The Blood-Brain Barrier Protects Against Inflammation but Creates Challenges for Brain Tumor Treatment

When it comes to inflammation, not all organs are created equal.

Some—including the brain and the spinal cord—are what’s known as “privileged.”By that, immunologists mean that it is very hard to produce inflammation in them, because these organs have very few immune cells. First, it is difficult for the immune cells to enter them to get in, and then the organs also have inhibitors that turn off the immune cells that do manage to gain entry.

Protecting the Brain and Spinal Cord From Infection and Immune Invasion

“There may be limits to immune invasion and having immune cells migrate en masse into them [privileged organs] even though they can enter in small numbers as part of ongoing immune surveillance,” said John MacMicking, PhD, associate professor of microbial pathogenesis and of immunobiology at Yale School of Medicine, and a Howard Hughes Medical Institute investigator.

On one level, this exclusion of immune cells makes sense. The brain and spinal cord, unlike skin or the liver, cannot regenerate themselves. Plus, unlike the kidneys (for example), there is no backup system for the brain and the spinal cord. Once brain cells are gone, they are gone forever. The last thing you want is the body’s powerful immune system rampaging through the brain, triggering neuron-destroying inflammation as it fights infection.

“In one sense, cells of the brain (like neurons)may be less well-equipped to deal with some of the toxic products generated during inflammation,” MacMicking said.

The good news is that it’s difficult for diseases to get into the brain and the spinal cord, but it does happen. So what then? Even worse, what if that disease is cancer? This is one of the reasons that treating brain carcinoma is so challenging.

Delivering Drugs Beyond the Blood-Brain Barrier

With brain tumors, doctors also face another challenge: the blood-brain barrier. This is a thicket of cells that screens out immune cells as well as microbes, said Lieping Chen, MD, PhD, the United Technologies Corporation Professor in Cancer Research and professor of immunobiology, of dermatology,and of medicine (medical oncology).

The blood-brain barrier is helpful in that it keeps illness out of the brain, but it represents a double-edged sword, Chen said. The barrier also makes getting cancer medication into the brain difficult, said Chen, the co-leader of cancer immunology at Yale Cancer Center. “There’s a block,” Chen said. “It protects the brain from most trouble, but it also makes it more difficult to treat brain cancer.”

The blood-brain barrier, however, is not rigid and unchanging. It can contract or expand. Researchers have learned to trick it to expand, increasing the amount of administered medicine that gets through to as high as 40%, Chen said.

Other research at Yale School of Medicine, in collaboration with Beijing Normal University, has found that nanoparticles could penetrate the blood-brain barrier to deliver chemotherapy drugs to tumor cells.

Treating Brain and Spinal Cancers While Controlling Inflammation Is a Balancing Act

Once medicine is inside the brain, clinicians confront an additional challenge: keeping inflammation as tamped down as possible to avoid damaging delicate neurons, Chen said. “If you overdo it a little, you damage the brain,” he said. Understanding and one day learning to control inhibitors that block immune cells will help make treatments more effective, he said.

Previous research, meanwhile, has shown that the blood-brain barrier is not as impenetrable as once believed, according to MacMicking. “Immune cells do get into the brain and look around,” he said, adding that “the idea of an impermeable, unforgiving physical structure is more of a conceptual model than a functional one.” This does allow the cells to initiate inflammatory responses to disease, including cancer, he said.

Spinal cancers, meanwhile, are very rare and inflammation likely plays a role in them as well, MacMicking and Chen agree. “We know that inflammation, along with genetics, is an underlying cause of another central nervous system disease, multiple sclerosis [MS],” said David Hafler, MD, chair of the Department of Neurology, the William S. and Lois Stiles Edgerly Professor of Neurology, and professor of immunobiology. An overly robust autoimmune response leads to inflammation when B cells spurT cells to attack the nervous system, Hafler said. This process causes inflammation predominantly in the white matter of the brain and spinal cord. The result is somewhat akin to stripping the insulation from an electrical wire.

“If you deplete the B cells, you stop the disease,” said Hafler, an MS expert.

As Yale researchers close in on a better understanding of inflammation (or a lack thereof) in the brain and spinal cord, conditions like MS and other nervous system disorders or diseases may soon be diseases of the past.

Originally published Winter 2020; updated May 16, 2022