National Jewish Health, Denver, USA
Professor Donna Bratton will study the mechanism behind inflammation
in CGD and test a new drug that may help treat it. Awarded in April
Project leaders: Professor Donna Bratton and Dr Ruby Fernandez-Boyanapalli
Location: National Jewish Health, Denver, USA
Research Fellow employed on project: Dr Ruby Fernandez-Boyanapalli
Duration: 2 years
Total project cost: £98,466
Official title: PPARg agonism enhances oxidant production and signaling by CGD neutrophils for resolution of exaggerated inflammation
People with CGD may have severe inflammation that can affect many organs and
can cause long-term damage. Work previously funded by CGDS has helped
shed light on what key signals are missing in CGD in the way the
specialised white blood cells (neutrophils and macrophages) work
together to clear infections and how this leads to inflammation.
Building on their findings the researchers will investigate how the drug
pioglitazone, currently approved for use in Type 2 Diabetes, works to
correct the missing signals in CGD and helps resolve inflammation.
What this research means to people with CGD
It will provide critical evidence for the use of an anti-inflammatory drug
that is already available and undergone safety testing, for treating
inflammation complications in CGD.
Improve the quality of life of people affected by reducing the formation of granulomas and limiting damage to internal organs.
Background to the work
During inflammation, white blood cells called neutrophils are recruited from the blood into tissues following infection or injury.
While this process is critical for defence of the body, the control and
resolution of inflammation is equally important. In healthy people once
the recruited neutrophils have sterilized the site, they die in a manner
that allows them to be recognized by other specialised cells called
macrophages, which “eat” them, and recycle their components. This
process stimulates the macrophages to signal that further recruitment of
new neutrophils should stop and tissues should heal.
In CGD because of
the lack of superoxide production neutrophils do not signal properly to
macrophages for ingestion and recycling. Instead they decompose and
their cellular components cause more tissue injury and can cause a
situation where the body starts to attack itself (known as
Research is beginning to unravel the signalling between
dying neutrophils and macrophages that has gone terribly wrong in CGD
and leads to over-exuberant inflammation. For instance, a signalling
molecule called phosphatidylserine, is not modified and displayed on
dying CGD neutrophils as is normally the case.
macrophages, having not received the proper programming signals, have
very little expression of a protein called peroxisome
proliferator-activated receptor gamma (PPARg), that is needed for
recycling dead cells and control of inflammation.
CGD macrophages are
also very inefficient in clearing dying cells, and they continue to
produce inflammatory signals for the recruitment of more neutrophils. As
a result, inflammation worsens and the body tries to wall off the
infection by forming a granuloma, a mass of immune cells, which obstruct
the patient’s internal organs.
Using CGDS funds, the researchers have investigated the medication
pioglitazone, a PPARg agonist currently approved for use in Type 2
Diabetes, for restoration of PPARg signalling during acute inflammation
in a CGD mouse model. The results were very encouraging. Pioglitazone
treatment, begun either prior to inducing inflammation or given after
inflammation was established, enhanced clearance of dead cells, and
restored production of anti-inflammatory mediators. The end result was
normal, not exaggerated inflammation. Analyses of the inflammatory
process suggested that early signals had been restored by pioglitazone
treatment, but their nature has yet to be defined.
Further information and links
The work is being undertaken at the number one respiratory hospital in the USA -The National Jewish Health Hospital - www.nationaljewish.org