Lecture 8 - Immunosuppressants Flashcards

1
Q

Allograft

A

One donating to another within the same species

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2
Q

Autograft

A

One donating within itself

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3
Q

Xenograft

A

Donation from a different species

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4
Q

There are 3 stages of graft (organ) rejection: Describe them

A

Hyperacute: happens in minutes

Acute: happens within 7-21 days

Chronic: happens within 3 months

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5
Q

The success of organ transplantation is due largely to the availability of effective ____________ agents

A

immunosuppressive

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6
Q

All current anti-rejection drugs target ____ and _____ activation/clonal expansion, cytokine production or antibody action

A

T-cell

B-cell

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7
Q

Describe how organ rejection happens

A

Foreign organ proteins are present and bind to a macrophage or other antigen presenting cell.
This activates the formation or Th cells and B cells which produce antibodies.

Neutralizaiton
Opsonization
Phagocytosis

Ultimately leads to:
ORGAN REJECTION

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8
Q

When an antigen binds to an antigen receptor and activates B cell, they proliferate to form ??

A

clone of B cells

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9
Q

Then the clones of B cells proliferate and differentiation into two cell types: what are they?

A

Plasma cell (antibody secreting cell)

Memory cell (dormant cell)

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10
Q

What are anti-rejection drugs?

A

Drugs that act on the induction and/or effector phase of the immune response.

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11
Q

Describe the induction phase of the immune response

A

Activated T cells cause antigen recognition and then B-cells proliferate into the two types of cells (plasma cells and memory cells)

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12
Q

Describe the effector phase of the immune response

A
Differentiation of B cells results in the two different types of cells (plasma cells and memory cells).
This triggers T cells or antibodies.
Causes interaction.
Causes complement pathway.
Produces antigen.
Results in tissue injury.
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13
Q

List 2 types of anti-rejection drugs (remember they act on the induction phase of the immune response)

A
  • Inhibitors of interleukin-2 production (cyclosporine, tacrolimus)
  • Inhibitor of cytokine gene expression (glucocorticoids)
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14
Q

Cyclosporine is a ??

A

interleukin-2 production inhibitor

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15
Q

Describe cyclosporine (IL-2 production inhibitor)

A
  • A fat soluble cyclic peptide with 11 amino acids derived from fungus Tolypocladium inflatum
  • Extensively used in the treatment of organ transplantation (kidney, heart, bone marrow)
  • Low doses have also proved useful in autoimmune diseases (ex. RA)
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16
Q

Cyclosporine:

MOA

A

-Antigen-MHC 2 complex binds to Th2 cell receptor and increases intracellular Ca2+
-Ca2+/calmodulin complex stimulates phosphatase called Calcineurin which increases activation of transcription factor (NF-AT).
This increases IL2 gene transcription

  • *Cyclosporine binds to cytosolic protein, Cyclophilin (immunophilin)
  • *Cyclosporine-Cyclophilin complex inhibits calcineurin/NF-AT activation and blocks IL-2 gene transcription
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17
Q

Cyclosporine:

Describe the results of the MOA

A
  • Decreases activation of T cells
  • Inhibit IL-2 release
  • Decrease expression of IL-2 receptors
  • Reduce function of the effector T cells that mediate cell mediated response
  • Reduction of T cell dependent B cell response
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18
Q

Cyclosporine (IL-2 Production Inhibitor):

Given ___ or ____

A

orally or IV

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19
Q

Cyclosporine (IL-2 Production Inhibitor):

____ absorption is slow and incomplete

A

Oral

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20
Q

Cyclosporine (IL-2 Production Inhibitor):

Metabolism occurs in both the ___ and _____

A

GI and liver

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21
Q

Cyclosporine (IL-2 Production Inhibitor):

Plasma half-life is ??

A

24 hours

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22
Q

Cyclosporine (IL-2 Production Inhibitor):

Cyclosporine is concentrated in _____ tissue (lymphomyeloid and adipose tissue)

A

peripheral

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23
Q

Cyclosporine (IL-2 Production Inhibitor):

Adverse effects?

A
  • Nephrotoxicity
  • Hypertension
  • Increase risk of infection
  • Liver dysfunction (regular blood level monitoring to avoid kidney and liver toxicity)
  • Others: hyperglycemia, anorexia, lethargy, hirsutism, tremore, paraesthesia, gum hypertrophy, GI upset
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24
Q

List some drugs that inhibit Cyclosporine metabolism

A
  • calcium channel blockers
  • antifungal agnets (ketoconazole, fluconazole)
  • antibacterial agents (erythromycin, clarithromycin)
  • grapefruit juice
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25
Q

List some drugs that induce cyclosporine metabolism

A
Anticonvulsants (phenytoin)
Antituberculosis agents (isoniazid, rifampin)
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26
Q

______ = macrolide antibiotic produced by Streptomyces tsukubaensis

A

Tacrolimus

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27
Q

Tacrolimus MOA

A

Similar to cyclosporine:

  • At cellular level, it binds to the immunophilin FK binding protein (FKBP) which inhibits Calcineurin phosphatase which decreases activation of transcription factor (NF-AT) which decrease IL-2 gene transcription
  • Prevents IL-2 gene activation

Look at picture on slide 21

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28
Q

Tacrolimus (Prevents IL-2 gene activation):

Given ____ or ___

A

orally or IV

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29
Q

Tacrolimus (Prevents IL-2 gene activation):

Plasma half life?

A

9-12 hours

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30
Q

Tacrolimus (Prevents IL-2 gene activation):

Metabolized by the ____

A

liver (99%)

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31
Q

Tacrolimus (Prevents IL-2 gene activation):

Active in preventing ??

A

organ transplant rejection

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32
Q

Tacrolimus (Prevents IL-2 gene activation):

Toxic effects similar to _____

A

cyclosporine

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33
Q

Cyclosporine and Tacrolimus both affect the _____ phase the immune response

A

induction

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34
Q

List some drugs acting on the effector phase of the immune response

A
  • Inhibit action of IL-2 (Sirolimus)
  • Inhibitors of purine synthesis (Mycophenolate mofetil, Azathioprine)
  • Aklylating cytotoxic agents (Cyclophosphamide)
  • Supressor of immune response (Glucocorticoids)
  • Immunosuppressive antibodies (Polyclonal and monoclonal antibodies)
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35
Q

______ = new macrolide antibiotic derived from Streptomyces hygroscopicus

A

Sirolimus

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36
Q

Sirolimus:

MOA

A
  • Binds to intracellular immunophilins but DOES NOT block IL-2 gene transcription
  • Interferes with IL-2 signal transduction pathway in activated T cells

Result: decreased clonal proliferation of T cells and B cells
*prevents active cell proliferation (slide 26)

  • Before we were blocking IL-2 production
  • Now were are blocking IL-2 signal transduction pathway of already produced IL-2
37
Q

What is Mycophenolate Mofetil converted to?

A

converted to mycophenolic acid

38
Q

Mycophenolate Mofetil:

MOA

A
  • Selectively inhibits proliferation of both T and B lymphocytes, and cytotoxic T cells
  • MOA: Potent inhibitor of inosine 5’ mono-phosphate dehydrogenase (a crucial enzyme in purine synthesis)
  • T cells and B cells are particularly dependent on this pathway for proliferation

**Inhibits purine synthesis therefore inhibits proliferation of B and T cells

39
Q
Mycophenolate Mofetil (purine synthesis inhibitor):
\_\_\_\_\_ administration (well absorbed)
A

oral

40
Q
Mycophenolate Mofetil (purine synthesis inhibitor):
What impairs absorption?
A

magnesium and aluminum

**therefore caution with antacids

41
Q
Mycophenolate Mofetil (purine synthesis inhibitor):
Metabolite mycophenolic acid and glucuronide conjugate undergoes \_\_\_\_\_\_ \_\_\_\_\_\_\_
A

enterohepatic circulation

42
Q
Mycophenolate Mofetil (purine synthesis inhibitor):
Eliminated by \_\_\_\_\_ as inactive glucuronide
A

kidney

43
Q
Mycophenolate Mofetil (purine synthesis inhibitor):
Indicated in transplant recipients with \_\_\_\_ and \_\_\_\_\_
A

cyclosporine and steroids

44
Q

Azathioprine is metabolized to __________ which is a purine antimetabolite - remember anti-cancer drugs

A

6-mercaptopurine

45
Q

Azathioprine:

MOA

A
  • Interferes with purine synthesis (inhibits HGPRT enzyme - catalyzes conversion of purine base to purine ribosyl monophosphate). Cytotoxic on dividing cells
  • Inhibit clonal T cell and B cell proliferation of immune response
  • Inhibits both cell-mediated and antibody mediated immune reactions

*similar mechanism to Mycophenolate Mofetil

46
Q

Azathioprine (purine synthesis inhibitor):

_____ loading dose on day of transplantation

A

IV

47
Q

Azathioprine (purine synthesis inhibitor):

____ dosing for maintenance

A

Oral

48
Q

Azathioprine (purine synthesis inhibitor):

Clinically used in combo with other ________ drugs (kidney, liver transplants, RA)

A

immunosuppressant

49
Q

Azathioprine (purine synthesis inhibitor):

Major side effect ?

A

bone marrow depression

50
Q

What is Cyclophosphamide?

A

A nitrogen mustard, an alkylating agent

51
Q

Cyclophosphamide:

___ absorbed

A

orally

52
Q

Cyclophosphamide:

half life ?

A

6.5 hours

53
Q

Cyclophosphamide:

_______ until metabolized by the liver into the active phosphoramide mustard

A

inactive

54
Q

Cyclophosphamide:

MOA

A
  • Alkyl groups cross-react with two DNA nucleophilic sites (intra/inter guanine) which inhibits DNA replication
  • Results in subsequent cell death (apoptosis)
  • Used for treatment of Lupus and RA
55
Q

Cyclophosphamide (DNA replication inhibitor):

Pronounced effect on _____

A

lymphocytes

56
Q

Cyclophosphamide (DNA replication inhibitor):

Adverse effects?

A
  • Bone marrow depression. Affects more white blood cells than platelets.
  • GI disturbance
57
Q

Cyclophosphamide (DNA replication inhibitor):

What is a toxic metabolite and what does it cause?

A

acrolein

causes hemorrhagic cystitis

58
Q

List some glucocorticoids

A
  • Prednisone
  • Methylprednisolone
  • Dexamethasone
59
Q

What do high doses of Glucocorticoids do?

A
  • High doses induce lymphocyte migration to extravascular space - subsequently reduce lymphocyte proliferation
  • Size reduction in lymphoid tissues
  • Affect more T cells than B cells
60
Q

Glucocorticoids:

Suppress what phase of the immune response?

A

BOTH induction and effector phases of immune response

61
Q

Glucocorticoids:

MOA

A
  • Inhibit macrophage activation (antigen presenting cell) and release of IL-1B
  • Decrease clonal expansion of T and B cells and IL-2 secreting T cells
  • Decrease production and action of cytokines (interleukins, TNF gamma)
  • Decrease generation of IgG
62
Q

Glucocorticoids:

Clinical use

A

Anti-inflammatory and immunosuppressive therapy:

-Asthma, allergic rhinitis, eczema, severe drug allergic reaction, RA, organ transplant

63
Q

Glucocorticoids:

Used for Neoplastic diseases such as ??

A

Hodgkin’s disease

Acute lymphocytic leukemia

64
Q

Glucocorticoids:

Used as replacement therapy for ?

A

Addison’s syndrome (autoimmune polyendocrine syndrome)

65
Q

Glucocorticoids:

Adverse effects

A
  • Insomnia and mood changes (Cause is unknown - take it in the morning)
  • Increased appetite and weight gain
  • Suppress response to injury or infection
  • Metabolic effects
    • Fluid retention (Na+ retention and K+ depletion)
    • Osteoporosis
    • GI bleeding
    • Hyperglycemia
66
Q

slide 38 - good review

A

swag

67
Q

Describe immunosuppressive antibodies

A

Antibodies against human lymphocytes or their surface receptors have significant immunosuppressant actions

68
Q

List 2 types of immunosuppressive antibodies

A

1) Polyclonal antibodies

2) Monoclonal antibodies

69
Q

Describe Polyclonal antibodies

A

Anti-lymphote immunoglobulin:
-Inhibits T cells. Lysis

  • Bind to proteins on the surface of lymphocytes triggering the complement response - Lysis of lymphocytes
  • Indiscriminate action on all T cells
70
Q

Describe Monoclonal antibodies

A

Antibodies against interleukin 2 receptors:
-Prevents T cell and B cell activation and proliferation

  • Directly against a specific surface component of T cells
  • Affects the induction and effector phases of immune response to allograft
71
Q

Polyclonal Antibodies:

Adverse effects

A

Newly synthesized antibodies against these polyclonal antibodies could produce anaphylactic reactions

72
Q

Monoclonal antibody targets?

A
  • CD3 proteins with antigen receptors
  • CD4 co-receptors
  • IL-2 receptors
73
Q

What is TNF alpha ?

A

a pro-inflammatory cytokine

74
Q

What is Infliximab?

A

chimeric human/mouse monoclonal antibody directed to TNF alpha

75
Q

42 - good summary slide

A

ya man

76
Q

Describe the prevention of acute rejection of organ transplants

A

-High does glucocorticoids, purine synthesis inhibitors, immunosuppressive antibodies

77
Q

Describe the prevention of chronic rejection of organ transplant

A

Triple drug therapy consisting of low dose:

  • Calcenurin inhibitor (Cyclosporine, Tacrolimus)
  • Inhibitor of purine synthesis (Mycophenolate, Azathioprine)
  • Glucocorticoid

Alkylating - cytotoxic mechanisms:
-cyclophosphamide

Immunosuppressive antibodies:
-Polyclonal and monoclonal antibodies

Anti-TNF therapy

78
Q

When do autoimmune diseases occur?

A

When the adaptive immune system loses self-tolerance rendering the system unable to distinguish between self and non-self antigens

79
Q

Describe self-tolerance

A
  • The immune system protects itself against auto reactive B and T cells via primary and peripheral tolerance.
  • In central tolerance, negative selection results in the clonal deletion of immature lymphocytes in the bone marrow (B cells) and thymus (T cells) that recognize self-antigens with high affinity.
  • In peripheral tolerance (beyond the lymphoid organs), mature auto reactive lymphocytes are inactivated or killed by mechanisms including anergy, immunological ignorance/antigen sequestration, programmed cell death (PCD) or suppression by regulatory T cells (Tregs)
80
Q

Describe loss of self-tolerance

A

When these self-tolerance mechanisms fail, the adaptive immune system responds as it would to non-self antigens and mounts an immune response.

The body’s inability to eliminate the self-antigen results in a sustained response that leads to chronic inflammation.

81
Q

List some causes of loss of self-tolerance

A
  • Viral infection of a tissue can activate non-virus specific T cells
  • Molecular mimicry (microbial antigens share epitopes similar to human self-proteins and induce an inflammatory response agains the self antigen
  • Immune cells targeting tumors may become or remain active and target healthy cells. Similarly, immunoediting theory suggests that antigens derived from cancer cells containing somatic mutations induce an adaptive immune response and generate cross-reactivity against native proteins
  • Damage associated molecular patterns
82
Q

List some drugs used in RA therapy

A
  • NSAIDs
  • Glucocorticoids
  • Disease-Modifying Antirheumatic Drugs (DMARDs)
    • Methotrexate
    • Sulfasalazine
    • Leflunomide
    • Anti-TNF alpha therapies
    • Anti-IL therapies
83
Q

Describe the 3 phases of RA

A

1) Initiation phase
- Inflammation within joint

2) Amplification phase
- T cell activation

3) Chronic inflammatory phase
- Tissue injury due to destruction of bone and remodelling of joint

84
Q

Why are anti-TNF and anti-IL effective DMARDs (disease-modifying anti rheumatic drugs)?

A
  • Are released within joint during chronic inflammatory phase
  • Are early participants in the inflammatory cascade
85
Q

List some anti-TNF based therapeutics

A
  • Entanercept
  • Infliximab
  • Adalimumab
  • Certolizumab
  • Golimumab
86
Q

Describe Etanercept

A
  • Only soluble receptor TNF antagonist
  • Fully human protein
  • Binds TNF, soluble and cell bound
  • No neutralizing antibodies; low immunogenicity
  • Does not bind complement, no cell lysis
87
Q

List some Anti-IL based therapeutics

A
  • Anakinra
  • Canakinumab
  • Tocilizumab
88
Q

The rest of this lecture is UC and CD - so see GI lecture flashcards

A

okie