Nature has equipped humans with a sophisticated immune system to defend themselves against disease. Immunologists are investigating the many switches and levers that make up this system in order to open up possibilities for new medical treatments. On the occasion of the International Day of Immunology on 29 April, scientists at the HZI offer an insight into their research on the human immune system.

Unleashing the immune system: The battle against pathogens

Nature has equipped humans with a sophisticated immune system to defend themselves against disease. Immunologists are investigating the many switches and levers that make up this system in order to open up possibilities for new medical treatments. On the occasion of the International Day of Immunology on 29 April, scientists at the HZI offer an insight into their research on the human immune system.

The immune system protects us from harmful substances and pathogens. It is a sophisticated network of different cells that communicate with each other via numerous messengers. Immunology is concerned with deciphering the complex processes in the immune system and their regulation.

An increasing understanding of how the body defends itself against invaders has led to many developments in medicine. For centuries now, people have used vaccines to protect themselves against infectious diseases. Vaccines train immune cells to respond to certain pathogens so that they can react quickly and efficiently in the event of an infection. Our immune system also recognises cancer cells as "foreign" and can fight them, but our natural protection against overreactions often prevents the immune system from containing a rapidly growing cancer. Last year, two immunologists received the Nobel Prize in Medicine: They discovered a way to unleash immune cells so that they can conquer cancer.

Scientists at the HZI are also investigating new ways of modulating the reactions of the natural defence system in order to better protect humans from infections and other diseases. For that matter, they pursue a range of different strategies.

Releasing the brakes of the defence

In our body, guard patrols of the immune system are constantly on the move: antigen-presenting cells. They destroy harmful invaders and display the intruders' markers on their own surface – as if they had impaled their opponent's helmet or coat of arms on their spear. These markers, called "antigens", can be parts of viruses, bacteria or cancer cells. The guard patrols send a signal to the immune cells to multiply and mobilise. They identify the pathogen using the presented antigen; however, they also can carry inhibiting "checkpoint" receptors – built-in brakes that prevent a harmful overreaction. This is where the innovative Nobel Prize-winning therapeutic concept comes in: The aim is to release these brakes with the aid of checkpoint inhibitors, so that the immune cells can fight a tumour without any restriction.

One of the checkpoint receptors that has been studied is CTLA4. It binds to the signal transmitter of the antigen-presenting cells and devours it, meaning that the cells cannot activate any other immune cells. The cell then recycles the receptor and places it back on its surface. Likewise, the cell devours a drug that binds to CTLA4 and blocks the receptor. The drug is broken down inside the cell and becomes ineffective. "This means it is crucial to develop drugs that block CTLA4 long enough to give immune cells time to fight the tumour," says Dr Sahamoddin Khailaie, mathematician in the department “Systems Immunology”. He and his colleagues have succeeded in showing that cells absorb the receptor from their surface extremely quickly. As recycling takes some time, a large part of the receptor is always inside the cell and is inaccessible to therapeutic compounds.

"The CTLA4 blockade must not be so strong, however, that the patient risks suffering pathological overreactions of the immune system," says Khailaie about the difficulty of finding the right active ingredients. Together with Prof Michael Meyer-Hermann, who heads the department, Khailaie has developed mathematical models that enable him to predict the uptake and recycling rate of CTLA4 under various conditions. "Our models allow us to predict the optimal strength of a blockade, in order to develop effective checkpoint inhibitors that are also safe for the patient," he says.

Modulating tolerance

Everyone has experienced swelling of their lymph nodes when they have a cold. The reason for this is that more immune cells are migrating into the lymph nodes. There, they receive a profile of the pathogens from the antigen-presenting cells, become active and multiply, and produce antibodies or destroy cells in the body that are already infected with the virus. Regulatory immune cells (regulatory T cells, or Tregs for short) are also recruited. Tregs ensure a balanced immune reaction so that the affected tissue does not suffer any major damage. Prof Jochen Hühn, head of the department “Experimental Immunology”, prefers to call them the peace-keeping soldiers of the immune system.

Lymph nodes are located next to all tissues of our body. Immune cells constantly pass through and exchange updated information about sources of infections in surrounding tissue. But the lymph nodes in the intestines are special – they are very efficient at producing Tregs. Jochen Hühn and his team recently discovered that the diverse bacteria that naturally colonise our intestine as microbiota shape these lymph nodes and teach them how to produce Tregs. The scaffold cells on which the lymph nodes are built store information about which bacteria are beneficial human co-inhabitants. Antigen-presenting cells detect this information, ensure that a large number of Tregs are produced and prevent immune responses against beneficial bacteria or food. Jochen Hühn explains the significance of his new scientific discoveries: "The more we know about how Tregs are created and how they work, the easier it will be to develop therapies to treat autoimmune diseases, for example." On the other hand, if the activation of Tregs could be prevented, i.e. by issuing a specific command for the peace-keeping soldiers to stop and thus briefly unleashing the immune system, this could significantly increase the effectiveness of vaccines.

Strengthening the immune response

Vaccines are one of humanity's oldest methods to prevent infectious diseases. Targeted treatment with weakened or dead pathogens mimics an infection process but without disease symptoms, and it results in the stimulation of pathogen-specific immune responses. The immune system's memory then protects the vaccinated person from infection and a more severe course of the disease.

Today's vaccines usually consist only of individual components of the pathogen, known as subunits. As a result, a vaccine no longer carries a risk of triggering a severe infection. However, these subunit vaccines do not always activate all parts of the immune system as strongly as the real pathogen. The response may therefore be weaker, the vaccine protection less complete or several vaccinations might be necessary. In order to compensate for this shortcoming, many vaccines also contain adjuvants – substances that strengthen the vaccine response. "Some adjuvants serve as delivery systems for the subunit vaccines," says Dr Peggy Riese, who works with Prof Carlos A. Guzmán in the HZI department “Vaccinology and Applied Microbiology”. "They support the targeted transport to the immune cells in order to activate them." Other adjuvants support the immune response by activating or strengthening individual parts of the immune system. Peggy Riese and her colleagues are working in the laboratory to find new substances that can be used as vaccination boosters. "These could be signal substances from bacteria, for example," says the immunologist. "Our experiments help us to understand how these substances specifically alter the response of the immune system and can strengthen the functions of important immune cells." Their findings could contribute to the development of novel vaccination strategies as well as adapting vaccines to specific patient groups, such as children, the elderly or pregnant women, for whom standard vaccines are not suitable or do not provide sufficient protection.

Unleashing, modulating, strengthening: The immunologists at the HZI are investigating various strategies for influencing the immune system. In the future, their findings may help to fight cancer more effectively, alleviate the effects of autoimmune diseases and prevent infections more efficiently.

Author: Ulrike Schneeweiß

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Dr Andreas Fischer

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