Side effects of possible anti-cancer strategy discovered

November 17, 2014

The Malt1 protein carries out a variety of tasks in immune cells, known as lymphocytes. Among other things, it acts as an enzyme - specifically, a protease - that breaks down messenger substances and thus controls their quantity. Until now it was not known what role the specific protease function plays in the development of immune cells. Several years ago Prof. Jürgen Ruland and his team at TUM's Klinikum rechts der Isar turned their attention to this question.

Blockade as a therapeutic approach

The scientists were able to show in earlier cell culture experiments that a blockade of the protease function of Malt1 kills lymphoma cells. The idea was therefore conceived that this strategy could be used against lymphomas, in which Malt1 is often excessively active due to a genetic defect. "A promising therapeutic approach is believed to be the development of substances that specifically inhibit the protease function of Malt1," explains Andreas Gewies, lead author of the study.

The next step was therefore to test this blockade strategy in an animal model in order to shed light on the exact function of Malt1 protease. "It's only possible to study complex interactions in the immune system, which comprises a finely orchestrated interplay of various cell types, in an intact organism - not in cell cultures. The processes are too complex to recreate in cells outside the body," says Ruland, in explanation of the step to using an animal model.

Unexpected effects in the mouse model

The mice used were genetically modified so that their Malt1 protein could no longer act as a protease but was still able to carry out all its other functions. The scientists were surprised to find that the mice developed severe signs of inflammation. Moreover, the immune system attacked and destroyed key neurons that coordinate movements. Consequently, the animals had difficulty controlling and coordinating their movements.

The scientists were able to explain how this serious malfunction of the immune system occurred and in doing so discovered an unexpected function of Malt1. They found that in the absence of the protease function, the mice were unable to produce a specific subset of lymphocytes known as regulatory T cells (Tregs). These cells are crucial for the precise control of immune responses. They ensure that immune responses are damped and, most importantly, finely controlled. Without Tregs, the mice's immune responses went out of control.

The researchers also found that normal lymphocytes can be activated without the protease function of Malt1, but they then release messenger substances uncontrollably, which causes inflammation. "Our study showed that Malt1 protease is surprisingly important for the development of regulatory T-cells and for damping the immune response in general," Ruland says, summarizing the results. "Since the blockade of the protease function in the organism produces undesirable effects, new alternatives should urgently be sought for the treatment of lymphoma."
Original publication

A. Gewies, Gorka O., Bergmann H., Pechloff K., Petermann F., Jeltsch K. M., Rudelius M., Kriegsmann M., Weichert W., Horsch M., Beckers J., Wurst W., Heikenwälder M., Korn T., Heissmeyer V. und J. Ruland, Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation, Cell Reports, 2014. DOI: 10.1016/j.celrep.2014.10.044


Prof. Dr. Jürgen Ruland
Institute for Clinical Chemistry and Pathobiochemistry
Klinikum rechts der Isar at TUM
Tel.: +49 89 4140-4751

Technical University of Munich (TUM)

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to