Blocking inflammation to improve the effect of vaccines

UCL-led research team has found that an anti-inflammatory pill could make vaccines more effective for elderly people. An excessive inflammation reaction in older people can obstruct the immune system. The immune system declines with age, and people can be affected by pathogens they were once immune to, when it comes to cutaneous immunity - specific to skin - the immune system was being obstructed by skin cells that were too prone to producing inflammation responses.

To investigate immune responses, the researchers injected an antigen - a derivative of a pathogen that creates an immune response without inducing illness - into the skin of 175 participants (78 were over 65 years old and the rest were under 40). The pathogen was the varicella zoster virus (VZV), which causes chicken pox. After a person contracts chicken pox, they become immune to VZV, but it can re-activate in old age and cause shingles if T cell immune responses aren't strong enough.

All study participants had previously had chicken pox, meaning they should be immune. The researchers found that the older subjects exhibited weaker immune responses, as there was less T cell activation, and less reddening and swelling of the skin. The reduced response was not due to a lack of resident memory T cells present in the skin. As a control, they also injected a benign saline solution into the other arm of each participant.

 The researchers noticed that even the saline solution brought about an inflammation response in some of the older participants. Those who had the strongest inflammation responses to the saline solution had the weakest immune responses to the VZV, suggesting that the excessive inflammation was inhibiting VZV-specific immunity. Normally inflammation is a healthy part of the body's immune response, too much inflammation was getting in the way of the rest of the body's defences.

By analysing skin biopsies post-injection, the researchers found that the excessive inflammation was associated with activation of the p38 MAP kinase pathway. To test whether this enzyme was to blame, they conducted a follow-up test with 18 of the over-65 participants, who took Losmapimod, a drug that inhibits the enzyme in order to reduce acute inflammation responses. While the drug was designed for long-term use and has been trialled for treatments of COPD and arthritis, the participants only took the pill for 4 days, before once again being injected with the VZV antigen. Losmapimod treatment successfully increased the immune responses to the VZV antigen.
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Activation of immune T cells changes behavior

Researchers have discovered that T cells immune cells that protect the body from infections and cancer change the body's metabolism when they are activated, and that this activation leads to changes in behavior.

It is currently known that individual T cells change their metabolism to meet their energy needs after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored.

 To understand the systemic effects, the group looked at T cell activation in mice designed to lack a surface receptor called PD-1, which is necessary for inhibiting the activity of T cells. T cells remain activated in mice without the receptor, similar to those in the immune systems of people with certain types of autoimmune disease.

In these mice, they found that amino acids molecules that are used to build proteins were depleted in the blood, and that they were increased in the T cells themselves, implicating the T cells in the change. The team tracked and imaged amino acids in many organs, and found that the depletion of amino acids from the blood was taking place due to the accumulation of amino acids in activated T cells in the lymph nodes, showing that strong or long lasting immune responses can cause metabolic changes elsewhere in the body.

Researchers analyzed the biochemistry of the brain, they found that the systemic decrease in the amino acids tryptophan and tyrosine in blood led to lower amounts available in the brain, limiting production of the neurotransmitters serotonin and dopamine. These neurotransmitters affect emotions, motivation and fear.

Serotonin is often a target of drugs that combat depression. The researchers found that their depletion in mice without PD-1 resulted in behavioral changes dominated by anxiety and exacerbated fear responses, which could be remedied by providing a diet rich in an essential amino acid.
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