunosuppressive agents?
1. increased risk of infections 2. increased risk of lymphomas and secondary malignancies
77
CYCLOPHOSPHAMIDE
like nitrogen mustard for cancer and immunosuppression DNA alkylating agent --> covalently binds DNA Produces interstrand DNA crosslinks Irreversible until NER
78
AZATHIOPRINE
becomes 6-mercaptopurine inhibits purine synthesis inhibits DNA/RNA synthesis
79
MYCOPHENOLATE MIFETIL (MMF)
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
METHOTREXATE
similar to DHF binds DHF reductase cannot make THF/thymidine inhibits methyl transfer reactions glutamated in cells --> cannot leave
81
MUROMONAB
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
BASILIXIMAB
humanized binds IL2Ra (CD25) to block IL-2 induced proliferation use with calcineurin inhibitors to prevent acute organ rejection
83
BELATACEPT
fusion protein binds CD80/86 on APC to block costimulation cannot activate T cells
84
INFLIXIMAB
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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