Monday, July 13, 2009

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TheNational

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Robert Matthews


Last Updated: July 04. 2009


We've all done it. Faced with some malfunctioning
gadget or computer, we pull the plug on it, switch it
back on – and find it works perfectly again.

Known to the cognoscenti as the "hard reboot", it's a
trick used more often in desperation than insight.

Now it's emerging as a promising new approach to
treating some notoriously debilitating medical
conditions.

Recent clinical trials have shown that "rebooting" our
disease-fighting immune system can dramatically
improve the condition of patients with multiple
sclerosis and rheumatoid arthritis.


And according to a study published last
week, it may even bring relief to patients
suffering from the enigmatic condition
Chronic Fatigue Syndrome, affecting
millions worldwide.


There is a growing sense of excitement about the
rebooting technique.

But behind it lies an inspiring story of how a pair of
scientists overcame indifference to convince the
medical community of the merits of what is now
called B-cell Depletion Therapy (BCDT).

B-cells are a type of white blood cell which randomly
churn out so-called antibodies, many of which prove
useful in destroying disease-causing pathogens.

Yet, like every defence system, mistakes sometimes
happen – and innocent bystanders end up being
targeted.

During the late 1990s, two medical researchers at
University College London began to wonder if this
"friendly fire" might hold the key to the debilitating
disease rheumatoid arthritis (RA).

Affecting about one in 100 people worldwide, RA can
strike anyone literally overnight, their immune
system suddenly attacking their joints.

The condition is excruciatingly painful, and for years
there seemed no hope of a cure. Until recently, the
prime culprit was held to be T-cells: white blood cells
that play a key role in the disease-fighting immune
system.

Yet despite intensive study, no one could explain
how or why T-cells should produce a lifelong ailment
such as RA. Most tellingly of all, therapies targeting
T-cells failed to benefit patients.


This prompted Professor Jonathan Edwards and Dr
Geraldine Cambridge at UCL to ponder the possibility
than B-cells might be to blame.

Their idea was based on the fact some B-cells are
known to make antibodies which inadvertently seek
out and destroy healthy tissue.

Normally, these would be destroyed by the B-cells
themselves. But what if some of the antibodies by
chance possessed the means to evade their own
destruction – and go on to attack the joints?

That led Prof Edwards and Dr Cambridge to a
radical new approach to treating RA: "rebooting"
the immune system by destroying all the B-cells,
and then starting over with fresh ones.


Fortunately, a compound capable of targeting just
B-cells had just become available: rituximab, a
so-called monoclonal antibody which homes in on
specific targets like a heat-seeking missile.

This could destroy all the B-cells, leaving patients to
develop a whole new set free of the renegade variety
that attack joints.


That at least was the theory, and with the
standard T-cell theory not getting
anywhere, the team thought it was worth
bringing to the attention of other
researchers.

They soon found that new ideas aren't
always welcome in science – even if the
old ones aren't working.


Their academic papers were rejected by journals
as "obviously" wrong – on the grounds that they
focused on B-cells, not T-cells.


They were not helped by a lack of experimental
evidence. Yet the pair found themselves in a
chicken-and-egg scenario: only if they already had
evidence from clinical trials could they persuade
funding bodies to pay for more clinical trials.


The pair managed to publish their idea in a medical
journal, only to be met with silence. Determined to
make their case, they set up a small but demanding
test, using rituximab to treat five patients with
severe RA.

The results were impressive: once their
B-cell systems had been "rebooted", their
condition improved dramatically. Yet
attempts to publish the results in journals
were rebuffed on the grounds that the
study involved too few patients.


So the pair tried again, cobbling together enough
money to treat 20 patients. Again, the results
were impressive, with all but two of the patients
showing dramatic improvements. It made no
difference: the medical community remained
utterly unimpressed.


Frustrated by the lack of interest, Prof
Edwards and Dr Cambridge decided some
media coverage might help. When the
reports of their success with 20 patients
emerged, they found themselves vilified by
fellow academics as hype-mongers.


Whatever the rights or wrongs of their decision to
approach the media, it certainly boosted awareness
of the B-cell depletion theory.

In 2000, just six people had turned up to hear a
lecture about the theory; a few months later, the
media coverage led to 3,000 packing a lecture hall to
hear what it was all about.


The coverage also helped win funding for a
substantial clinical trial involving more than 160
patients.

By 2002, the results were in: when combined with
a standard therapy for RA, rituximab proved
three times more effective than the standard
therapy alone.

In 2006, the B-cell depletion therapy (BCDT) was
approved by regulators in the US and Europe for
use alongside the standard therapy.


Despite this vindication, the two researchers have
not rested on their laurels. Since the late 1990s,
they have suggested that BCDT might help in
treating another disease linked to a
malfunctioning immune system: multiple
sclerosis.


Last year, a study of more than 100 patients showed
that BCDT could halve their relapse risk. The UCL
team has also shown that the technique brings
benefits to patients with the auto-immune disease,
lupus.


Now a team of researchers in Norway is
claiming the therapy could help treat
Chronic Fatigue Syndrome, sometimes
called myalgic encephalomyelitis (ME).
Characterised by mental and physical
exhaustion, with muscle and joint pain,
this enigmatic condition has no accepted
cause.

Many researchers have suspected a link with the
immune system – a possibility now tentatively
backed by researchers at Haukeland University
Hospital, Norway. In the current issue of the online
journal BioMed Central- Neurology, the team reports
treating three CFS patients with BCDT, and observing
marked improvements.

With so few patients, it's hardly definitive proof of a
cure. Yet it is just the situation Prof Edwards and Dr
Cambridge found themselves in a decade ago. CFS
sufferers must be hoping medical researchers are not
about to repeat history by rejecting these intriguing
findings out of hand – despite not having any better
ideas themselves.


Robert Matthews is a Visiting Reader in Science at
Aston University, Birmingham, England

````````

Rituximab

From Wikipedia, the free encyclopedia

Rituximab, sold under the trade names Rituxan and
MabThera, is a chimeric monoclonal antibody against
the protein CD20, which is primarily found on the
surface of B cells. Rituximab is used in the treatment
of many lymphomas, leukemias, and some
autoimmune disorders. See: _http://bit.ly/ZkUa9_ (http://bit.ly/ZkUa9)


``

See also next Help ME Circle:
*Clinical impact of B-cell depletion with the
anti-CD20 antibody rituximab in CFS*


~jvr


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