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I&I WC2 > Clinical pharmacology > Flashcards

Clinical pharmacology Flashcards

Lecture 1, 2 en 3 van dinsdag 21/1

1
Q

Why do we use immunosuppression after organ transplantation?

A

To prevent acute rejection

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2
Q

Describe the short- and long term graft survival pattern

A

Improvement in the first year, after that parallel

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3
Q

What are the causes of death in patients with a functioning graft? (5)

A
  1. Cardiovascular
  2. Infection
  3. Malignancy
  4. GI-liver complication
  5. Other
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4
Q

Incidence of malignancy after transplantation is increased for which tumor types?

A

Almost all tumor types

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5
Q

How much higher is the chance to get skin cancer for transplantation patients?

A

~125x

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6
Q

Which division in skin cancer types can be made? (2)

A
  1. Melanoma
  2. Non-melanoma
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7
Q

What are the types of non-melanoma skin cancer? (4)

A
  1. Squamous cell carcinoma
  2. Basel cell carcinoma
  3. Kaposi sarcoma
  4. Merkel cell
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8
Q

Which type of non-melanoma skin cancer most often occurs post-transplantation?

A

Squamous cell carcinoma

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9
Q

Do patients with skin cancer often just get it once and one type?

A

No -> often more than once and more than one type

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10
Q

What are risk factors for developing skin cancer post-transplantation? (9)

A
  1. Ultraviolet radiation
  2. Light colored hair and eyes
  3. Geographic location
  4. Age at transplantation
  5. History of SCC or BCC (pre- or post transplant)
  6. Type of transplant
  7. Type/duration/intensity of immunosuppressive medication
  8. Viral infection
  9. Genetic factors
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11
Q

Describe the relation between age and the risk to develop skin cancer

A

The older you become, the higher the risk to develop skin cancer

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12
Q

Which types of transplant have a higher incidence of skin cancer? (2)

A
  1. Lung
  2. Heart
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13
Q

Which viral infections are mostly associated with malignancy? (2)

A
  1. HHV8
  2. HPV
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14
Q

In Australia, how many transplantation patients have skin cancer after 5/20 years?

A

5 years: ~30%
20 years: ~ 80%

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15
Q

Why do transplantation patients in The Netherlands/United Kingdom get skin cancer post transplantation less often then Australian patients?

A

Less sun exposure

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16
Q

The incidence of solid tumors after transplantation depends on? (4)

A
  1. Genetics
  2. Environmental conditions
  3. Patient population accepted for Tx
  4. Immunosuppressive regime
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17
Q

True or false: Patients with invasive cancer live shorter than patients with skin cancer

A

True

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18
Q

Which risk factors for cancer after solid organ transplantation do you need to consider? (3)

A
  1. General risk factors
  2. After Tx: immunological- and non-immunological risk factors
  3. Cumulative exposure of immunosuppressive
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19
Q

What are the general risk factors for solid tumors after transplantation? (5)

A
  1. Age
  2. Gender
  3. Smoking
  4. Genetic predisposition
  5. Race
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20
Q

Which immunosuppressant therapies contribute to tumor growth after transplantation? (6)

A
  1. Antibody therapy
  2. Anti-B-cell therapy
  3. CNI
  4. AZA
  5. MMF
  6. Sirolimus
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21
Q

What are examples of anti-T cell therapy? (3)

A
  1. OKT3
  2. ATG
  3. Alemtuzumab
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22
Q

How does CNI contribute to tumor growth after transplantation? (3)

A

Increase of:
1. TGF-B (tumor growth, invasive behavior)
2. VEGF (pro-angiogenic effect)
3. IL-6 (EBV-induced B-cell growth)

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23
Q

How does AZA contribute to tumor growth after transplantation?

A

Interaction with DNA repair -> mutagenesis

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24
Q

Mutations induced by AZA are mostly associated with which type of malignancy?

A

Skin cancer

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25
Q

How does MMF contribute to tumor growth after transplantation?

A

Impairs lymphocyte function by blocking purine biosynthesis

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26
Q

What is the relationship between Sirolimus and tumor growth post-transplantation?

A

Suppresses the growth and proliferation of tumors in various animal models

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27
Q

What are examples of calcineurin inhibitors (CNI)? (2)

A
  1. Cyclosporin
  2. Tacrolimus
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28
Q

How long after transplantation does malignancy occur?

A
  1. Invasive -> ~50% after 5 years
  2. Skin -> ~50% after 10 years
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29
Q

Where in the cell do tacrolimus and cyclosporin inhibit cell function?

A

Downstream of TCR -> inhibits calcineurin enzyme

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30
Q

Cyclosporine A and B did not have a strong antibacterial effect, but they did have another beneficial effects. Which effects?

A

Antibody and cellular immunosuppressive effects

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31
Q

What are complications surrounding the operation of a kidney transplantation? (4)

A
  1. Thrombosis
  2. Bleeding
  3. Infection
  4. Ureter obstruction/leakage
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32
Q

How would you study/institute ways to reduce the cancer burden? (2)

A
  1. Screening
  2. Reactive strategy
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33
Q

What would be possible screening strategies? (2)

A
  1. Screening before and after transplantation
  2. Population screening
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34
Q

What are possible screening option enhancements after transplantation? (2)

A
  1. More frequent screening
  2. Start at an earlier age
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35
Q

What entails a reactive strategy to reduce the cancer burden?

A

Reducing immunosuppression

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36
Q

In which cancer types has a reactive strategy proven to be effective? (2)

A
  1. Lymphoma
  2. Kaposi sarcomas
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37
Q

Patients with skin cancers often get their immunosuppression changed to?

A

Sirolimus -> seems to reduce skin cancer (small degree)

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38
Q

When does sirolimus have the biggest effect?

A

After your first skin cancer

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39
Q

In clinical practice, we make an individualized decision how to reduce the cancer burden. What are parameters to consider in making this decision (i.e what is done in daily practice)? (5)

A
  1. Risk of side effects/graft loss
  2. Other treatment options
  3. Sunlight exposure prevention
  4. Frequent screening
  5. Low index of suspicion for malignancy
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40
Q

What are caveats in the interpretation of studies on cancer in kidney transplantation? (4)

A
  1. Database research can be biased
  2. Amount of drugs in blood largely unknown
  3. Incidence of cancer is poorly reported
  4. Intervention studies are long/short after Tx and many/few cancers
41
Q

What is Intravenous immunoglobulin (IVIg)

A

Human IgG purified from pooled plasma of > 1000 donors (administered intravenously)

42
Q

True or false: trace amounts of IgA and IgM can be found in IVIg

43
Q

True or false: IVIg mainly consists of dimers

A

False -> mainly monomers

44
Q

What is the estimated variety in antibodies in IVIg?

A

10^9 Ag-specificities

45
Q

What are the two main indications for treatment with IVIg?

A
  1. Replacement therapy for primary IgG deficiencies [low dose]
  2. Immunomodulation [high dose]
46
Q

What are the three types of therapy where IVIg leads to immunomodulation?

A
  1. Anti-inflammatory therapy
  2. Prophylaxis treatment
  3. Hyperimmunoglobulins
47
Q

In which instances is IVIg used as anti-inflammatory therapy?

A

Auto-immune diseases

48
Q

In which instances is IVIg used as prophylaxis or treatment?

A

Antibody-mediated rejection after kidney transplantation

49
Q

In which instances are hyperimmunoglobulins used? (2)

A
  1. Antiviral therapy (HBV or CMV)
  2. Rhesus-negative mothers carrying rhesus-positive baby
50
Q

Which indications are FDA-approved for treatment with IVIg? (7)

A
  1. Hypogammaglobulinemia
  2. CLL
  3. Kawasaki’s disease
  4. ITP
  5. MMN
  6. CIDP
  7. Dermatomyositis
51
Q

IVIg is highly demanded in which clinical expertises? (2)

A
  1. Hematology
  2. Neurology
52
Q

What is Kawasaki’s disease?

A

Vasculitis -> inflamed medium size blood vessels

53
Q

What is the therapy for Kawasaki’s disease? (2)

A
  1. High dose aspirin -> suppress inflammation
  2. High dose IVIg
54
Q

What is Immune Thrombocytopenia Purpura (ITP)?

A

Low platelet counts due to auto-antibodies against platelets

55
Q

What is the therapy for ITP?

A
  1. Corticosteroids -> suppress inflammation
  2. If insufficient response: high dose IVIg
56
Q

True or false: high dose IVIg is not as effective as plasmaexchange when treating GBS

A

False -> they are as effective

57
Q

What are the two anti-inflammatory mechanisms-of-action of IVIg?

A
  1. F(ab)2-dependent
  2. Fc-dependent
58
Q

Which mechanisms entail the F(ab)2-dependent mechanism-of-action of IVIg? (4)

A
  1. Cell depletion via ADCC
  2. Blocking cellular receptors
  3. Cytokine/auto-antibody neutralization
  4. Anaphylatoxin scanning
59
Q

Which mechanisms entail the Fc-dependent mechanism-of-action of IVIg? (5)

A
  1. Saturating neonatal Fc receptor
  2. Treg expansion
  3. Blocking activating receptors
  4. DC modulation
  5. FcyR expression modulation
60
Q

Which Fcy-receptor has a high affinity for immunoglobulins?

61
Q

Besides FcyRI, what do the other Fcy-receptor need to become activated in a sufficient way?

A

Immune complexes

62
Q

ITP: Platelets bound with antibodies can be phagocytosed by macrophages. This leads to?

A

Loss of thrombocytes

63
Q

Mechanism 1: IVIg-dimers are able to block binding of pathogenic immune complexes to activating Fcy-receptors. Is this F(ab)2- or Fc-dependent?

A

Fc-dependent

64
Q

Mechanism 1: IVIg-dimers are able to block binding of pathogenic immune complexes to activating Fcy-receptors. Which cell types are involved? (3)

A
  1. Macrophages
  2. NK cells
  3. Neutrophils
65
Q

Mechanism 1: IVIg-dimers are able to block binding of pathogenic immune complexes to activating Fcy-receptors. What does this prevent? (2)

A
  1. Phagocytosis
  2. Further activation
66
Q

Mechanism 1: What is important for FcR-mediated inhibition?

A

Glycosylation of IVIg

67
Q

Mechanism 1: Why is glycosylation of IVIg important for FcR-mediated inhibition?

A

Some glycosylation patterns result in stronger binding to Fcy-receptors compared to others

68
Q

Mechanism 1: Which glycosylation pattern on immunoglobulins result in binding to target cell leading to killing of this cell?

A

Gal (-), Fuc (+)

69
Q

Mechanism 1: Which glycosylation pattern on immunoglobulins results in higher affinity binding of these antibodies to especially FCyRIII?

A

Gal (+), Fuc(-)

70
Q

Mechanism 1: What does higher affinity of antibodies to especially FCyRIII lead to?

A

Displacement of autoantibodies -> prevents phagocytosis of target cell

71
Q

Mechanism 2: IVIg enhances serum IgG levels. It thereby competes with? In which type of cells?

A

Auto-antibodies for binding to neonatal FcRn in endothelial cells

72
Q

Mechanism 2: IVIg enhances serum IgG levels, and thereby competes with auto-antibodies for binding to neonatal FcRn in endothelial cells. This leads to?

A

Increased degradation of auto-antibodies

73
Q

Mechanism 2: For which process is the neonatal Fc-receptor important?

A

Recycling IgG

74
Q

Mechanism 2: What are the steps of the catabolism of normal IgG? (5)

A
  1. Immunoglobulins are taken up via endo- or pinocytosis
  2. Affinity of immunoglobulin for the neonatal Fc-receptor increased
  3. Immunoglobulins bind to neonatal Fc-receptor
  4. Recycling back to cell surface
  5. Rest of cargo within endo-lysosome is degraded
75
Q

Mechanism 2: Why does the affinity of immunoglobulins for the neonatal Fc-receptor increase within the endosome?

A

Due to the acidic environment within the endosome

76
Q

Mechanism 2: What happens when you overload the system of catabolization of IgG with IVIg?

A

Saturation of binding spaces of neonatal Fc-receptor

77
Q

Mechanism 2: What does the saturation of binding spaces of neonatal Fc-receptors lead to?

A

Antibodies that are unable to bind are degraded -> decrease of pathogenic antibodies

78
Q

Mechanism 3: IVIg up regulates the inhibitory FcyRIIB expression on macrophages. This leads to?

A

Inhibition of phagocytosis of opsonized cells

79
Q

Mechanism 3: The balance between activating and inhibitory Fc-receptors is important for?

A

The activation of different myeloid cells

80
Q

True or false: normally, you have more activating than inhibiting Fc-receptors

81
Q

Mechanism 3: Normally, you have more activating than inhibiting Fc-receptors. What happens if IVIg is inducing more expression of FCyRIIB?

A

Dampen immune activation

82
Q

Mechanism 3 - In mice: How does IVIg affect FCyRIIB expression? (4)

A
  1. IVIg bound to DC-sign
  2. Induction of IL-33
  3. IL-33 induces basophil IL-4 secretion
  4. IL-4 upregulates FCyRIIB expression
83
Q

Mechanism 3: Is this anti-inflammatory mechanism of IVIg also operational in humans?

A

Yes -> high-dose IVIg therapy is still effective in splenectomized humans

84
Q

Mechanism 3: Does IVIg treatment stimulate IL-33 FcyRIIB pathway in humans?

A

Yes -> upregulation of IL-33 and IL-4

85
Q

Mechanism 4: IVIg induces Tregs. Which model is most often example for this mechanism?

A

EAE -> MS mouse model

86
Q

Mechanism 4: What do you see when you treat mice with IVIg after EAE has been induced? (2)

A
  1. Disease severity much less
  2. Percentage of Treg within CD4 T cell compartment is increased
87
Q

Mechanism 4: What do you observe when you treat patients with high-dose IVIg therapy? (4)

A
  1. No Increase in no. Tregs
  2. More activated status
  3. Increase in HLA-DR
  4. Increase of suppressive activity of Treg
88
Q

Mechanism 4: IVIg may expand and stimulate CD4+Foxp3+ Treg via different mechanism of action. What are the hypotheses about these mechanisms? (4)

A
  1. IL-33 -> expansion
  2. IVIg can bind to DCIR -> conversion
  3. IVIg can bind to DC-sign -> expansion
  4. IVIg is internalized -> peptides lead to Tregs
89
Q

True or false: the working mechanism of IVIg differs in antibody-mediated diseases versus T-cell mediated diseases

90
Q

How can you discriminate endogenous IgG from IVIg?

A

Use of allotypes -> can trace these back in patients

91
Q

What are allotypes in the context of IVIg?

A

Polymorphisms in immunoglobulins

92
Q

Which assay can you use to discriminate between endogenous and exogenous IgG?

93
Q

What are the pro’s of expanding the use of IVIg to treat auto-immune disease? (3)

A
  1. No acute adverse effects
  2. No long-term adverse effects
  3. Long half-life
94
Q

What are the con’s of expanding the use of IVIg to treat auto-immune disease? (4)

A
  1. Intravenous administration with long infusion times
  2. Variation between different branches/lots IVIg
  3. Expensive
  4. Safe human plasma limited
95
Q

What are different strategies to replace IVIg? (3)

A
  1. Multimeric IgG Fc
  2. Anti-FcRn Ab
  3. Hypersialyated IVIg
96
Q

How does Multimeric IgG Fc work?

A

Trimeric IgG Fc block binding pathogenic immune complexes to FcR -> mimics IgG dimer

97
Q

How does anti-FcRn Ab work?

A

Block neonatal Fc receptor

I&I WC2 (22 decks)

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