Walworth - Anti-cytokines

Question 1

What are some examples of diseases resulting from chronic inflammation?

Answer 1

RA, IBD (chron’s ulcerative colitis), lupus, psoriasis

Question 2

What is the general mechanism of how autoimmunity works???

Answer 2

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.

Question 3

Macrophage-lymphocyte interactions in chronic inflammation

Answer 3

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

Question 4

Major effects of IL-1 and TNF-alpha

Answer 4

• 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)

Question 5

General mechanism of RA

Answer 5

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.

Question 6

DMARDS

Answer 6

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.

Question 7

What do leflunomide and methotrexate do?

Answer 7

Prevent proliferation of lymphocytes and reduce the inflammatory process.

Question 8

Etanercept

Answer 8

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.

Question 9

“Cept”

Answer 9

If it has “Cept” in the name you know it has a portion of a receptor in the drug.

Question 10

Infliximab

Answer 10

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

Question 11

Adalimumab

Answer 11

Synthetic antibody against TNF-alpha

Question 12

“Mab”

Answer 12

If it has “mab” in the name that means that it has a monoclonal antibody in the drug.

Question 13

Anakinra

Answer 13

IL-1 receptor agonist.

Question 14

CTLA-4

Answer 14

Antagonizes B7 so it can’t co-stimulate CD28. It is a mechanism on the T cell to stop the immune response.

Question 15

Abatacept

Answer 15

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.

Question 16

Peyer’s Patches

Answer 16

Lymphoid organ found beneath the epithelium in the ileum. Dendritic cells are exposed to antigens here before they travel to the lymph nodes.

Question 17

What is the basic mechanism of IBD?

Answer 17

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

Question 18

What drugs can you give for Chron’s?

Answer 18

Infliximab (which we saw was used for RA) and cetrolizumab

Question 19

Cetrolizumab

Answer 19

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.

Question 20

Benlysta

Answer 20

Lupus drug. It is a monoclonal antibody to BAFF/BLyS.

Question 21

BAFF

Answer 21

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.

Question 22

anatomical difference between Chron’s and Ulcerative colitis

Answer 22

Chron’s is whole GI tract and Ulcerative colitis is just colon

Question 23

BAFFs involvement in lupus

Answer 23

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.

Question 24

Limitations for anti-cytokine therapy

Answer 24

Cytopenias
Infections

• also - infection site reactions, infusion reactions, lymphomas and with infliximab (hepatotoxicity)

Question 25

Secukinumab

Answer 25

Treatment for psoriasis. Its target is IL-17, which plays an important role in the pathogenesis so psoriasis.

Question 26

What are some of the preformed mediators of inflammation? Newly synthesized?

Answer 26

Preformed - histamine, serotonin, Lysosomal enzymes

Newly synthesized - PGs, Leukotrienes, platelet activating factor, activated O2 species, NO, cytokines