Time-Based Immune System Activation for Immunotherapy

When bacteria or viruses infect us, our immune system responds and attacks the invaders. It has been extensively trained to detect and remove diseases and repair any harm caused by them.

According to most theories, immune systems work the same whether an illness arises during the day or night. However, more than half a century of study shows that our bodies operate differently during the day and night. The different times are because we have a biological clock, and every cell in our body, including our immune cells, can tell what time of day it is.

For millions of years, our body clock has been evolving to help us stay alive. Proteins in the body accumulate at different rates depending on how much time has passed. Our bodies need to know whether it’s day or night so that they can time their functions and behaviors accordingly (like eating).

Because of our biological clock, our bodies’ internal processes operate on a 24-hour cycle. Melatonin, for example, is produced by our biological clock only when night falls, causing us to feel tired and signaling that it is time to sleep.

Immune System – Cancer and Immunotherapy

Your immune system is critical in the fight against cancer. It is capable of eradicating newly developed cancers. Immunotherapy is a term that refers to a group of therapies that make use of the immune system’s strength. Immunotherapy enables the immune system to specifically target and potentially treat all forms of cancer, therefore saving more lives.

Although the immune system is powerful, it frequently fails to combat cancer due to cancer’s strength.

Vaccinations and immunotherapies are successful because immune cells migrate from organs to lymph nodes periodically. These cells collect and display foreign proteins in order to elicit immune responses directed at specific targets.

Immune system regulation

As revealed in a study conducted by scientists at the University of Geneva (UNIGE) in Switzerland and the Ludwigs-Maximilians University (LMU) in Germany, immune function is at its highest just before the day’s activities begin-early morning in humans and mid-afternoon in nocturnal species such as mice.

An analysis of dendritic cell migration from the skin to lymph nodes during 24 hours presented evidence that the immune system activation was regulated by the time of day.

The joint study findings by the Swiss and German scientists were published in the scientific journal Nature Immunology in an article titled, “Circadian clocks guide dendritic cells into skin lymphatics.”

This research suggests that the timing of vaccination or immunotherapy administration should be addressed to maximize efficacy.

Immune responses are instantaneous, but the innate system does not target or preserve them. On the other hand, Adoptive immune systems require time to develop because they tailor their responses to specific pathogens, such as influenza. They also store their responses in long-term memory so that anti-cancer action may be used again in the future.

Christoph Scheiermann, Ph.D., a corresponding author of the new study, says it takes weeks for the adaptive immune system to develop a response unique to a certain pathogen.

This reaction then persists for an extended time as a result of a cellular memory process. This function is frequently the mechanism that is working during a viral vaccine.

To understand more about how the time of day affects immunity, the researchers looked at dendritic cell migration from the skin into lymphatic veins. Dendritic cell migration is an important part of the adaptive immune response. Dendritic cells transport antigens-fragments of foreign material from the skin and other organs to lymph nodes through lymphatic channels. This migration is the first stage in building an immune response to a particular pathogen.

The study looked at the capacity of dendritic cells to migrate four times a day in mice and compared it to mice without working circadian clocks. Stephan Holtkamp, Ph.D., a researcher at the Biomedical Center of the Ludwig-Maximilian University and the first author of this study, says dendritic cells and lymphatic vessel cells must respond to a circadian rhythm for proper cell migration to occur.

Researchers found that the circadian clock mechanism has to work in both migrating dendritic cells and the cells that line the skin’s lymphatic endothelial cells in mice for the rhythmic daytime migration of dendritic cells to peak in the morning. Otherwise, migration proceeds in slow motion.

Researchers studied human skin cells collected from patients at various times of the day to uncover molecules that regulate rhythmic trafficking. They discovered that the chemokine CCL21 and cell adhesion molecules are responsible for the rhythmic migration in mice and humans.

Professor Scheiermann and his team identified many molecules. Particularly chemokines, proteins secreted by cells that play a vital role in cell migration and are regulated by circadian clocks.

The research discovered identical molecules in human and mouse cells. However, the cells of mice had rhythms aligned to nighttime habits, and human cells followed daytime rhythms.

This difference in rodents and humans demonstrates that natural activities determine this rhythm following the day-night cycle. Additionally, the scientists demonstrated that dendritic cells move rhythmically with a morning peak when the immune system is activated at different times.

Optimizing the immune system and immunotherapy

Patterns of migration rhythms may be making efficient use of the body’s available energy. Putting an immune system on full alert when the danger of infection is greater reduces expensive defensive mechanisms when the body is resting or less likely to come into contact with infectious organisms. Such findings, however, will require more experimentation to understand our remarkable immune systems fully.

Circadian clocks play a key role in the control of the immune system. Science is only beginning to understand fully the complexity of this biochemical oscillator that’s synchronized with solar time. The authors of the new study came to the following conclusion:

“As this process is fundamental for the generation of adaptive immunity, it should prove useful to exploit in vaccination and immunotherapeutic regimens, considering that rhythmicity in innate and adaptive immune responses is maintained in inflammatory reactions.”

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