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
2
Q
Describe the short- and long term graft survival pattern
A
Improvement in the first year, after that parallel
3
Q
What are the causes of death in patients with a functioning graft? (5)
A
- Cardiovascular
- Infection
- Malignancy
- GI-liver complication
- Other
4
Q
Incidence of malignancy after transplantation is increased for which tumor types?
A
Almost all tumor types
5
Q
How much higher is the chance to get skin cancer for transplantation patients?
A
~125x
6
Q
Which division in skin cancer types can be made? (2)
A
- Melanoma
- Non-melanoma
7
Q
What are the types of non-melanoma skin cancer? (4)
A
- Squamous cell carcinoma
- Basel cell carcinoma
- Kaposi sarcoma
- Merkel cell
8
Q
Which type of non-melanoma skin cancer most often occurs post-transplantation?
A
Squamous cell carcinoma
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
10
Q
What are risk factors for developing skin cancer post-transplantation? (9)
A
- Ultraviolet radiation
- Light colored hair and eyes
- Geographic location
- Age at transplantation
- History of SCC or BCC (pre- or post transplant)
- Type of transplant
- Type/duration/intensity of immunosuppressive medication
- Viral infection
- Genetic factors
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
12
Q
Which types of transplant have a higher incidence of skin cancer? (2)
A
- Lung
- Heart
13
Q
Which viral infections are mostly associated with malignancy? (2)
A
- HHV8
- HPV
14
Q
In Australia, how many transplantation patients have skin cancer after 5/20 years?
A
5 years: ~30%
20 years: ~ 80%
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
16
Q
The incidence of solid tumors after transplantation depends on? (4)
A
- Genetics
- Environmental conditions
- Patient population accepted for Tx
- Immunosuppressive regime
17
Q
True or false: Patients with invasive cancer live shorter than patients with skin cancer
A
True
18
Q
Which risk factors for cancer after solid organ transplantation do you need to consider? (3)
A
- General risk factors
- After Tx: immunological- and non-immunological risk factors
- Cumulative exposure of immunosuppressive
19
Q
What are the general risk factors for solid tumors after transplantation? (5)
A
- Age
- Gender
- Smoking
- Genetic predisposition
- Race
20
Q
Which immunosuppressant therapies contribute to tumor growth after transplantation? (6)
A
- Antibody therapy
- Anti-B-cell therapy
- CNI
- AZA
- MMF
- Sirolimus
21
Q
What are examples of anti-T cell therapy? (3)
A
- OKT3
- ATG
- Alemtuzumab
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)
23
Q
How does AZA contribute to tumor growth after transplantation?
A
Interaction with DNA repair -> mutagenesis
24
Q
Mutations induced by AZA are mostly associated with which type of malignancy?
A
Skin cancer
25
How does MMF contribute to tumor growth after transplantation?
Impairs lymphocyte function by blocking purine biosynthesis
26
What is the relationship between Sirolimus and tumor growth post-transplantation?
Suppresses the growth and proliferation of tumors in various animal models
27
What are examples of calcineurin inhibitors (CNI)? (2)
1. Cyclosporin
2. Tacrolimus
28
How long after transplantation does malignancy occur?
1. Invasive -> ~50% after 5 years
2. Skin -> ~50% after 10 years
29
Where in the cell do tacrolimus and cyclosporin inhibit cell function?
Downstream of TCR -> inhibits calcineurin enzyme
30
Cyclosporine A and B did not have a strong antibacterial effect, but they did have another beneficial effects. Which effects?
Antibody and cellular immunosuppressive effects
31
What are complications surrounding the operation of a kidney transplantation? (4)
1. Thrombosis
2. Bleeding
3. Infection
4. Ureter obstruction/leakage
32
How would you study/institute ways to reduce the cancer burden? (2)
1. Screening
2. Reactive strategy
33
What would be possible screening strategies? (2)
1. Screening before and after transplantation
2. Population screening
34
What are possible screening option enhancements after transplantation? (2)
1. More frequent screening
2. Start at an earlier age
35
What entails a reactive strategy to reduce the cancer burden?
Reducing immunosuppression
36
In which cancer types has a reactive strategy proven to be effective? (2)
1. Lymphoma
2. Kaposi sarcomas
37
Patients with skin cancers often get their immunosuppression changed to?
Sirolimus -> seems to reduce skin cancer (small degree)
38
When does sirolimus have the biggest effect?
After your first skin cancer
39
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)
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
40
What are caveats in the interpretation of studies on cancer in kidney transplantation? (4)
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
What is Intravenous immunoglobulin (IVIg)
Human IgG purified from pooled plasma of > 1000 donors (administered intravenously)
42
True or false: trace amounts of IgA and IgM can be found in IVIg
True
43
True or false: IVIg mainly consists of dimers
False -> mainly monomers
44
What is the estimated variety in antibodies in IVIg?
10^9 Ag-specificities
45
What are the two main indications for treatment with IVIg?
1. Replacement therapy for primary IgG deficiencies [low dose]
2. Immunomodulation [high dose]
46
What are the three types of therapy where IVIg leads to immunomodulation?
1. Anti-inflammatory therapy
2. Prophylaxis treatment
3. Hyperimmunoglobulins
47
In which instances is IVIg used as anti-inflammatory therapy?
Auto-immune diseases
48
In which instances is IVIg used as prophylaxis or treatment?
Antibody-mediated rejection after kidney transplantation
49
In which instances are hyperimmunoglobulins used? (2)
1. Antiviral therapy (HBV or CMV)
2. Rhesus-negative mothers carrying rhesus-positive baby
50
Which indications are FDA-approved for treatment with IVIg? (7)
1. Hypogammaglobulinemia
2. CLL
3. Kawasaki's disease
4. ITP
5. MMN
6. CIDP
7. Dermatomyositis
51
IVIg is highly demanded in which clinical expertises? (2)
1. Hematology
2. Neurology
52
What is Kawasaki's disease?
Vasculitis -> inflamed medium size blood vessels
53
What is the therapy for Kawasaki's disease? (2)
1. High dose aspirin -> suppress inflammation
2. High dose IVIg
54
What is Immune Thrombocytopenia Purpura (ITP)?
Low platelet counts due to auto-antibodies against platelets
55
What is the therapy for ITP?
1. Corticosteroids -> suppress inflammation
2. If insufficient response: high dose IVIg
56
True or false: high dose IVIg is not as effective as plasmaexchange when treating GBS
False -> they are as effective
57
What are the two anti-inflammatory mechanisms-of-action of IVIg?
1. F(ab)2-dependent
2. Fc-dependent
58
Which mechanisms entail the F(ab)2-dependent mechanism-of-action of IVIg? (4)
1. Cell depletion via ADCC
2. Blocking cellular receptors
3. Cytokine/auto-antibody neutralization
4. Anaphylatoxin scanning
59
Which mechanisms entail the Fc-dependent mechanism-of-action of IVIg? (5)
1. Saturating neonatal Fc receptor
2. Treg expansion
3. Blocking activating receptors
4. DC modulation
5. FcyR expression modulation
60
Which Fcy-receptor has a high affinity for immunoglobulins?
FcyRI
61
Besides FcyRI, what do the other Fcy-receptor need to become activated in a sufficient way?
Immune complexes
62
ITP: Platelets bound with antibodies can be phagocytosed by macrophages. This leads to?
Loss of thrombocytes
63
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?
Fc-dependent
64
Mechanism 1: IVIg-dimers are able to block binding of pathogenic immune complexes to activating Fcy-receptors. Which cell types are involved? (3)
1. Macrophages
2. NK cells
3. Neutrophils
65
Mechanism 1: IVIg-dimers are able to block binding of pathogenic immune complexes to activating Fcy-receptors. What does this prevent? (2)
1. Phagocytosis
2. Further activation
66
Mechanism 1: What is important for FcR-mediated inhibition?
Glycosylation of IVIg
67
Mechanism 1: Why is glycosylation of IVIg important for FcR-mediated inhibition?
Some glycosylation patterns result in stronger binding to Fcy-receptors compared to others
68
Mechanism 1: Which glycosylation pattern on immunoglobulins result in binding to target cell leading to killing of this cell?
Gal (-), Fuc (+)
69
Mechanism 1: Which glycosylation pattern on immunoglobulins results in higher affinity binding of these antibodies to especially FCyRIII?
Gal (+), Fuc(-)
70
Mechanism 1: What does higher affinity of antibodies to especially FCyRIII lead to?
Displacement of autoantibodies -> prevents phagocytosis of target cell
71
Mechanism 2: IVIg enhances serum IgG levels. It thereby competes with? In which type of cells?
Auto-antibodies for binding to neonatal FcRn in endothelial cells
72
Mechanism 2: IVIg enhances serum IgG levels, and thereby competes with auto-antibodies for binding to neonatal FcRn in endothelial cells. This leads to?
Increased degradation of auto-antibodies
73
Mechanism 2: For which process is the neonatal Fc-receptor important?
Recycling IgG
74
Mechanism 2: What are the steps of the catabolism of normal IgG? (5)
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
Mechanism 2: Why does the affinity of immunoglobulins for the neonatal Fc-receptor increase within the endosome?
Due to the acidic environment within the endosome
76
Mechanism 2: What happens when you overload the system of catabolization of IgG with IVIg?
Saturation of binding spaces of neonatal Fc-receptor
77
Mechanism 2: What does the saturation of binding spaces of neonatal Fc-receptors lead to?
Antibodies that are unable to bind are degraded -> decrease of pathogenic antibodies
78
Mechanism 3: IVIg up regulates the inhibitory FcyRIIB expression on macrophages. This leads to?
Inhibition of phagocytosis of opsonized cells
79
Mechanism 3: The balance between activating and inhibitory Fc-receptors is important for?
The activation of different myeloid cells
80
True or false: normally, you have more activating than inhibiting Fc-receptors
True
81
Mechanism 3: Normally, you have more activating than inhibiting Fc-receptors. What happens if IVIg is inducing more expression of FCyRIIB?
Dampen immune activation
82
Mechanism 3 - In mice: How does IVIg affect FCyRIIB expression? (4)
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
Mechanism 3: Is this anti-inflammatory mechanism of IVIg also operational in humans?
Yes -> high-dose IVIg therapy is still effective in splenectomized humans
84
Mechanism 3: Does IVIg treatment stimulate IL-33 FcyRIIB pathway in humans?
Yes -> upregulation of IL-33 and IL-4
85
Mechanism 4: IVIg induces Tregs. Which model is most often example for this mechanism?
EAE -> MS mouse model
86
Mechanism 4: What do you see when you treat mice with IVIg after EAE has been induced? (2)
1. Disease severity much less
2. Percentage of Treg within CD4 T cell compartment is increased
87
Mechanism 4: What do you observe when you treat patients with high-dose IVIg therapy? (4)
1. No Increase in no. Tregs
2. More activated status
3. Increase in HLA-DR
4. Increase of suppressive activity of Treg
88
Mechanism 4: IVIg may expand and stimulate CD4+Foxp3+ Treg via different mechanism of action. What are the hypotheses about these mechanisms? (4)
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
True or false: the working mechanism of IVIg differs in antibody-mediated diseases versus T-cell mediated diseases
True
90
How can you discriminate endogenous IgG from IVIg?
Use of allotypes -> can trace these back in patients
91
What are allotypes in the context of IVIg?
Polymorphisms in immunoglobulins
92
Which assay can you use to discriminate between endogenous and exogenous IgG?
ELISA
93
What are the pro's of expanding the use of IVIg to treat auto-immune disease? (3)
1. No acute adverse effects
2. No long-term adverse effects
3. Long half-life
94
What are the con's of expanding the use of IVIg to treat auto-immune disease? (4)
1. Intravenous administration with long infusion times
2. Variation between different branches/lots IVIg
3. Expensive
4. Safe human plasma limited
95
What are different strategies to replace IVIg? (3)
1. Multimeric IgG Fc
2. Anti-FcRn Ab
3. Hypersialyated IVIg
96
How does Multimeric IgG Fc work?
Trimeric IgG Fc block binding pathogenic immune complexes to FcR -> mimics IgG dimer
97
How does anti-FcRn Ab work?
Block neonatal Fc receptor
98
