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Toronto Scientists Discover Master Immune System Switch
By Helen Branswell, The Canadian Press

TORONTO - A team of Toronto scientists has found the Holy Grail of the body's signaling system: the switch that turns off hormones and proteins which trigger diseases like cancer, heart disease, diabetes and other auto-immune syndromes.

The discovery, which they say they made in a "Eureka!" moment, could provide the key to developing ways to stop the progression of those ailments as well as organ rejection in transplant patients, says lead author Dr. Josef Penninger.

The findings were reported Thursday in the scientific journal Nature.
Scientists the world over have been searching for years for the master switch, said Penninger, who took great satisfaction from the fact that he and his team discovered something that was under everyone's nose all along.

"It's the Holy Grail of the signaling system, to switch it off," he said in an interview Wednesday. "Everybody was looking for this molecule. And we had it in front of our eyes all the way.
"We were kind of looking out of our left eye and didn't see what was out of our right eye."
The research team is drawn from the Ontario Cancer Institute at Princess Margaret Hospital, Toronto General Hospital and the semi-private Amgen Institute, which is affiliated with the University of Toronto.

The team has been responsible for a remarkable string of discoveries over the last couple of years, including finding a protein that stops the growth of colon cancer tumours and learning that a virus can cause some forms of heart disease.

Their latest revelation is that a protein called CD45 is the master switch for the immune system. It sends the ceasefire order once the body has vanquished a foe such as a virus.

"Although the attack signal is a good thing when the body is invaded by disease, you must have a way to call in the troops once the enemy has been defeated," Penninger said.

"Otherwise the immune system . . . goes after healthy cells and results in diseases such as diabetes, multiple sclerosis, heart disease and even cancer."

Scientists have thought for more than a decade that CD45 played a much more limited role, that it simply regulated the behaviour of a couple of types of cells that are part of the immune system.

"This just became absolute paradigm in the field and two years ago I would have also believed in it completely," said Penninger, who in fact published papers supporting that view of CD45's role.

But almost by accident his team discovered that CD45 has a much broader role and is responsible for regulating how the body's cells manage functions such as the growth of red and white blood cells, the regulation of viral infections and heart disease.

They proved their theory in mice, finding that CD45 controlled the development of a virus that induces heart disease.

"We know that in vivo" meaning in a living animal, not just a test tube "it has real relevance....We can change how a disease happens," Penninger said.

The discovery helps make sense of some things that had been previously reported but could not be explained. For instance, it was recently reported that a young boy who had a mutant CD45 developed fatal leukemia. Likewise there have been cases of people with lymphoma whose CD45 didn't work.

And it will help frame future research. Researchers can focus on restoring missing, mutant or damaged CD45 as a way to shut down the growth of rogue cells in the case of cancer or halt the immune system's attack on the pancreas, in the case of diabetes.

Penninger noted that a number of drug companies have already been developing drugs to alter CD45 function for entirely different reasons.
"I'm betting as soon as our paper will appear tomorrow they will all run to the freezers," he said with a chuckle.
While the findings hold great promise, it is too soon to say whether scientists will be able to find a way to activate CD45 flip the master switch without causing damage elsewhere in the system.

For instance, such a therapy might stop the progression of a cancer but suppress the immune system to the point where the patient is susceptible to all sorts of other ailments.

"This will be the question," Penninger said.

The research was funded by Amgen, the Canadian Institute for Health Research, the Heart and Stoke Foundation and the National Cancer Institute of Canada.

Reprinted with permission from Canadian Press, C-Health.

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