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From the Sunday Times, 12/9/99. Interesting:
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JW

 Medicine

     Fooling killer cells will make organ
              transplants safer               

TRANSPLANT patients may soon be able to
receive organs without the danger of
disabling their immune systems, writes Roger
Dobson.

Instead of taking out the patient's entire
immune system with powerful drugs, the new
technology makes it possible for doctors to
target and de-activate only those killer
cells - called T-cells - that are a threat.

The breakthrough means it may soon be
possible to carry out transplants with donor
tissue that is not fully matched, and without
the need to use the anti-rejection drugs,
which can have undesirable side effects.

In the first trial of the new technology on
humans, out of 12 patients, including one
only six months old and suffering from
leukaemia, only one developed grant-versus
host disease or GVHD, a potentially fatal
condition caused by rejection. Normally,
60%-90% of patients would get GVHD. Trials
involving heart and kidney patients are
expected soon.

In bone-marrow transplants, doctors have to
suppress the T-cells in the incoming tissue
rather than in the recipient.

The T-cells in the donor tissue need two
signals to go on the attack. One comes from
an antigen, a protein on the surface of the
tissue in the recipient, and the other from
the interaction between the antigen and the
T-cells in the donor tissue. When both these
signals get through to the T-cell receptors,
the killer cells are sent into action. But if
only one signal from the antigen gets through
and the other is blocked, the T-cells go into
a mode known as anergy, in which they are
incapable of reacting to that specific
antigen.

Work by a team at the Dada-Farber Cancer
Institute in Boston, Boston Children's
Hospital and Harvard Medical School, which is
also based in the city, has found that
interference with the interaction signal
allows successful transplants of bone marrow
to take place without the need for
immunosuppression drugs.

To block the signal they have identified a
soluble compound that has a much stronger
attraction to the antigen than has the
molecule on the surface of the T-cell.

By incubating the bone marrow for transplant
in a solution of this material along with
cells from the recipient, the team reasoned
that they would be able to disrupt the signal
from the antigen to the T-cells.

Having developed the idea in the laboratory,
they then enrolled 12 patients for
bone-marrow transplants using tissue from
donors who had only one or two main areas of
compatibility with the recipient. Although
all the patients were at high risk of GVHD,
only one developed the condition.

According to Eva Guinan of Dada-Farber, the
results have been astounding. She says: "With
conventional drugs we would have expected to
see severe GVHD in 60% to 90% of recipients,
yet only one case of acute GVHD was observed
and no deaths were attributable to it."

It was also found that patients were able to
overcome any infections they acquired,
showing that the immune system was intact
apart from its inability to attack the
antigens on the incoming tissue.

Guinan says the technology has big advantages
over the present ways of suppressing T-cells:
"The real weakness of transplantation now,
whether it is a heart or bone marrow, is that
you are using a sledgehammer in the form of
global immunosuppression to suppress a very
tiny specific event, the targeting of the
specific antigen," she says. "The other
T-cells may be busy killing flu and other
infections and when you give these drugs you
are very inefficiently dealing with the
entire population of cells."

Guinan says the technology has big
implications for other kinds of transplants.
"Blocking the second signal has been done in
animal models of kidney, heart and pancreatic
transplants very successfully, but not on
humans," she says.

"It now needs to be brought to human trials
and I expect to see people doing that within
the next couple of years. Ours is the first
application in humans of this form of
targeted suppression."


Copyright 1999 Times Newspapers Ltd.