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Israeli scientists move closer to averting deadly immune overreaction to COVID

Technion team says it has identified the T-cell mechanism that launches ‘cytokine storms,’ which have caused many coronavirus deaths

Nathan Jeffay is The Times of Israel's health and science correspondent

A cytokine storm. (selvanegra via iStock by Getty Images)
A cytokine storm. (selvanegra via iStock by Getty Images)

Israeli researchers say they have identified a possible method to stop the immune system overreaction that has been linked to many deaths from COVID-19, as well as other diseases.

The body’s T cells normally protect it against disease, but they can cause serious health problems when they become overactive. These include cytokine storms, the immune reaction that causes major inflammation and is believed to be behind many of the deaths among COVID-19 patients. The cytokine storms also harm many people suffering from autoimmune diseases.

But researchers at the Technion – Israel Institute of Technology think they have identified a possible route for stopping this overreaction. They have pinpointed a “regulatory site” in a protein within T cells which decides whether or not to launch immune reactions.

Prof. Debbie Yablonski and her team believe it’ll someday be possible to “dial down” the reaction through medication.

They have published their research in the peer-reviewed Journal of Immunology, where it was recommended by the editorial board as a top read, and are now trying to work out how to harness the knowledge to actually halt cytokine storms. The team is already working on identifying drugs that may have that desired effect.

A COVID-19 patient receives a family visit at the Hadassah Ein Kerem hospital in Jerusalem, February 1, 2021. (Olivier Fitoussi/Flash90)

“Sometimes the immune system gets revved up too much and produces a cytokine storm, and following our findings we believe that, in the future, we will be able to fine-tune the level of immune response using drugs,” Yablonski told The Times of Israel.

T cells, a central element of the immune system, can only spring into action once there are two indications that the body is facing a problem, like a tumor or a virus.

“They are like the safety mechanism on a coffee machine which checks that two buttons are being pressed to ensure it’s an adult asking for a drink and not a toddler playing with the machine,” Yablonski said.

Inflammation in human lungs, like that caused by a cytokine storm (sompong_tom via iStock by Getty Images)

One signal is generated as the T cells recognize a specific threat, like a virus. Another, the so-called co-stimulatory signal, is a general signal that confirms there is a problem in the body.

This much is well known, but what Yablonski has discovered is the exact mechanism that first determines whether an individual T cell will initiate an immune response or whether it will refrain.

The ability of T cells to correctly make this decision is important because too little responsiveness would impair immunity to pathogens; however, if the response is triggered too easily, this can have deleterious consequences such as autoimmunity or perhaps a cytokine storm.

“The question is how, exactly, do T cells know that both signs of infection are provided,” Yablonski said. ”And what we have identified is the very mechanism that the cells use to first do this.”

Professor Debbie Yablonski of the Technion-Israel Institute of Technology (courtesy of the Technion-Israel Institute of Technology)

Yablonski said the mechanism — which relies on a protein contained within T cells — verifies the proofs, akin to a bank clerk verifying that two signatures are present on checks from a joint account before authorizing payment.

Her hope now is that, with the mechanism identified, it will be possible to identify ways to manipulate it and tone down the immune response when there is danger of a cytokine storm.

Yablonski’s lab has patented this approach for addressing the problem of immune overreaction — and she believes that finding the right drug for the job can happen within a few years.

“We are at the very early stages, and I’m very hopeful about finding inhibitors that could be very useful for modulating cells,” she said.

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