Now, a new mouse study led by researchers at Imperial College London shows that this may be due to T cells blocking nerve cells’ regeneration signals as they age.
The findings, published in the journal Science, also provide positive evidence that these T cells can be suppressed using targeted drugs called monoclonal antibodies to restore and improve nerve cell regeneration.
To better understand the mechanisms behind the age-related decline in the ability of nerve cells to regenerate, the team performed RNA sequencing in young and old mice before and after sciatic nerve injury. RNA sequencing is a technique used to identify which genes are expressed (turned on) or suppressed (turned off) over time in different types of cells.
The researchers sequenced a specific network of nerve cells called the dorsal root ganglia and found that the highest numbers of significantly differently expressed genes appeared in aged mice after injury. Patterns of genes that are “turned on” also appear to be involved in adaptive immune responses, particularly T-cell and cytokine/chemokine signaling.
Targeting T cells
Chemokines are small proteins that stimulate cell migration. The team found that a chemokine called CXCL13, which is specifically induced in neurons of aged animals, attracts a type of T cells called CD8+ T cells, or cytotoxic T cells. These cells were again shown to inhibit nerve cell regeneration after injury in aged mice. Importantly, the researchers used a humanized monoclonal antibody against CXCL13 to deplete cytotoxic T cells in aged mice following sciatic nerve injury.
Monoclonal antibodies are lab-made molecules that work similarly in mice and humans to change the way our immune system interacts with different cells. They are used to treat many different diseases, including cancer. By blocking these cytotoxic T cells, the team found that nerve regeneration was significantly improved. The team also observed that other immune cells — CD4 T cells and B cells — did not alter the nerve cells’ reduced ability to regenerate after injury.
The study shows that an age-related mechanism enables cytotoxic T cells to prevent regeneration of damaged nerve cells, and that monoclonal antibodies could be an effective treatment. The researchers now need to investigate whether the current findings can be replicated in humans.
Senior author Professor Simone Di Giovanni commented. “The use of monoclonal antibodies to prevent these T cells from damaging nerves could promote repair and recovery in large numbers of people affected by traumatic nerve injury. This also has the potential to have implications for a range of diseases, such as diabetes, cancer and in the context of autoimmune diseases neuropathy. We still need to test whether these T cells cause damage to nerve cells in humans, and whether monoclonal antibodies can promote repair. We are also exploring whether this mechanism and therapeutic strategy can promote repair and recovery after spinal cord injury.” .
Professor Giovanni added. “The T cells that cause damage to nerves in older animals are also T cells that normally protect us from viruses, including COVID-19. In older animals, these cells infiltrate the nervous system and other organs, causing tissue damage as a result. This is one of the reasons why older adults are more susceptible to viral infections and tissue damage, including in the nervous system. Therefore, counteracting this problem may protect people from viral infections and neurodegeneration.”