When we are young, the immune system is a precise mechanism that responds to threats and shuts down. Over the years, neutrophils and monocytes, which give the first response to invaders, lose mobility and effectiveness, and the ability to generate T lymphocytes, which take days to develop because they are specifically trained against the microorganism or cancer cell that threatens us, decreases. The immune system becomes disordered and remains on unnecessarily, the body’s defense becomes weak and chronic inflammation weakens us. Therefore, older people respond less well to vaccines, and become more susceptible to infections, cancer and death.
Today, a team of scientists from several leading US institutions publishes an article in the journal Nature in which it presents a technology to rejuvenate the immune system. The team, led by Feng Zhang, a researcher at the Massachusetts Institute of Technology (MIT) and protagonist in the development of revolutionary technologies such as CRISPR gene editing or optogenetics, has been able to improve the functioning of T lymphocytes in mice by using the liver to produce three factors that promote the maturation of these cells.
The mice that received this treatment were 18 months old, the equivalent of about 50 years in humans, and had an immune system that was beginning to fail. After receiving the treatment, it was seen that the vaccines worked better, generating more T lymphocytes, and they responded better to cancer immunotherapy treatments.
The technique to rejuvenate the immune system is a display of scientific ingenuity. Normally, T lymphocytes are produced in the thymus (that’s where your T comes from), a small organ behind the sternum, which begins to atrophy already at puberty. By 75, it is practically useless. Previous attempts to rejuvenate the immune system have inserted lymphocyte growth factors into the blood, but that can have harmful effects. A stem cell transplant to reconstruct the thymus has also been considered, but even if successful, doing so is not without risk. The thymus is a training place for T lymphocytes, which have to know what is healthy and what is pathological, and beyond puberty, the body loses its pristine health. An active thymus in an elderly person, which trains T lymphocytes with its cells, could classify something as healthy that is not.
Zhang’s team thought of another solution. The researchers first studied what signals fail in the immune system in old age to explain the decline in T cells and identified three important pathways that decline with age: FLT3L, which ensures that enough cells reach the thymus for lymphocyte production, DLL1, which instructs them to specialize into T cells, and IL-7, which keeps them alive throughout the development process.
Later, they considered how to artificially replace these signals and they did so using messenger RNA (mRNA) technology, the same one that was used to develop vaccines against Covid, to convert the liver into a temporary factory that replaces the thymus. Unlike the thymus, the liver maintains a great capacity to produce proteins in old age and it is easy to introduce mRNA into it.
The scientists packaged the information needed to produce the three factors into mRNA sequences and put it into fat nanoparticles to inject into the blood. These particles began to accumulate in the liver, which began to produce the three proteins. After treatment, they saw a clear increase in T lymphocytes.
The researchers then tested how the mice responded to a mock vaccine made with ovalbumin, the most abundant protein in egg white, and saw that T cells with ovalbumin-specific toxicity doubled compared to mice of the same age that received the vaccine but not the mRNA treatment.
They also tested the effect of the treatment on the effectiveness of cancer immunotherapy. After injecting the mRNA into the mice, they implanted tumors in them and treated them with an immunotherapy drug. They saw that they survived longer than those who had only the T lymphocyte production typical of mice of their age. In aggressive melanoma models there were even complete tumor suppressions, something that was not seen in untreated mice.
The researcher at the Severo Ochoa Molecular Biology Center (Madrid) of the CSIC María Mittlebrunn, who has not participated in the study, considers the work “very original and with immense potential.” The biochemist, whose research has shown that the aging of the immune system leads to systemic aging of the entire organism, points out that “if you look at your body, the cells that accumulate the most changes are T lymphocytes.” “They are our bumpers, which protect us from internal and external damage, they are very exposed and that wears them out,” he says.
Mittlebrunn also points out that, for better or worse, the effect of the treatment is temporary. mRNA only makes proteins in the liver for a short time. Afterwards, the factors that increase the production of T lymphocytes disappear. “Awakening the immune system always has risks, because it has an exquisite precision that, if altered, has consequences, such as inflammation or autoimmune diseases, in which the body attacks itself,” adds the researcher. The authors of the article you publish Nature They did not see the mice suffer from autoimmune problems or toxicity.
“The immune enhancement is diluted once treatment administration stops, something we see as a safety feature rather than a limitation,” says Mirco Friedrich, first author of the study and an oncologist at Heidelberg University Hospital. “Determining the optimal balance between duration and safety will be a central question of future research,” he adds.
Regarding the way to apply this therapy, Friedrich explains that “rather than a continuous systemic treatment, it would probably be used in specific windows, such as before vaccination or during immunotherapy treatment for cancer or in periods where the risk of infection is greater.”
Although the messenger RNA platform is well established and allowed effective vaccines against Covid to be developed in months, the application of Zhang’s team is more complex and will have to comply with regulatory standards that will slow down its application. However, Friedrich affirms that they are already considering a first clinical trial with cancer patients in Germany. “A realistic forecast for this phase 1 trial in humans would be 2 years,” he concludes.
