Immunity and Infection - Recent Highlights

Insight into disease pathogenesis and outcome from genetics

Todd (Type 1 diabetes), Parkes (IBD), Smith (Vasculitis) and Sandford (primary biliary cirrhosis) all lead national or international genetics consortia.

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Todd (Type 1 diabetes), Parkes (IBD), Smith (Vasculitis) and Sandford (primary biliary cirrhosis) all lead national or international genetics consortia. IIIT provides these with informatics and data curation support, and the Cambridge BioResource is critical for follow-up studies. Highlights include defining the role of rare variants in the genetics of common disease (Nature 2013), finding ANCA-associated vasculitis is comprised of 2 genetically distinct diseases (NEJM 2012), describing over 140 genetic associations with IBD (Nature 2012), discovering a prognosis-associated pathway driven by FOXO3A (Cell 2013), providing insight into the genetics of PBC (PNAS), and guiding therapeutic approaches in T1D (see above).


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Defining new immunodeficiencies

Cambridge play a leading role in the BRIDGE Consortium, aiming to discover novel genetic causes of immunodeficiency and autoimmunity in humans using genome sequencing.

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Cambridge play a leading role in the BRIDGE Consortium, aiming to discover novel genetic causes of immunodeficiency and autoimmunity in humans using genome sequencing. This project is just commencing, but recently Griffiths defined new disease-causing mutations in Munc18-2 (PNAS 2013), and Nejentsev and Condliffe defined a syndrome of recurrent respiratory infection caused by a gain-of-functin mutation n PI3Kδ leading to experimental medicne studies (Science 2013)


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Bringing molecular microbiology to the clinic

Peacock has received major funding to translate genomic technologies into routine microbiological diagnostics, and has provided insight into the clinical biology of MRSA and TB (NEJM 2013).

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Peacock has received major funding to translate genomic technologies into routine microbiological diagnostics, and has provided insight into the clinical biology of MRSA and TB (NEJM 2013). BRC support enabled to recruitment of Bentley (joint appointment with the Sanger Institute) who focuses on the genetics of pneumococcus (Nat Gen 2014), and supports Floto, whose work on Mycobacterium abscessus in cystic fibrosis has changed clinical practice (Lancet 2013).


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New approaches to experimental medicine

The ability to rapidly set up, recruit and analyse results of early phase trials has been greatly enhanced by BRC funding to support translational research.

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The facilities and platforms supported by the BRC have transformed our ability to carry out experimental medicine and early phase trials. For example, in less than 18 months John Todd and Frank Waldron-Lynch of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory have, from regulatory and ethical approvals to recruiting the last of 40 patients newly diagnosed type 1 diabetes, conducted a deep mechanistic study of the effects of ultra low doses of interleukin-2 in patients. Their approach is to understand the genetically-validated pathways of autoimmune disease, identify biomarkers in these pathways and test relevant, potential therapeutics for their ability to modulate these immune biomarkers and in later phase trials, clinical outcomes.

The BRC also assisted in creating a readership for Jayne, to promote experimental medicine studies in vasculitis and SLE. Smith’s group has identified an outcome-predicting biomarker now entering clinical studies in Crohn’s disease supported by a Wellcome Trust Translational Award.


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Two serious immune diseases hiding under one umbrella

Scientists supported by the NIHR and funded through the British Heart Foundation (BHF) have shed new light on a rare but deadly disease of the circulatory system. In a study published in the New England Journal of Medicine, researchers at the University> of Cambridge and European Vasculitis...

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Affecting more than 9,000 people in the UK sufferers see their blood vessels - particularly in the kidney and lungs- attacked by their body's own white blood cells, which are supposed to patrol circulation to rid it of harmful invaders. The resulting inflammation can affect any organ but in particular causes kidney, lung and respiratory tract disease.

The researchers tracked down more that 1200 people in the UK and 1400 in Europe who were diagnosed with ANCA-associated vasculitis. Using cutting edge genetic analyses they showed that four genetic variants play a crucial role in causing the condition. All of the genes affected are involved in the body's natural response to infection and injury, and mistakes make the immune system more likely to turn on its own host.

Importantly, the scientists showed that patients with ANCA-associated vasculitis fell into two distinct groups, depending on which genetic variants they carried. In each case the body produces a different molecule, called an autoantibody; the result of which is the immune system turning against its own host.

The discovery is important because it could pave the way for new treatments in the future that could specifically tackle these two different auto immune diseases.

Dr Paul Lyons, Senior Research Associate at the Cambridge Institute of Medical Research (CIMR), one of the leaders of the study said:

''Our study demonstrates for the first time that ANCA-associated vasculitis is not really one condition, but two diseases with different causes hiding under one umbrella. Because the condition is rare this has been difficult to prove until now. Our key finding is that an important difference between two groups is in the genes, and not only in the symptoms we can see.''


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Allergy (Ewan, Clark)

The BRC has provided support to assist in the clinical translation of a promising novel oral tolerance method to treat children with severe peanut allergy, which may have a major impact on clinical care in the short to medium term.

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The work of NHS consultants Dr Andrew Clark and Dr Pamela Ewan to develop an oral immunotherapy programme to treat peanut allergy was recently published in the Lancet. Two trials conducted on children with a severe allergic reacton to peanuts was very successful. At the end of the treatment 84 percent of children in one trial and ninety one per cent in a second trial were able to tolerate 5 peanuts a day. (The Lancet, January 2014).

The research, supported by the MRC-NIHR (Medical Research Council and National Institute for Health Research) partnership, involved young people, aged between seven and sixteen, eating daily doses of peanut protein. Starting with a tiny dose and slowly building up over four to six months, they trained their bodies to tolerate the equivalent of five whole peanuts. Peanut allergy affects around half a million people in the UK and over 10 million people across the globe. Unlike other childhood food allergies, such as cow’s milk, peanut allergy rarely goes away.

The trial was carried out over five and a half years in the NIHR Wellcome Trust Clinical Research Facility at Addenbrooke’s, part of Cambridge University Hospitals (CUH). It was funded by the MRC-NIHR partnership through the Efficacy and Mechanism Evaluation (EME) Programme. Initial pilot work was funded by the Evelyn Trust, Cambridge.

March 2014


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A genetic approach to inflammatory bowel disease (Parkes)

Miles Parkes is an NHS gastroenterologist who chairs the International IBD Genetics Consortium. BRC funding has been used to fund research sessions for Dr Parkes, the salary of part time statistician Carlo Berzuini (role: analysis of association data, data QC and analysis for nsSNP data, current...

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Miles Parkes is an NHS gastroenterologist who chairs the International IBD Genetics Consortium. BRC funding has been used to fund research sessions for Dr Parkes, the salary of part time statistician Carlo Berzuini (role: analysis of association data, data QC and analysis for nsSNP data, current modeling for multi-marker cluster analysis) and research nurse Francesca Bredin (who co-ordinates the expanding inflammatory bowel disease DNA collection, undertakes patient phenotyping, data entry), and some reagent costs for DNA collection and extraction.

The consortium has just published a meta-analysis in Crohn's disease in Nature Genetics, and a similar study in Ulcerative Colitis is under review with the same journal ' there are now 100 confirmed genome-wide significant IBD associated genes. Some of these are being followed up using expression analysis to correlate genotype with expression of candidate genes using the BRC-supported Cambridge Bioresource. A large South Asian IBD cohort is being recruited for transethnic studies, in the hope that different LD patterns will help fine-map some of the IBD-associated intervals and hence identify causal variants. Cambridge is also coordinating the IBD consortium involvement in the Immunochip study.

Work in Inflammatory Bowel Disease will be greatly enhanced by the appointment of the first Professor of Gastroenterology at the University of Cambridge, Dr Arthur Kaser from Innsbruck. Dr Kaser brings with him substantial ERC funding, and an enviable track record in Inflammatory Bowel Disease research. The BRC will support the establishment of his translational research programme in Cambridge through the provision of a postdoctoral fellow for two years.


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Neutrophils and lung disease (Chilvers)

The Chilvers group has established novel methodology to define the kinetics of neutrophil transit across the lung in man using autologous 111In-labelled neutrophils and 99mTc-labelled red blood cells, demonstrating that more than 95% of neutrophils transit the capillary network rapidly, and that...

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The Chilvers group has established novel methodology to define the kinetics of neutrophil transit across the lung in man using autologous 111In-labelled neutrophils and 99mTc-labelled red blood cells, demonstrating that more than 95% of neutrophils transit the capillary network rapidly, and that smokers have a greater neutrophil loss compared to severitymatched non-smoking COPD patients.

More recently, NIHR BRC funding has supported the establishment of a method which has allowed the measurement of eosinophil circulating half life in man, something never achieved before. The eosinophil t1/2 is 21 hours (compared to 7 hours for neutrophils) and suggests that early re-circulation occurs, as with lymphocytes. This method should allow them to establish sites of eosinophil destruction in health and disease, to quantify lung uptake in asthma, and to develop a clinically applicable 111In-labelled eosinophil scan.


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