Alpaca nanobodies target and dissolve root cause of chronic inflammation
By tapping into the unique immune system of alpacas, scientists have developed a promising technique for tempering chronic inflammation associated with conditions such as arthritis. The breakthrough hinges on what are known as nanobodies, which when taken from the woolly mammals were shown to neutralize the alarm system for the immune system and, in doing so, treat excessive inflammation in unhealthy mice.
The research was carried out by scientists at Germany's University of Bonn and Brazil's University of São Paulo, who were taking aim at something they refer to as ASC specks. These are large molecular complexes made up of ASC proteins, which are critical to the immune response in human cells, acting as an alarm system when they sense an attack from a pathogen, for example, and banding together.
The resulting ASC specks trigger the accumulation of large numbers of messenger substances that call for help from the immune system, and also bust holes in the cell membrane, enabling the messenger molecules to escape and sound their alarm. But these pores also ultimately lead to the dramatic downfall of the cell.
"At some point, the cell basically explodes and empties its entire contents into the tissue," said study author 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."
Also among the materials released from the cells are the ASC specks, which can build up in the tissue and linger to have lasting effects.
"We have now been able to show in mice that their activity activates the immune system even after the threat has been averted," Franklin says. "This can result in chronic inflammation, which severely damages the tissue."
The researchers believe they have a countermeasure for the role of ASC specks in chronic inflammation, and this is where the alpacas come in. They are among only a handful of animals that produce single-domain antibodies as part of their immune defenses. Often called nanobodies, these are appealing to scientists for a number of reasons, including the fact that they are easier and cheaper to mass produce, and could bring new options to the table when it comes to treating disease.
Among the possibilities is cancer, with one 2018 study demonstrating how alpaca nanobodies can bind to and inhibit a key driver in a range of cancers called epidermal growth factor (EGF). More recently, researchers have leveraged alpaca nanobodies to develop promising new treatments for COVID-19, which could possibly even take the form of a nasal spray.
The authors of this new study injected ASC proteins into alpacas and let nature go to work, with the animals then developing specialized antibodies to match, from which fragments, or nanobodies could be taken. The scientists collected the genetic information for these nanobodies and incorporated it into bacteria, enabling them to produce the nanobodies in large amounts. These nanobodies then proved effective at dissolving ASC specks in human cell cultures. Experiments on mice returned even more promising results.
"The mice in our experiments have rheumatoid (arthritis) and gout-like symptoms," said study author Dr. Damien Bertheloot. "After administration of the nanobody, the inflammation and also the general health of the rodents improved significantly."
Beyond arthritis and gout, the scientists believe these nanobodies could also play a role in treating or preventing neurological conditions. ASC specks are also thought to cause damage in the brain and contribute to the formation of amyloid beta clumps, which are aggregations of proteins associated with Alzheimer's.
"So perhaps it's possible to slow down this process with the help of our nanobodies," Franklin hopes. "We now plan to investigate this possibility in a follow-up study."
The research was published in the journal EMBO Molecular Medicine.
Source: University of Bonn