By Dean A. Haycock

Special To BioWorld Today

Following a stroke, the immune system isn't much help. In fact, soon after cerebral damage occurs, it may become part of the problem.

This "self"-imposed complication is a consequence of the special treatment evolution has given the brain. In addition to being protected from exterior threats by a thick skull, it is protected from interior threats by the blood-brain barrier (BBB). This network of tightly packed cells in the walls of cerebral blood vessels shields sensitive neurons from many foreign and native elements in the blood that might otherwise interfere with the brain's job.

The BBB breaks down when the brain is damaged by stroke or cerebral ischemia. Immune cells, which under normal circumstances would never be granted access to the central nervous system, leak into the brain. And, conversely, breakdown products from damaged nervous tissue leak out into the periphery. There, brain proteins may be treated as antigens by the immune system. Quickly primed against these antigens, immune system cells may cause inflammation and subsequent damage to brain tissue where the BBB has been compromised.

"It is clear that following a stroke, people do develop a sensitization, as it were, to brain-specific antigens. You can find T cell clones in [stroke patients'] blood that are now reactive to myelin basic protein and you can find immunoglobulins in their blood to myelin basic protein or other central nervous system antigens," Kyra Becker, assistant professor of neurology at the University of Washington, in Seattle, told BioWorld Today. Myelin basic protein (MBP) is a component of the fatty material that insulates the long fibers of neurons called axons that carry electrical signals in the nervous system.

Suppressing the immune system limits stroke damage in animal models but this approach is not practical for humans, who could suffer serious side effects of all-out immune suppression. Furthermore, the immune responses induced by brain antigens following stroke are not well-understood.

This is why Becker, then at the National Institutes of Health (NIH), and her NIH colleagues considered another approach to limiting damage that may be caused by immune cells following stroke.

Instead of suppressing the entire immune system, the NIH team decided to forewarn the immune system about one antigen it might see after a stroke, MBP. By feeding it to rats, they hoped the animals' immune systems would develop oral tolerance to MBP.

Oral tolerance is a well-established form of immune tolerance that can be achieved by feeding antigen to an animal according to a specific pattern and schedule.

The researchers fed MBP to rats before inducing strokes using a technique called transient middle cerebral artery occlusion.

The results are described in a paper titled, "Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia," which appears in the Sept. 30 Proceedings of the National Academy of Sciences.

The protein diet seemed to work. Oral tolerance to MBP translated into significantly smaller areas of damage 24 and 96 hours after stroke was induced in the experimental animals compared to controls. In contrast, rats whose immune systems were made more sensitive to MBP did not survive the post-stroke period. Their immune systems were sensitized to MBP after the protein was injected into their foot pads together with adjuvant to increase the immune response.

Immunologists are not sure why these two methods of exposure, ingestion and injection, produce opposite responses in the immune system, but they are well documented.

Histologic examination of the stroke-damaged brain tissue revealed that T cells in tolerized animals, but not controls, produced transforming growth factor beta-1, an indication that the T cells were changed.

Potential For Stroke Prevention Exists

The results suggest that antigen-specific modulation of the immune system before a stroke can lessen stroke damage while increasing immune sensitivity to the same antigen can increase it.

The authors raise the possibility of inducing oral tolerance in humans who are at substantial risk of stroke.

"There would also be the possibility of aerosolizing MBP and administering it to patients at the time of their stroke," Becker said.

Rapid changes in T cell function following inhalation of aerosolized antigens have been reported in the literature.

"You might actually see rapid changes in lymphocyte function. It might be beneficial even [if administered] post-stroke if you could deliver it in a reasonable time frame. That is something we need to look at as well," Becker said.

The researchers stress that the results of other animal experiments raise the possibility that such treatments might elicit other, unwanted immune responses in addition to the positive results they reported. Long-term testing in animal models will be needed before anyone could seriously suggest testing the idea in the human clinic.

Becker's future plans include documenting that the protective effect she and her co-authors observed was indeed related to a change in lymphocyte activity.

"I further want to document that transforming growth factor beta was responsible for the protective effect. We plan on doing that by doing transforming growth factor beta blocking experiments," Becker said.

Another question for the future is whether a first stroke creates changes in the immune system that effect responses to subsequent strokes.

"One would hypothesize that later strokes may actually be worse because you have immunized yourself. We don't know if that is the case, though," Becker said. *

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