Clinical pharmacology Flashcards
What is IVIg?
Human IgG (with trace IgA) purified from pooled plasma of 1000-15000 donors with a variety of 10^9 antigen specificities.
What is the IgG composition of IVIg?
It is mostly monomers with <5% IgG-dimers. Most is IgG1 and IgG2. Up to 4% is IgG3 and 0.5% is IgG4.
How is IVIg administered?
Intravenously, but increasingly administered subcutaneously since this can also be done at home
What doses can IVIg be given in, and when is each given?
Low dose is given as replacement therapy such as in primary antibody deficiencies.
High dose is given in certain autoimmune diseases as immunomodulation.
What IVIg dose is given to people with primary antibody deficiencies
Low dose as replacement therapy
What is Kawasaki’s and what is used as therapy for this? How does this work?
Vasculitis of medium-sized vessels, causing necrosis. For therapy, first aspirin is given to reduce inflammation, then high-dose IVIg, which clears symptoms within 2 days.
In Kawasaki’s macrophages, neutrophils and DCs are activated through their Fcy receptors. IgG in IVIg blocks Fcy receptors through dilution.
How does IVIg work in ITP?
ITP is caused by auto-antibodies against platelets, where macrophages in the spleen phagocytose them. IgGs bind to macrophage Fcy receptors, blocking them from being able to attack the platelets.
What are the two routes by which IVIg has effects?
F(ab)2-dependent and Fc-dependent
How does F(ab)2-dependent IVIg treatment work? (2)
IgGs can directly neutralize antibodies, cytokines, soluble receptors and toxins, and they themselves can bind to cells for cell depletion by NK cells and macrophages
How does FcRn saturation work? What is it used for?
Harmful antibodies are able to persist due to the recycling function of FcRn. By saturating FcRn, these harmful antibodies can’t be recycled (as easily).
How does IVIg expand Tregs?
Engagement of FcyRIIb on DCs increases production of IL-10 and TGF-ß
Is complement inhibition Fc- or F(ab)2-dependent?
It can be both. F(ab)2 can directly bind and neutralise C3a and C5a and saturate out auto-antibodies that lead to complement activation.
Fc can bind to other complement proteins such as those involved in MAC, they can bind to FcyRIIb which upregulates inhibitory receptors, and bind to DC-SIGN on DCs which increases IL-10 production and thus dampens complement activation.
How can IVIg modulate DCs?
They can bind to DC-SIGN through Fc and increase IL-10 production
Which FcyR is found on neutrophils?
FcyRIIIB
Which FcyR is inhibitory?
FcyRIIB
How can IVIg be anti-inflammatory? (mechanism 1)
They can block binding of pathogenic immune complexes through activating FcyR on macrophages, NK cells and neutrophils
What role does glycosylation play in FcR-mediated inhibition?
Composition of different sugars can determine affinity, where higher affinity binding can lead to more effective displacement of auto-antibody binding
How does IVIg affect FcyRIIB expression and what is the significance of this?
It can upregulate inhibitory FcyRIIB expression, thereby inhibiting phagocytosis of (by antibody) opsonized cells and preventing potentially pathogenic degradation in the case of auto-antibodies.
Are Fc studies in mice directly translatable to humans?
No, they have different Fc receptors and the anatomy of the spleen is different.
Does IVIg expand Tregs?
No, but increases HLA-DR (activation) and foxp3 expression, leading to an enhanced suppressive capacity through IL-10 and TGF-ß.
What is the mechanism of action of tacrolimus?
It is a calcineurin inhibitor downstream of signal 1 in T cells (MHC+peptide). This disrupts transcription of IL-2, thereby interfering with T-cell activation, proliferation, and differentiation.
What are the main side effects of transplantation? (3)
- Surgery complications (bleeding, infection)
- Medication side effects (immunosupression)
- Negative effects of immunosuppression (infection, cancer, kidney damage)
What is the most common type of cancer after transplantation?
Skin, especially squamous cell carcinoma. About half of patients have at least one skin cancer 20-25 years after transplant. A large proportion have >3 skin cancers every year.
What is the main risk factor for developing skin cancer after transplantation?
Sunlight exposure
What is an example as to why we should be careful interpreting database results of cancer risks in transplant patients?
If the question is: What would be the effect if we would lower immunosuppressive therapy after the first year of transplantation?
You could do database research looking at graft survival and compare people that continued immunosuppressive therapy and those that reduced or withdrew altogether.
When doing so, it was found that those who continued immunosuppression had a higher graft survival than those who reduced or withdrew altogether. However, it was not indicated whether those in withdrawal or deduction groups were already experiencing nephrotoxicity from the drugs and thus already had poor graft function.
Is changing immunosupressive therapy the best strategy for reducing skin cancer?
It is not routinely done due to the risk for the transplant and the risk of side effects, since ~25% of patients do not toletate sirolimus. However, it does appear to reduce formation of skin cancer to a small degree, especially when done shortly after transplantation. The choice is different per person. Prevention of sunlight exposure is key.
What is membranous nephropathy?
Glomerular disease that leads to protein and/or blood in the urine
How can acute glomerular disease present?
Nephrotic or nephritic. Nephrotic is protein in the urine due to leakage or dysfunctional filtering, whereas nephritic is due to inflammation such as vasculitis or glomerulitis
What type of acute glomerular disease is characterized by hematuria?
Nephritic syndrome. Urine can look like coca cola or smoky
What is ANA testing?
It is used to detect autoantibodies that target components of the cell nucleus. It is primarily used in the diagnosis of autoimmune diseases, particularly systemic lupus erythematosus (SLE).
What happens to podocytes in membranous nephropathy?
Foot processes are fused, and there are subepithelial deposits of immune complexes at the glomerular basement membrane.
What causes GBM deposits?
Glomerular basement membrane deposits are caused by auto-antibodies against the M-type PLA2 receptors, which are transmembranous receptors in podocytes
What is the result of membranous nephropathy?
Proteinuria, due to podocyte damage cause by auto-antibodies against receptors on podocytes, leading to immune complexes and complement activation
What type of antibodies are those present in membranous nephropathy?
IgG4
How can biopsies lead to diagnosis of membranous nephropathy?
Multiplex staining of IgG and PLA2R (the receptor to which the auto-antibodies bind), where overlap of these indicates the disease
What is the best way to treat membranous nephropathy?
Anti-CD20 (Rituximab) to target B cells, including those that produce auto-antibodies.
IVIg doesn’t work because this is an IgG4-mediated disease, for which IVIg doesn’t work well since IgG4 does not activate complement and is monomeric, so it only really neutralizes and does not induce Fc-dependent pathways.
T cells can be targeted, such as with corticosteroids or calcineurin inhibitors.
How to assess treatment response in membranous nephropathy patients?
Assess proteinuria levels (creatinine and albumin)
What is hemolytic uremic syndrome?
A spectrum of syndromes that cause hemolysis and uremia.
What are diagnostic signs of hemolytic uremic syndrome?
Signs of red blood cell lysis: Low RBC, hemoglobin present (shouldnt be in serum), fragmentocytes (fragmented blood cells). Also high creatinine due to the uremia.
What are the 3 hallmarks or hemolytic uremic syndrome?
Microangiopathic hemolytic anemia
Thrombocytopenia
Acute kidney injury
What are the histological indications for HUS?
Narrowing and blockage (by thrombi and red blood cells) of renal blood vessels
What are the 4 underlying diseases that lead to HUS?
Co-existing diseases or conditions (transplantation, hematological malignancies, drugs)
Infections (S. pneumoniae, e. coli shiga toxin, viruses)
Cobalamin C defect
Atypical HUS
What is the most common cause of HUS?
STEC: Shiga toxin in e. coli. It causes 90% of HUS in children
What is the pathogenesis of atypical HUS?
Atypical HUS is complement-mediated. Mutations lead to dysregulation of the complement system, particularly in the alternative pathway, where complement leads to destruction of RBC and endothelial cells
What are two genes in which mutations can be found in atypical HUS patients?
Factor H (Can be due to a mutation or an antibody) -> regulates C3
Mutation in C3 itself
Both lead to dysregulation of the alternative pathway
What is the best and only targeted treatment (on the market) for atypical HUS?
Eculizumab. It prevents C5 cleavage and MAC formation
