[ RadSafe ] Article: Study reveals risks of interfering with immune system

[John Jacobus]

I have often hear that radiation can have a hormetic
effect by boosting the immune response.  However,
sometimes the responses are not all good.

>From News at Nature.com
Published online: 17 March 2006

http://www.nature.com/news/2006/060313/full/060313-17.html

Tragic drug trial spotlights potent molecule

Study reveals risks of interfering with immune system.
Helen Pearson
 
Researchers are trying to explain how a prototype drug
that manipulates the immune system triggered
devastating side effects in a British clinical trial.

The trial shot into headlines earlier this week when
all six patients who took an experimental antibody
fell rapidly and severely ill. Such an extreme
reaction among so many trial participants is extremely
rare. The UK medical products regulatory agency
swiftly halted the trial and launched an
investigation.

It is not clear whether the problem is due to a
manufacturing error, contamination or the wrong
dosage. It is also possible that this first trial in
humans simply shows we are affected by the drug in a
way that animals are not.

Extreme response

The drug, an antibody called TGN1412, is being
developed by German company TeGenero with the aim of
directing the immune system to fight cancer cells, or
calm joints inflamed by rheumatoid arthritis. The
antibody binds to a receptor molecule called CD28 on
the surface of the immune system's infection-fighting
T cells. 

The immediate focus of researchers is on helping the
patients, who are suffering multiple organ failure.
But scientists note that the trial illustrates how
incredibly potent some immune-altering agents can be.
"The immune system is capable of extraordinary power
and we must be very careful when we tinker with it,"
says Louis Weiner who studies immunotherapy at Fox
Chase Cancer Center in Philadelphia, Pennsylvania.

Some say that TGN1412, or drugs like it, might still
find a use in medicine, if researchers can learn how
to harness and direct its power. "Can we get the good
without the bad?" asks Carl June of the University of
Pennsylvania, who pioneered work on the CD28 molecule.

Critical system

CD28 is a pivotal molecule in the immune system. "So
the potential for off-target effects is enormous,"
says Keith Knutson, an expert in T-cell therapy at the
Mayo Clinic in Rochester, Minnesota.

Normally, a T cell needs two incoming signals before
it fires up: one from CD28 and a second from a
separate T-cell receptor. This double signal is
thought to act as a safeguard to ensure that T cells
react only to real threats such as toxins or invading
pathogens. 

The drug TGN1412 overrides this basic control
mechanism. When it binds to the CD28 receptor, the T
cell becomes active without the need for a signal from
the second receptor. 

Scientists who work in the field say there are several
possible ways that the drug could have triggered
multiple organ failure. It may have stimulated T cells
so much that they released an overwhelming flood of
inflammatory molecules called cytokines. Or perhaps
wayward T cells launched an attack on the body's own
tissues, ignoring the safety mechanisms that normally
keep this in check.

Early trials

A statement from TeGenero expresses the company's
concern for the patients and notes that its trial
adhered to standard clinical research guidelines. It
adds that TGN1412 showed no adverse effects in
previous studies with animals.

At least one similar drug has already shown side
effects in human trials. Skin rashes and gut reactions
have been seen during tests of a drug called
anti-CTLA4 antibody. This also boosts the effects of
the CD28 receptor, but to a lesser degree than
TGN1412.

Scientists have continued to work with anti-CTLA4
antibody and it is now in large-scale clinical trials
to treat cancer. 

+++++++++++++++++++
"Those who corrupt the public mind are just as evil as those who steal from the public purse."
Adlai Stevenson

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

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