New approach against chronic inflammation: Treating mice with so-called 'nanobodies'

Date:
April 19, 2022
Source:
University of Bonn
Summary:
Researchers have succeeded in mitigating chronic inflammation
in mice using customized 'mini-antibodies.' These nanobodies
enabled them to dissolve molecular complexes in tissue that
normally activate the immune system. The nanobodies produced may
in future help to slow down unwanted inflammatory reactions that
cause diseases such as arthritis or neurodegeneration.



FULL STORY ==========================================================================
Not only the villas of the rich and famous have a direct line to the
police.

The cells in our body also have a sophisticated alarm system, the
inflammasome.

Its central component is the so-called ASC protein. In the event of
danger, such as an attack by a pathogen, many of these molecules join
together to form a large complex, the ASC speck. This ensures two things: First, its activity causes the cell to accumulate large quantities of
messenger substances, which can be used to summon the help of the immune system. And secondly, numerous pores are formed in the cell membrane
through which these alarm molecules can reach the outside and fulfill
their task.


==========================================================================
Last cry for help from the dying cell 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," explains Prof. 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 defense is hugely important.

However, in this process, 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 says. "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 very simple structure. "In collaboration with Prof. Dr. Florian Schmidt from the Institute of Innate Immunity, we generated nanobodies that specifically target ASC and
can dissolve the specks," explains Franklin's collaborator Dr. Damien Bertheloot. The researchers got help from an alpaca: They injected the
animal with the ASC protein so that it developed matching antibodies. Some
of the alpaca antibodies have a very simple structure. This makes it
possible to produce and test fragments of these antibodies as so-called nanobodies.

Rheumatism and gout symptoms alleviated in mice The researchers were
able to obtain the genetic information for the ASC nanobodies from 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 explains. The team demonstrated
that the compound can dissolve ASC specks using human cell cultures
as well as mice. "The mice in our experiments have rheumatoid and
gout-like symptoms," Bertheloot explains. "After administration of the nanobody, the inflammation and also the general health of the rodents
improved significantly." Nanobodies are very small compared to normal antibodies. They are therefore excellent for breaking up such molecular complexes. This is because they can still reach sites that would be too
cramped for large agents. Moreover, normal antibodies provide additional stimulation to the immune system and can therefore exacerbate inflammation
-- a property that nanobodies lack.

The results are also interesting for another reason: Studies indicate
that ASC specks can also cause significant damage to the brain. There,
they seem to serve as a kind of "crystallization nucleus" for the Ass
protein. In the brains of Alzheimer's patients, Ass clumps together
to form large protein complexes called plaques. Presumably, ASC specks
can trigger this clumping. "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." Bernardo Franklin is
a member of the ImmunoSensation2 Cluster of Excellence at the University
of Bonn.

At the same time, however, he warns against overly high expectations:
Even in the ideal case, it will be years before the results might
translate into new drugs.

The Institute of Innate Immunity and the Nanobody Core Facility at the University Hospital Bonn were involved in the study. Partners on the
part of the University of Sao Paulo were the Center for the Study of Inflammatory Diseases and the Department of Pharmacology.


========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Damien Bertheloot, Carlos WS Wanderley, Ayda H Schneider, Lisa DJ
Schiffelers, Jennifer D Wuerth, Jan MP To"dtmann, Salie
Maasewerd, Ibrahim Hawwari, Fraser Duthie, Cornelia Rohland,
Lucas S Ribeiro, Lea‐Marie Jenster, Nathalia Rosero, Yonas
M Tesfamariam, Fernando Q Cunha, Florian I Schmidt, Bernardo S
Franklin. Nanobodies dismantle post‐pyroptotic ASC specks
and counteract inflammation in vivo.

EMBO Molecular Medicine, 2022; DOI: 10.15252/emmm.202115415 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220419112439.htm

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