Our immune system is like a well-trained brigade.
Each unit has a unique specialty. Some cells directly kill invading foes; others release protein “markers” to attract immune cell types to a target. Together, they’re a formidable force that fights off biological threats—both pathogens from outside the body and cancer or senescent “zombie” cells from within.
With age, the camaraderie breaks down. Some units flare up, causing chronic inflammation that wreaks havoc in the brain and body. These cells increase the risk of dementia, heart disease, and gradually sap muscles. Other units that battle novel pathogens—such as a new strain of flu—slowly dwindle, making it harder to ward off infections.
All these cells come from a single source: a type of stem cell in bone marrow.
This week, in a study published in Nature, scientists say they restored the balance between the units in aged mice, reverting their immune systems back to a youthful state. Using an antibody, the team targeted a subpopulation of stem cells that eventually develops into the immune cells underlying chronic inflammation. The antibodies latched onto targets and rallied other immune cells to wipe them out.
In elderly mice, the one-shot treatment reinvigorated their immune systems. When challenged with a vaccine, the mice generated a stronger immune response than non-treated peers and readily fought off later viral infections.
Rejuvenating the immune system isn’t just about tackling pathogens. An aged immune system increases the risk of common age-related medical problems, such as dementia, stroke, and heart attacks.
“Eliminating the underlying drivers of aging is central to preventing several age-related diseases,” wrote stem cell scientists Drs. Yasar Arfat Kasu and Robert Signer at the University of California, San Diego, who were not involved in the study. The intervention “could thus have an outsized impact on enhancing immunity, reducing the incidence and severity of chronic inflammatory diseases and preventing blood disorders.”
Stem Cell Succession
All blood cells arise from a single source: hematopoietic stem cells, or blood stem cells, that reside in bone marrow.
Some of these stem cells eventually become “fighter” white blood cells, including killer T cells that—true to their name—directly destroy cancerous cells and infections. Others become B cells that pump out antibodies to tag invaders for elimination. This unit of the immune system is dubbed “adaptive” because it can tackle new intruders the body has never seen.
Still more blood stem cells transform into myriad other immune cell types—including those that literally eat their foes. These cells form the innate immune unit, which is present at birth and the first line of defense throughout our lifetime.
Unlike their adaptive comrades, which more precisely target invaders, the innate unit uses a “burn it all” strategy to fight off infections by increasing local inflammation. It’s a double-edged sword. While useful in youth, with age the unit becomes dominant, causing chronic inflammation that gradually damages the body.
The reason for this can be found in the immune system’s stem cell origins.
Blood stem cells come in multiple types. Some produce both immune units equally; others are biased towards the innate unit. With age, the latter gradually take over, increasing chronic inflammation while lowering protection against new pathogens. This is, in part, why elderly people are advised to get new flu shots, and why they were first in line for vaccination against Covid-19.
The new study describes a practical approach to rebalancing the aged immune system. Using an antibody-based therapy, the scientists directly obliterated the population of stem cells that lead to chronic inflammation.
Blood Bath
Like most cells, blood stem cells have a unique fingerprint—a set of proteins that dot their surfaces. A subset of the cells, dubbed my-HSCs, are more likely to produce cells in the innate immune system, which triggers chronic inflammation with age.
By mining multiple gene expression datasets from blood stem cells, the team found three protein markers they could use to identify and target my-HSCs cells in aged mice. They then engineered an antibody to target the cells for elimination.
Just a week after infusing it into elderly mice, the antibody had reduced the number of myHSC cells in their bone marrow without harming other blood stem cells. A genetic screen confirmed the mice’s immune profile was more like that of young mice.
The one-shot treatment lasted “strikingly” long, wrote Kasu and Signer. A single injection reduced the troublesome stem cells for at least two months—roughly a twelfth of a mouse’s lifespan. With my-HSCs no longer dominant, healthy blood stem cells gained ground inside the bone marrow. For at least four months, the treated mice produced more cells in the adaptive immune unit than their similarly aged peers, while having less overall inflammation.
As an ultimate test, the team challenged elderly mice with a difficult virus. To beat the infection, multiple components of the adaptive immune system had to rev up and work in concert.
Some elderly mice received a vaccine and the antibody treatment. Others only received the vaccine. Those treated with the antibody mounted a larger protective immune response. When given a dose of the virus, their immune systems rapidly recruited adaptive immune cells, and fought off the infection—whereas those receiving only the vaccine struggled.
Restoring Balance
The study shows that not all blood stem cells are alike. Eliminating those that cause inflammation directly changes the biological “age” of the entire immune system, allowing it to better tackle damaging changes in the body and fight off infections.
Like a leaking garbage can, innate immune cells can dump inflammatory molecules into their neighborhood. By cleaning up the source, the antibody could have also changed the environment the cells live in, so they are better able to thrive during aging.
Additionally, the immune system is an “eye in the sky” for monitoring cancer. Reviving immune function could restore the surveillance systems needed to eliminate cancer cells. The antibody treatment here could potentially tag-team with CAR T therapy or classic anti-cancer therapies, such as chemotherapy, as a one-two punch against the disease.
But it isn’t coming to clinics soon. Without unexpected setbacks or regulatory hiccups, the team estimates three to five years before testing in people. As a next step, they’re looking to expand the therapy to tackle other disorders related to a malfunctioning immune system.
Image Credit: Volker Brinkmann
