Researchers successfully mitigate chronic inflammation in mice using customised “mini-antibodies”, a discovery that could transform future treatments.
A discovery by a team of researchers at the Universities of Bonn and Sao Paulo could mean that chronic inflammation may reduce with customised “mini-antibodies”. These nanobodies enabled them to dissolve molecular complexes in tissue that normally activates the immune system. This reaction may slow down unwanted inflammatory reactions that cause diseases such as arthritis or neurodegeneration.
The study is published in the journal EMBO Molecular Medicine.
The function of the cells during chronic inflammation
The inflammasome is located in cells and has a central component called the ASC protein. In the event of danger, such as an attack by a pathogen, many molecules form a large complex called the ASC speck. This leads to the cell accumulating large quantities of messenger substances that can summon the help of the immune system; numerous pores form in the cell membrane through which these alarm molecules can reach the outside and fulfil their task.
These holes ultimately lead to the demise of the cell. “At some point, the cell basically explodes and empties its entire contents into the tissue”, explained Professor Dr Bernardo Franklin of the Institute of Innate Immunity at the University Hospital Bonn. “The messenger substances that are now abruptly released then act like a last great cry for help. This triggers the immune system to mount a strong inflammatory response that contains the infection.” That is why this mechanism of innate immune defence is hugely important.
However, ASC specks also accumulate in the tissue and may persist there for a long time. “We have now been able to show in mice that their activity activates the immune system even after the threat has been averted,” Franklin said. “This can result in chronic inflammation, which severely damages the tissue.” Together with researchers from the University of Sao Paulo, Franklin’s team has succeeded in preventing this undesirable effect. They used so-called nanobodies for this purpose.
These agents are antibody fragments with a simple structure. “In collaboration with Professor Dr Florian Schmidt from the Institute of Innate Immunity, we generated nanobodies that specifically target ASC and can dissolve the specks,” explained Franklin’s collaborator Dr Damien Bertheloot. The researchers utilised an alpaca and injected the animal with the ASC protein so that it developed matching antibodies. Some of the alpaca antibodies have a simple structure. This makes it possible to produce and test fragments of these antibodies as so-called nanobodies.
Rheumatism and gout symptoms alleviated
The researchers obtained the genetic information for the ASC nanobodies from the blood samples of the animal using a complex technique. “We then incorporated this genetic makeup into bacteria so that we could have them produce the nanobody in large quantities,” Bertheloot explained.
The team demonstrated that the compound could dissolve ASC specks using human cell cultures as well as mice. “The mice in our experiments have rheumatoid and gout-like symptoms,” Bertheloot further added. “After administration of the nanobody, the inflammation and also the general health of the rodents improved significantly.”