Investigating new treatments

Professor Donna Bratton will study the mechanism behind inflammation in CGD and test a new drug that may help treat it. Awarded in April 2011.

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 autoimmunity).

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.

Additionally, CGD 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