Penn Dental Study Finds Altering Bone Marrow Can Train Innate Immune System

PHILADELPHIA, Jan. 18, 2018 /PRNewswire-USNewswire/ -- When you receive a vaccine against a disease, your adaptive immune system gears up to defend against that particular infection,  a function carried out by hyperspecific T and B cells, each targeted to a particular threat.

But what if a more general vaccine existed, that could steel the immune system against threats of various sorts? In a recent paper published in Cell, Penn Dental Medicine researchers collaborated with an international team to show how the innate immune system can also be trained to "remember" past threats and respond more robustly to future challenges.

The scientists show that this innate immune training takes place in the bone marrow. The findings point to a strategy of priming the immune system prior to a situation where the risk of infection was high, or prior to chemotherapy to avoid a depletion of the immune system's neutrophils, some of the first cells to travel to points of infection.

Dr. George Hajishengallis, Thomas W. Evans Centennial Professor of Microbiology at Penn Dental Medicine, was a co-senior author along with Mihai Netea of Radboud University and Triantafyllos Chavakis of the University of Dresden.

The dogma in immunology has been that the innate immune system does not possess a memory. Recently, however, studies have questioned this notion, showing that the innate immune system can be trained to have a robust response by challenging it with stimuli, such as ?-glucan, a sugar molecule found in fungus. These initial investigations of innate immune training suggested that this effect was mediated by epigenetic changes to mature myeloid cells. But, because these mature cells survive only a day or two and the training effect can last months, the researchers knew there had to be some other mechanism at work.

Their hypothesis was that the changes had to somehow affect the bone marrow, the site of hematopoietic stem cells, or HSCs, and specifically those that serve as myeloid cell precursors. To test this, they gave mice an injection of ?-glucan and within a day their HSCs expanded in number.

"But it was not a random expansion," Hajishengallis says. "There was a bias toward myelopoiesis," that is, the generation of myeloid precursor cells. What's more, they confirmed that the HSC changes were lasting.

To see if this myeloid cell expansion had a protective effect, the researchers challenged mice that had received ?-glucan with a substance that mimics a bacterial infection, finding they had a greater production of myeloid cells and less evidence of DNA damage in their HSCs.

The ?-glucan challenge also had a beneficial impact after chemotherapy. While chemotherapeutics can deplete critical immune cells, the researchers found ?-glucan stimulation resulted in mice having more white blood cells after treatment with two common chemotherapeutic drugs. These mice also lived longer than those that received a control injection.

These results do come with a caveat. The researchers note that, despite the protective effects from infection and chemotherapy, there are reasons to be cautious about innate immune training. Amping up the innate immune system could cause an overabundance of inflammatory signaling, leading to problems, such as tissue damage or autoimmune disease.

Going forward, the researchers plan to look at innate immune system training in the context of ageing and how it affects the course of a variety of disease conditions.

The work was supported by the European Research Commission (Grant DEMETINL), Deutsche Forschungsgemeinschart (grants CH279/5-1, TR-SFB127 and SFB854/B26N) and National Institutes of Health (grants DE024716 and DE026152).

CONTACT: Beth Adams, 215-573-8224, [email protected]

SOURCE Penn Dental Medicine