WHAT CAUSES PERSISTENT INFLAMMATION IN CGD?
Professors D. Goldblatt, C. Kinnon, and AJ Thrasher.
The Institute of Child Health, London
2 1/2 -Year Project Grant: £97,476 Ended in 2003
This project studied the mechanisms involved in tissue inflammation and
granuloma formation in CGD patients. Inflammation can affect various tissues,
including the lungs, liver, joints and gastrointestinal tract. Normally,
the inflammation occurs when the patient's cells fight infection. Once
the infection has been eliminated the inflammatory process is turned off
through the production of specialised anti-inflammatory chemicals. CGD
patients appear to lack the means to 'switch off' the inflammatory reactions,
so those sites of inflammation continue to build up and become granulomas,
or abscesses. Significantly this study found that CGD phagocytes, the cell
type responsible for the killing and the clearing of bacteria and fungi,
produce less of two key anti-inflammatory molecules compared to normal
cells. It is thought that the deficient production of these factors leads
to the inefficient clearing of cellular debris from the site of inflammation.
This continual presence of the uncleared remains of cells then leads to
a prolonged inflammatory response.
By defining this aberrant production of anti-inflammatory molecules in
CGD it is hoped that novel treatments can be better tailored to specifically
treat inflammation in CGD patients.
DEVELOPING METHODS TO FIND OUT WHICH PARTS OF THE KEY ENZYME AFFECTED
IN CGD MAY CONTROL THE PRODUCTION OF INFLAMMATORY MOLECULES
Dr D. Willis.
University College, London
1 Year Award: £27,000 Ended in 2003
CGD patients have a dysfunction in parts of the enzyme, NADPH oxidase that
is important in killing invading microorganisms. Persistent inflammation
is a common occurrence in CGD and it is important to find out ways in which
this abnormal inflammation can be switched off. In this pilot study, a
new method of investigating the role of NADPH oxidase in controlling inflammation
was developed that uses 'RNA interference' to inhibit the specific function
of parts of this important enzyme in CGD. In 'proof of principle' experiments
specially designed reagents were used successfully to inhibit the function
of specific parts of the oxidase enzyme. This new method may help dissect
out and unravel the precise roles of key parts of the NADPH oxidase enzyme
and could help highlight possible ways by which chronic inflammation can
be controlled.
STUDYING INFLAMMATORY BOWEL DISEASE AND TISSUE INFLAMMATION IN CGD
Dr Marcus Harbord and Professor Anthony Segal.
University College, London
3 Year Project Grant: £210,000 Ended in 2002
Inflammatory bowel disease can be a recurrent and severe problem in CGD.
This team is currently investigating a possible association between p47phox
pseudogenes and inflammatory bowel disease. This would help improve the
understanding and treatment of this unpleasant and painful condition.
The group has also discovered the presence of strange crystals at sites
of chronic inflammation in the tissues of the lung, liver, gut and skin
in a model mimicking CGD. These crystals were identified as a protein called
Ym1, whose function is, as yet, not known. High magnification photographs,
obtained using an electron microscope, showed that the Ym1 protein originates
from the granules within neutrophils, the cells that are affected in CGD.
Similar proteins to Ym1 are found in humans and are also found at inflammatory
sites, although they have yet to be studied in CGD patients.
EVALUATION OF GRANULOMA FORMATION IN CGD
Professor A Rosen-Woolf, H. von B. Bernuth and J Roesler.
Dresden University, Germany
1 Year Award: £20,000 Ended in 2002
One of the problems that CGD patients face is the formation of granulomas
(abscesses). These form when cells do not die as they should and cause
sites of inflammation. In this one-year grant a laboratory model of granuloma
formation was established. This allowed a time lapse study of the formation
of this inflammatory tissue to be examined. The group were able to determine
the profile of growth mediators at different stages of formation of the
granuloma tissue and show that an over abundance of pro-inflammatory factors
actively promotes granuloma formation. In the longer term, this work should
lay the foundation for the clinical treatment of granuloma in CGD by altering
the rate at which the cells die.
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2005 The Chronic Granulomatous Disorder (CGD)
Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
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