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Pharm > Lecture 28: Immunopharmacology > Flashcards

Lecture 28: Immunopharmacology Flashcards

1
Q

What are the three main application of immunosuppressive drugs?

A
  • Suppression of rejection of transplanted organs and tissues
  • Suppression of graft-versus-host disease
  • Autoimmune diseases
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2
Q

What is Graft-Versus-Host disease?

A

When donor lymphocytes react against host, especially in bone marrow transplants

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3
Q

What occurs in graft versus host disease?

A

If there are immunocompetent cells in the donor graft, they can mount an immune response against the host

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4
Q

What tissues are targeted in GVHD?

A

Liver, skin, mucosa and gut

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5
Q

What are autoimmune diseases?

A

When the immune system fails to recognize antigens as part of self and attacks them

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6
Q

What is Rheumatoid arthritis?

A

An autoimmune disease primarily affecting the joints

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7
Q

What is Lupus?

A

A multi organ immune disease with a characteristic rash on cheeks

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8
Q

What is ulcerative colitis?

A

T-cell infiltration and ulcertation of the colon

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9
Q

What is Psoriasis?

A

An autoimmune disease leading to scaly patches of skin

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10
Q

What are the two phases of the immune response?

A
  • Induction phase

* Effector phase

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11
Q

What are the two subdivisions of the induction phase?

A
  • Antigen presenting

* Clonal expansion and mutation

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12
Q

What is the first step in the simplified immune response?

A

Antigen presentation

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13
Q

What occurs in Antigen presentation?

A

An antigen presenting cell presents an antigen to a T-helper cell/CD4+ lymphocyte

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14
Q

how does antigen presenting affect the the T-helper cell?

A

It leads to activation of the T-helper cell

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15
Q

What happens after a T-helper cell is activated?

A

It divides and propagates

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16
Q

What is released by the T-helper cell once it is activated?

A

It releases interleukin-2 (IL-2)

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17
Q

What does interleukin-2 released by T-helper cells do?

A

Acts on the receptors of the same cell and causes them to divide and proliferate

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18
Q

What are the two types of cells that T-helper cells divide into?

A

Th1 and Th2

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19
Q

What do Th2 cells divide into?

A

B cells

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20
Q

What are B cells involved in the generation of?

A

Antibodies

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21
Q

What do Th1 cells differentiate into?

A

Different types of T-cells

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22
Q

What do Cytotoxic T-cells do?

A

They bind to and kill cells that are infected with a virus

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23
Q

What do Th1 cells release?

A

Cytokines that that circulate and promote further activation of the immune response

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24
Q

What happens in the induction phase?

A
  • Antigen presenting

* Activation and proliferation of the Th0 cells

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25
Q

What occurs in the effector phase?

A

Activation of T cells and B cells

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26
Q

What are the five main steps/regulators targeted by available immunosuppressant drugs?

A
  1. Inhibition of IL-2
  2. Inhibition of cytokine gene expression (glucocorticoids)
  3. Cytotoxicity (killing immune cells or preventing their maturation/expansion)
  4. Inhibition of nucleic acid synthesis
  5. Blockage of various T-cell surface receptors to prevent immune activation
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27
Q

What are the two Calcineurin inhibitors?

A

Cyclosporine and Tacrolimus

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28
Q

What kind of drugs are Cyclosporine and Tacrolimus?

A

Calcineurin inhibitors

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29
Q

What do Calcineurin inhibitors target?

A

An early step in the activation of naive Th0 cells

30
Q

What does the activation of naive Th0 cells require?

A

Activation of the calcineurin-NFAT pathway

31
Q

What are the steps after the activation of T-cells?

A

They generate a Ca2+ signal leading to activation of calcineurin (phosphatase) and dephosphorylation of NFAT

32
Q

What does NFAT do once dephosphorylated?

A

Migrates to the nucleus, leading to expression of IL-2 which is required for proliferation of T-cells

33
Q

What is the target of Cyclosporine?

A

Cyclophilin

34
Q

What is the target of Tacrolimus?

A

FKBP

35
Q

What do Cyclosporine and Tacrolimus do?

A

Bind to the targets and suppress calcineurin which suppresses IL-2

36
Q

What is the key detail in Cyclosporine mechanism?

A

The generation of cyclophilin-cyclosporin complex which inhibits calcineurin

37
Q

What does the inhibition of calcineurin do?

A

Prevents NFAT-mediated gene transcription leading to inhibition of T-cell maturation and proliferation

38
Q

How does Cyclosporine work?

A

It forms a complex with cyclophilin which binds to calcineurin preventing it from dephosphorylating NFAT. So NFAT cannot go on to increase gene transcription and increase IL-2

39
Q

How does Tacrolimus work?

A

It binds to FKBP which inhibits the activation of calcineurin and prevents the dephosphorylation of NFAT and prevents the downstream signalling of IL-2

40
Q

What is the Proliferation Signal Inhibitor Drug?

A

Rapamycin aka sirolimus

41
Q

What kind of drug is Rapamycin aka Sirolimus?

A

A proliferation Signal Inhibitors

42
Q

How do Proliferation Signal Inhibitors work?

A

They interfere with the downstream signals of IL-2 receptor activation

43
Q

What does Rapamycin bind to?

A

FKBP (the same target as tacrolimus)

44
Q

What does the Rapamycin-FKBP complex inhibit?

A

A protein complex called mTOR

45
Q

What is mTOR responsible for?

A

Promoting cell growth and proliferation

46
Q

How does mTOR work?

A

It binds to FKBP which inhibits mTOR. So the cell is unable to create a response to IL-2 receptor activation

47
Q

What are the two Cytotoxic Agent drugs?

A
  • Cyclophosphamide

* Azathioprine

48
Q

What kind of drugs are Cyclophosphamide and Azathioprine?

A

Cytotoxic agents

49
Q

How does Cyclophosphamide work?

A

It leads to cross-linking of neighboring bases interfering with DNA replication

50
Q

Where is Cyclophosphamide most effective?

A

In rapidly dividing cells

51
Q

How does Azathioprine work?

A

It is metabolized into 6-mercaptopurine and it inhibits the synthesis of nucleotides and interferes with cell division by acting as a fraudulent nucleotide

52
Q

What kind of nucleotide does Azathioprine look like?

A

A purine

53
Q

What are the components of antibodies?

A
  • 2 heavy chains

* 2 light chains

54
Q

What region determines antigen specificty?

A

The Fab region

55
Q

What does the Fc region determine?

A

Antibody class (IgA, IgG, IgM etc)

56
Q

What do the different Fc regions lead to?

A

Different types of immune response

57
Q

Which region binds to the antigen on monoclonal antibodies?

A

The Fab region

58
Q

What are antibodies always raised in?

A

Other animals

59
Q

Why are antibodies raised in other animals a problem?

A

Because they are recognized by our immune system and rapidly degraded

60
Q

What is the solution to the antibody issue?

A

Use Chimeric or humanized version version of monoclonal antibodies

61
Q

What is the upside to using Chimeric or Humanized antibodies?

A

Their antigenicity is reduced so they have a higher lifeltime in the body

62
Q

What is humanization/chimerization?

A

The replacement of the conserved (Fc) region of mouse monoclonal antibodies with corresponding sequence from human antibodies

63
Q

What do therapeutic monoclonal antibodies end with?

A

mab

64
Q

What is the suffix for humanized antibodies?

A

-umab or - zumab

65
Q

What is the suffix from chimeric products?

A

-imab and -ximab

66
Q

What is Alemtuzumab and what does it recognize?

A

A humanized IgG1 that recognizes CD52 on many immune cell types

67
Q

What is the IgG1 Fc domain recognized by and what does it do?

A

Phagocytic immune cells and causes their death

67
Q

What is the IgG1 Fc domain recognized by and what does it do?

A

Phagocytic immune cells and causes their death

68
Q

How does Alemtuzumab work?

A

It binds to CD52 on immune cells and this signals phagocytic cells to kill the cell through the IgG1 domain

69
Q

How does Basiliximab work?

A

It is a chimeric mouse-human IgG1 that binds to CD25 part of the IL-2 receptor on activated lymphocytes and blocks IL-2 from activating lymphocytes as an antagonists

70
Q

What are the two antibody based therapies?

A

Basiliximab and Alemtuzumab

Pharm (31 decks)

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