Anti-inflammatory in the balance

Inflammation is a good thing, it is the body's response to physical and biological assault and mostly it works a treat. The other day I was yanking my boots out of the car-trunk and nicked my finger on a tooth of the chainsaw.  It didn't hurt but bled quite a bit and the hole was sore for about 24 hours. A nice clean cut; any bacteria flushed out by the blood flow; some local white blood cell activity to mop up the remaining bugs involved a little swelling, a little tenderness and a little redness. Sounds like inflammation to me - I share an old Latin mnemonic with my Hum Physiol students:

• Calor heat
• Dolor pain
• Rubor redness
• Tumor swelling

Sometimes, however, inflammation can be a disastrous over-reaction. Cholera toxin is no fun - it's a toxin after all - but the body's response to the presence of Vibrio cholerae is to flood the intestine with fluid to flush out the toxin producing bacteria: flush flush flush until the cistern and the header-tank run dry and you die of dehydration. They say that fit young people, with active inflammatory /immune systems died disproportionately during the Spanish 'flu pandemic of 1918: the treatment worked but the patient died. One of the consequences of developing an auto-immune disease - rheumatoid arthritis; multiple sclerosis; psoriasis; psoriatic arthritis; lupus; Goodpasture syndrome - is that there is tissue damage. Tissue damage means an inflammatory response which means calor dolor rubor & tumor which is a bloody nuisance and makes you feel utter crap for much of the waking day.

What if, some medical researchers asked, we could damp down the immune response. That would alleviate many of the distressing symptoms of auto-immune diseases and might even promote a bit of healing in the damaged tissue. One of the positive outcomes of 30 years of molecular biological research is that we now have model incorporating some of the key players in the inflammatory response: both what molecules are involved and what cells play a part. As with the nervous system, we reckon that the cellular response is controlled by external molecules = "ligands" which dock and bind with receptors embedded in the cell membrane. "Molecules which are produced by one cell type and act on another cell not in immediate proximity" is a definition of a hormone. But in the context of immunology and inflammation such molecules tend to be called cytokines. Each cytokine will have a particular look&feel and function and will only be effective if it makes contact with a specific receptor. Both cytokines and their receptors are proteins of which we have an inventory of about 100,000 different forms, some quite closely related to each other. Clearly there are two ways to turn inflammation down a notch or two:

• destroy, disable or interfere with the production of one of the cytokines
• put a spanner in the cytokine receptor to prevent docking

Stress is also A Good Thing - it is a way of keying up your physiology to deal with a problem - tiger; alpha-male; sudden change in weather; potential mate - but is ultimately damaging if it goes on for too long. Human Physiology, I intone at almost every lecture, is about the checks and balances of homeostasis. Short cartoon, reasonably on the right track. Homeostasis is maintained in the normal run of things by having both pro-inflammatory and anti-inflammatory cytokines and dribbling them out in the correct proportion for the given situation.

One way of nobbling a cytokine is to develop a 'biologic' an antibody against that molecule. I've written before about the absurd unmemorable hard-to-say names for drugs. But there are some clues: if it ends in -mab it is a monoclonal antibody developed by injecting the . . . heck I'm not going to explain this because it's w-a-a-a-a-y outside my competence so I'll hand you off to John Nguyen at Massachusetts College of Pharmacy and Health Sciences - what's a MAb and how are they made.
More etymological clues:

• omab (original and not the best) = murine monoclonal antibody
• ximab = chimeric (part human part mouse) monoclonal antibodies like infliximab [prev]
• zumab = humanized (less mouse more human than ximabs)
• mumab = fully human monoclonal antibodies are made in human cell lines skipping the mouse protocol. Try saying adalimumab with clarity and authority when explaining its potential to a worried patient.
• Another John Nguyen gallop through a bunch of specific MAbs, their names pronounced and the uses described

The point about MAbs is that they are extremely specific; they will nobble the target molecule and leave everything else alone. So there are usually fewer side-effects. I've written about infliximab before which targets TNF-α a cytokine that cranks up the inflammatory response when cancerous cells appear.  Its name tumour necrosis factor tells the story: with TNF-α tumours are suppressed without it they grow.  Clearly TNF-α is A Good Thing because cancer is the Black Hat of modern Western medicine . . . except when it runs away with itself and cranks up inflammation when it shouldn't. This is the case for a string of auto-immune diseases including rheumatoid arthritis RA, ankylosing spondylitis, inflammatory bowel disease IBD , psoriasis, and refractory asthma and all these disorders can be treated with anti-TNF therapies.

The trouble is that although the MAb is extremely specific - it will take down TNF-α only - TNF-α is a key work-horse in maintaining homeostasis all around the body. By controlling the level of this cytokine to mitigate the debilitating effects of RA or IBD, the patient no longer has enough of the stuff to do its says-on-the-tin tumour necrosis job and lymphomas are a common side effect under long-term use of infliximab. This robbing Peter to pay Paul is a problem in many aspects of modern medicine and the good doctors spend a lot of time and money juggling the competing forces to get a drug and a dose that is a Goldiloxian just right. Cue not strictly relevant fragment of verse:

I balanced all, brought all to mind,  

The years to come seemed waste of breath,  

A waste of breath the years behind

In balance with this life, this death.

WB Yeats An Irish Airman foresees his death