Funded in 2008
Investigating treatments for abscesses in CGD
Dr Brian Cobb and Miss Colleen Lewis
Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. $115,040 over two years.
This project helped develop treatments for abscess formation in CGD. Abscesses are the immune system’s way of quarantining harmful microbes within the body. They are very painful and often require surgical drainage because they prevent antibiotics from working and can serve as reservoirs leading to larger systemic infections.
Using animal models of CGD nitric oxide was shown to be a central player in abscess formation. More nitric oxide was produced in CGD compared to non-CGD healthy counterparts, with levels sustained over a longer period of time. Neutrophils and macrophages were shown to be the source of the nitric oxide and the hypersensitivity to abscess formation in CGD was found to be due to the activation of specific T cell populations. Significantly pharmacologic intervention using drugs that interfere with nitric oxide production were found to significantly reduce abscess size and formation.
In 2008 Dr Cobb was awarded a 2008 National Institutes of Health (NIH) Director's New Innovator Award and $2.35M award over five years to continue this work which may be of benefit to many other conditions.
Read how this work has led to further funding from the National Institutes of Health.
Funded in 2007
Developing anti-inflammatory strategies in CGD Professor Luigina Romani and Dr Silvia Bozza Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy. £47,970 over one year.
This one-year project aimed to find ways of dampening down the inflammatory response that occurs following Aspergillus infections using animal models of CGD. The work gave valuable new insights into the role of a particular type of T lymphocyte cell population in CGD inflammation and tested ways of reducing inflammation. Significantly, the researchers showed that the drug Pentraxin-3 was able to inhibit local fungal growth, the spread of infection to Aspergillus. This was shown to be due to Pentraxin-3 influencing the down-regulation of certain pathogenic white blood cell populations that allowed the emergence of protective mechanisms to the fungus. Although further work is needed to demonstrate that similar mechanisms work in humans the study has highlighted new ways of treating fungal infections and infection in CGD.
'Although inflammation is required for prompt control of fungal infections, resolution of inflammation is essential for maintaining the balance between protection and immunopathology in infections and fungal diseases. Therefore, the search for drugs or substances that limit inflammation has become a priority in the management of severe, often intractable, fungal infections. With funding from the Trust we were able to explore a new drug that may help limitation in CGD.'
Multiple defects in the immune system contributes to the severity of CGD Dr Andrew Smith and Dr Farooq Rahman Department of Medicine, University College London, £32,288 over one year.
Emerging evidence implies the immunological defect in CGD is much more diverse than previously thought. This project identified and characterised specific immune pathways that are affected in CGD. This involved analysing macrophages isolated from blood of CGD patients and comparing responses to bacterial challenge with healthy cells. The studies demonstrated that CGD macrophages produce abnormal levels of both pro- and anti- inflammatory cell mediators. More work is on-going to further characterise immunological abnormalities in CGD with the aim of identifying new cellular pathways so that novel drugs can be developed to improve the clinical management of CGD.
This study investigated that the link between inflammatory bowel disease in CGD and the clinical features of Crohn's Disease with the results supporting the possibility of similar mechanisms being involved in the pathogenesis of both conditions. Significantly in a study analysing the oxidative burst of cells from 100 people with Crohn's Disease two people were found to have abnormally low responses indicative of CGD. Further investigation showed that the people concerned had been misdiagnosed, that they had CGD and could be given appropriate antibiotic and antifungal prophylactic treatment. This finding highlights the need for a diagnosis of CGD to be considered in people with Crohn's Disease.
Funded in 2006
Phagocytic oxidase: extracellular antimicrobial synergy. Effect of interferon gamma Professor Jerrold Weiss and William Nauseef, Department of Internal Medicine, University of Iowa. $59,182 over one year.
Gamma interferon (IFN) can sometimes be given to people with CGD to help reduce the frequency of serious bacterial infections. However, how this treatment actually works is not completely understood. The aim of the project was to test if the beneficial effect of IFN-gamma observed in some CGD patients was due to increased activity of a certain soluble enzyme called phospholipase A2 produced by cells of the immune system. This enzyme is known to be toxic to bacteria. The results showed that the action of IFN-gamma is not through increased phospholipase A2 enzyme activity but through the stimulation of other potent antimicrobial molecules. Unfortunately, the identification of these molecules was beyond the scope of the project. Additionally the work highlighted species dependent differences in the expression of the enzyme phospholipase A2. Although the results were negative one avenue of research was explored. Useful information was gained on the best animal models to study the effects of IFN-gamma.
From 2002-2005
INVESTIGATION OF CHRONIC INFLAMMATION IN CGD
Professors David. Goldblatt, Christine. Kinnon, and Adrian Thrasher
Institute of Child Health, London
Two Year Project Grant: £109,682, ended in 2005
Patients with CGD can now overcome many infections with new antibiotics, but inflammation can have a serious impact on their quality of life. This project studied the mechanisms involved in causing tissue inflammation and granulomas (abscesses) in CGD patients. The group examined the mechanisms behind the lack of production of certain key anti-inflammatory factors in CGD cells and investigated if specific drugs affected their production. This work provided key insights into why inflammation persists in CGD.
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 2002
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 Dean 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 investigated a possible association between p47phox pseudogenes and inflammatory bowel disease. This helped improve the understanding and treatment of this unpleasant and painful condition.
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.
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.
© 2001-2007 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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