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immune cells

Replenishing the Liver’s Immune Protections

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Kupffer cells
Credit: Thomas Deerinck, National Center for Microscopy and Imaging Research, University of California, San Diego.

Most of our immune cells circulate throughout the bloodstream to serve as a roving security force against infection. But some immune cells don’t travel much at all and instead safeguard a specific organ or tissue. That’s what you are seeing in this electron micrograph of a type of scavenging macrophage, called a Kupffer cell (green), which resides exclusively in the liver (brown).

Normally, Kupffer cells appear in the liver during the early stages of mammalian development and stay put throughout life to protect liver cells, clean up old red blood cells, and regulate iron levels. But in their experimental system, Christopher Glass and his colleagues from University of California, San Diego, removed all original Kupffer cells from a young mouse to see if this would allow signals from the liver that encourage the development of new Kupffer cells.

The NIH-funded researchers succeeded in setting up the right conditions to spur a heavy influx of circulating precursor immune cells, called monocytes, into the liver, and then prompted those monocytes to turn into the replacement Kupffer cells. In a recent study in the journal Immunity, the team details the specific genomic changes required for the monocytes to differentiate into Kupffer cells [1]. This information will help advance the study of Kupffer cells and their role in many liver diseases, including nonalcoholic steatohepatitis (NASH), which affects an estimated 3 to 12 percent of U.S. adults [2].

The new work also has broad implications for immunology research because it provides additional evidence that circulating monocytes contain genomic instructions that, when activated in the right way by nearby cells or other factors, can prompt the monocytes to develop into various, specialized types of scavenging macrophages. For example, in the mouse system, Glass’s team found that the endothelial cells lining the liver’s blood vessels, which is where Kupffer cells hang out, emit biochemical distress signals when their immune neighbors disappear.

While more details need to be worked out, this study is another excellent example of how basic research, including the ability to query single cells about their gene expression programs, is generating fundamental knowledge about the nature and behavior of living systems. Such knowledge is opening new possibilities to more precise ways of treating and preventing diseases all throughout the body, including those involving Kupffer cells and the liver.

References:

[1] Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, Ego KM, Bruni CM, Deng Z, Schlachetzki JCM, Nott A, Bennett H, Chang J, Vu BT, Pasillas MP, Link VM, Texari L, Heinz S, Thompson BM, McDonald JG, Geissmann F3, Glass CK. Immunity. 2019 Oct 15;51(4):655-670.

[2] Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Spengler EK, Loomba R. Mayo Clinic Proceedings. 2015;90(9):1233–1246.

Links:

Liver Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Nonalcoholic Fatty Liver Disease & NASH (NIDDK)

Glass Laboratory (University of California, San Diego)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Cancer Institute


FDA Approves First CAR-T Cell Therapy for Pediatric Acute Lymphoblastic Leukemia

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Emily Whitehead

Caption: Cancer survivor Emily Whitehead with her dog Lucy.
Credit: Emily Whitehead Foundation

Tremendous progress continues to be made against the Emperor of All Maladies, cancer. One of the most exciting areas of progress involves immunotherapy, a treatment strategy that harnesses the natural ability of the body’s own immune cells to attack and kill tumor cells. A lot of extremely hard work has gone into this research, so I was thrilled to learn that the Food and Drug Administration (FDA) just announced today its first approval of a promising type of immunotherapy called CAR-T cell therapy for kids and young adults with B-cell acute lymphoblastic leukemia (ALL)—the most common childhood cancer in the U.S.

ALL is a cancer of white blood cells called lymphocytes. Its treatment with chemotherapy drugs, developed with NIH support, has transformed ALL’s prognosis in kids from often fatal to largely treatable: about 90 percent of young patients now recover. But for those for whom the treatment fails, the prognosis is grim.

In the spring of 2012, Emily Whitehead of Philipsburg, PA was one such patient. The little girl was deathly ill, and her parents were worried they’d run out of options. That’s when doctors at Children’s Hospital of Philadelphia gave Emily and her parents new hope. Carl June and his team had successfully treated three adults with their version of CAR-T cell therapy, which is grounded in initial basic research supported by NIH [1,2]. Moving forward with additional clinical tests, they treated Emily—their first pediatric patient—that April. For a while, it was touch and go, and Emily almost died. But by May 2012, her cancer was in remission. Today, five years later, 12-year-old Emily remains cancer free and is thriving. And I’ve had the great privilege of getting to know Emily and her parents over the last few years.


Snapshots of Life: Host vs. Pathogen

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Cryptoccocus neoformans

Caption: This scanning electron microscopy image shows mouse macrophages (green) interacting with a fungal cell (blue).
Credit: Sabriya Stukes and Hillary Guzik, Albert Einstein College of Medicine

Macrophages are white blood cells that generally destroy foreign invaders by engulfing them. It’s a tried-and-true strategy, but it doesn’t always work. Cryptoccocus neoformans, a deadly fungal pathogen commonly found in the feces of pigeons, can foil even the best macrophages. No one has captured this grand escape—but researchers are getting a whole lot closer to doing so.

Sabriya Stukes, an NIH-funded microbiologist at New York’s Albert Einstein College of Medicine, studies the interactions between C. neoformans and macrophages to determine how the former causes the lung infection cryptococcosis, which can be deadly for people with compromised immune systems. Stukes believes what makes C. neoformans so dangerous is that it can survive the acid death chamber inside macrophages—a situation that spells doom for most other pathogens. A big reason behind this fungus’s power of survival is its thick coat of polysaccharides, which serves as woolly-looking armor. Once a macrophage engulfs the fungus, this coat can give the white blood cell “indigestion,” prompting it to spit the fungus back into the lungs where it can cause disease. 


Rare Disease Sleuths Uncover New Clues to Stroke

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Drawing of a brain section with an inflamed blood vessel

Caption: A variation in the gene that codes for a key blood vessel enzyme makes children prone to fevers, rash, and strokes.
Credit: Jonathan Bailey, National Human Genome Research Institute, NIH

A medical mystery that began when a 3-year-old girl came to the NIH Clinical Center here in Bethesda, MD, a decade ago has just been solved. The findings not only promise to help children suffering from a devastating rare disease, but to advance our overall understanding of stroke and other blood vessel disorders.

When researchers first met the little girl, they were baffled. She had a most unusual—and unexplained—constellation of symptoms: recurring fevers, rashes, and strokes, which, sadly, had left her severely disabled. Researchers thought the cause probably wasn’t genetic, because none of the girl’s family members were affected, plus they hadn’t seen other children with similar problems. While they searched for clues, they treated the girl with immunosuppressive drugs to reduce blood vessel inflammation and thereby lower the chance of future strokes.