Walworth - Anti-cytokines Flashcards
What are some examples of diseases resulting from chronic inflammation?
RA, IBD (chron’s ulcerative colitis), lupus, psoriasis
What is the general mechanism of how autoimmunity works???
You have some sort of susceptibility gene that somewhat fails in the maintenance of self-tolerance. Then you have an environmental trigger, like an infection which promotes the influx of lymphocytes into tissue and the activation of self-reactive T-cells.
Macrophage-lymphocyte interactions in chronic inflammation
Activated Macrophage spits out IL-1 and TNF-alpha at the lymphocyte, which activates them. Then the activated lymphocyte spits out IFN-gamma, which activates the macrophage.
- it is a cycle
Major effects of IL-1 and TNF-alpha
- fever, increased sleep, decreased appetite (basically all things you associate with being sick)
- leukocyte adherence to endothelium, procoagulant activity
- increased proliferation of fibroblasts, increased collagen synthesis
- increased secretion of pro-inflammatory cytokines (IL-6)
General mechanism of RA
There is an inciting antigen that gets phagocytose do. By a dendritic cell and drives lymphocyte proliferation at the lymph node. Then the T cell will activate the B cells and there will be production of rheumatoid factor (which is IgM and anti-IgG). Complement gets fixed on to rheumatoid factor, and there is upregulation of pro-inflammatory markers and thus tissue (joint) damage.
DMARDS
Non-biological disease modifying anti-rheumatic drugs
- examples are leflunomide and methotrexate
Upon my own investigation, it seems that DMARDs actually treat the underlying cause of the disease and halts the proliferation of rheumatoid factor whereas NSAIDS will just treat the inflammation.
What do leflunomide and methotrexate do?
Prevent proliferation of lymphocytes and reduce the inflammatory process.
Etanercept
EMBREL
- What this drug is is basically the portion of the TNF receptor that binds to TNF. They combine that portion of the receptor with the constant region of the IgG antibody. This way, the TNF binds to this molecule rather than to the actual receptor and TNF-alpha can’t exert its inflammatory effects.
“Cept”
If it has “Cept” in the name you know it has a portion of a receptor in the drug.
Infliximab
Antibody against TNF-alpha. It is a chimeric antibody though with mouse at the variable region and human at the constant region. You want to have as little mouse as possible so you don’t set off an immune response
Adalimumab
Synthetic antibody against TNF-alpha
“Mab”
If it has “mab” in the name that means that it has a monoclonal antibody in the drug.
Anakinra
IL-1 receptor agonist.
CTLA-4
Antagonizes B7 so it can’t co-stimulate CD28. It is a mechanism on the T cell to stop the immune response.
Abatacept
It is a CTLA-4 analog, so it binds to B7 and tones down the immune system. Works well for people with over-active immune systems and certain types of cancers.
Peyer’s Patches
Lymphoid organ found beneath the epithelium in the ileum. Dendritic cells are exposed to antigens here before they travel to the lymph nodes.
What is the basic mechanism of IBD?
It is chronic intestinal inflammation. The intestinal mucosa gets messed up by the increased inflammatory cytokines so more bacteria will be able to penetrate and cause disease.
- chronic self-amplifying loop of inflammation in IBD
What drugs can you give for Chron’s?
Infliximab (which we saw was used for RA) and cetrolizumab
Cetrolizumab
A drug used to treat Chron’s. The way it works is that it is the variable region of a TNF-alpha receptor attached to PolyEthyleneGlycol (PEG), which prolongs the half-life. Essentially the same things as Adalimumab but instead of a constant region you have the PEG to increase the half life in the tough environment.
Benlysta
Lupus drug. It is a monoclonal antibody to BAFF/BLyS.
BAFF
B-cell activating factor. It basically up regulates the amount of B cells. If you have something that is an antibody against BAFF then you will have less B cell production.
- it is on the surface and gets cleaved and eventually makes a 60-mer which causes upregulation of genes responsible for B cell proliferation.
anatomical difference between Chron’s and Ulcerative colitis
Chron’s is whole GI tract and Ulcerative colitis is just colon
BAFFs involvement in lupus
With increased BAFF you have increased pro-inflammatory auto-antibodies. This mostly happens in the kidney, so we often see tissue destruction in the kidney.
Limitations for anti-cytokine therapy
Cytopenias
Infections
- also - infection site reactions, infusion reactions, lymphomas and with infliximab (hepatotoxicity)
Secukinumab
Treatment for psoriasis. Its target is IL-17, which plays an important role in the pathogenesis so psoriasis.
What are some of the preformed mediators of inflammation? Newly synthesized?
Preformed - histamine, serotonin, Lysosomal enzymes
Newly synthesized - PGs, Leukotrienes, platelet activating factor, activated O2 species, NO, cytokines
