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Doctors Looking to Customise Brain-Immune System Interactions

Peripherally derived macrophages infiltrate the brain after bone marrow transplantation and during central nervous system (CNS) inflammation. It was initially suggested that these engrafting cells were newly derived microglia and that irradiation was essential for engraftment to occur.

However, it remains unclear whether brain-engrafting macrophages acquire a unique phenotype in the brain, whether long-term engraftment may occur without irradiation, and whether brain function is affected by the engrafted cells.

Researchers at the University of Virginia neuroscience lab have now found that the engrafting of these immune cells inside the brains of lab mice without the need for radiation is possible.

There are certain diseases where we already know that [the presence of macrophages] is clearly beneficial, but irradiation is a massive barrier clinically,” said researcher James C. Cronk of the UVA School of Medicine’s Medical Scientist Training Program. “This supports the idea that you could do this and get these cells in the brain without having to irradiate, which is a huge step forward in terms of making it feasible.”

There are groups [of scientists] that have gone back and forth publishing papers on Alzheimer’s or ALS debating whether during the normal disease process these cells are coming in and replacing not all, but some of the microglia,

” Cronk said. “If you find out that engraftment is detrimental and we figure out what’s bringing them in, you might block it. Or you might want to increase engraftment, depending on the condition.”

Jonathan Kipnis (from left), James C. Cronk and Christopher C. Overall.

In the course of their investigation, the team identified a “gene signature” to recognize and distinguish the enigmatic macrophages from other cell types. They identified a core set of genes for both the engrafting macrophages and microglia, which enables them to recognize engrafting macrophages as compared to microglia, and microglia really compared to anything.

Lead researcher Jonathan Kipnis, chair of the Department of Neuroscience and director of the Center for Brain Immunology and Glia, noted that the ability to detect macrophages may eventually allow doctors to predict patients’ risk of neurological disease.

It is very possible that these cells somehow get into the brain and then either predispose the brain to disorder or protect the brain from disorder,” he said. “One day we may be able to say you probably will not have Parkinson’s because you have these cells in that area.”

There is a very, very active area of research in terms of whether these macrophages are already present in neurodegenerative disease and whether they’re beneficial or not,” Cronk said. “We’re establishing that yes, this is a unique cell type. … The next step is, ‘OK, what are they doing in the physiology? Can they be artificially put there, or removed, as a therapeutic strategy?’”

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