Clinical implications and utility of an endotoxin-tolerant (ET) state in cystic fibrosis

Lead Researcher:

Dr Barry Plant

Award Date:

1 January 2013

Host Institution:

Irish Thoracic Society

Scheme:

Medical Research Charities Group Co-Fund Award

Summary:

The immune system is very important for responses to infection. Recent studies in non-CF adults with severe bacterial infection show that the immune system generates a large initial response to the bacteria followed by a temporarily reduced one. This concept is known as endotoxin tolerance (ET). It is thought that this pattern exists as a protective mechanism to prevent death due to an overwhelming immune response to infection but there is a risk of secondary infection associated with it.
Recent small studies have shown a similar reduction in inflammatory immune system responses in stable patients with Cystic Fibrosis (PWCF). Our group has already demonstrated that this effect is present and more marked with poorer lung function. We believe that PWCF with different levels of lung disease not only will have different immune responses when well but that this effect will impact on their acute exacerbations and potentially recovery. We also believe that this blunting of the immune system is acquired, i.e. that PWCF are not born with a decreased immune response but, instead, develop it as a consequence of recurrent exposure to bacteria with the development of lung bacteria colonisation.
By measuring immune responses in serial blood samples of adult PWCF during and after an infective exacerbation, we will determine whether the patients with poorer lung function when stable have lower immune responses during infections influencing recovery. We will also measure the immune responses from the routine blood samples of children and compare them with clinical status. We believe that endotoxin tolerance will not be seen in those who are Pseudomonas free.
These studies will answer important questions regarding inflammatory responses in both stable and acute exacerbations in paediatric and adult CF. Measuring ET response may be a novel marker of disease progression and/or prognostic indicator which will help the clinician target preventative therapies in children and aggressive urgent treatments in acute adult exacerbations at a patient specific appropriate time.