̽��ֱ�� of Cambridge - inflammation

When inflammation goes too far

lkm37 — Tue, 11 Mar 2025 10:05:23 +0000

Clare Bryant, Professor of Innate Immunity, is a molecular detective. Clare allows us to see how inflammation functions across species, and when our defence systems go too far.

Ultra-powered MRI scans show damage to brain’s ‘control centre’ is behind long-lasting Covid-19 symptoms

sc604 — Tue, 08 Oct 2024 01:28:45 +0000

Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.

̽��ֱ��study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. ̽��ֱ��researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.

̽��ֱ��powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.

̽��ֱ��brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.

“Things happening in and around the brainstem are vital for quality of life, but it had been impossible to scan the inflammation of the brainstem nuclei in living people, because of their tiny size and difficult position.” said first author Dr Catarina Rua, from the Department of Clinical Neurosciences. “Usually, scientists only get a good look at the brainstem during post-mortem examinations.”

“ ̽��ֱ��brainstem is the critical junction box between our conscious selves and what is happening in our bodies,” said Professor James Rowe, also from the Department of Clinical Neurosciences, who co-led the research. “ ̽��ֱ��ability to see and understand how the brainstem changes in response to Covid-19 will help explain and treat the long-term effects more effectively.”

In the early days of the Covid-19 pandemic, before effective vaccines were available, post-mortem studies of patients who had died from severe Covid-19 infections showed changes in their brainstems, including inflammation. Many of these changes were thought to result from a post-infection immune response, rather than direct virus invasion of the brain.

“People who were very sick early in the pandemic showed long-lasting brain changes, likely caused by an immune response to the virus. But measuring that immune response is difficult in living people,” said Rowe. “Normal hospital-type MRI scanners can’t see inside the brain with the kind of chemical and physical detail we need.”

“But with 7T scanners, we can now measure these details. ̽��ֱ��active immune cells interfere with the ultra-high magnetic field, so that we’re able to detect how they are behaving,” said Rua. “Cambridge was special because we were able to scan even the sickest and infectious patients, early in the pandemic.”

Many of the patients admitted to hospital early in the pandemic reported fatigue, breathlessness and chest pain as troubling long-lasting symptoms. ̽��ֱ��researchers hypothesised these symptoms were in part the result of damage to key brainstem nuclei, damage which persists long after Covid-19 infection has passed.

̽��ֱ��researchers saw that multiple regions of the brainstem, in particular the medulla oblongata, pons and midbrain, showed abnormalities consistent with a neuroinflammatory response. ̽��ֱ��abnormalities appeared several weeks after hospital admission, and in regions of the brain responsible for controlling breathing.

“ ̽��ֱ��fact that we see abnormalities in the parts of the brain associated with breathing strongly suggests that long-lasting symptoms are an effect of inflammation in the brainstem following Covid-19 infection,” said Rua. “These effects are over and above the effects of age and gender, and are more pronounced in those who had had severe Covid-19.”

In addition to the physical effects of Covid-19, the 7T scanners provided evidence of some of the psychiatric effects of the disease. ̽��ֱ��brainstem monitors breathlessness, as well as fatigue and anxiety. “Mental health is intimately connected to brain health, and patients with the most marked immune response also showed higher levels of depression and anxiety,” said Rowe. “Changes in the brainstem caused by Covid-19 infection could also lead to poor mental health outcomes, because of the tight connection between physical and mental health.”

̽��ֱ��researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. ̽��ֱ��7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.

“This was an incredible collaboration, right at the peak of the pandemic, when testing was very difficult, and I was amazed how well the 7T scanners worked,” said Rua. “I was really impressed with how, in the heat of the moment, the collaboration between lots of different researchers came together so effectively.”

̽��ֱ��research was supported in part by the NIHR Cambridge Biomedical Research Centre, the NIHR Oxford Biomedical Research Centre, and the ̽��ֱ�� of Oxford COVID Medical Sciences Division Rapid Response Fund.

Reference:
Catarina Rua et al. ‘7-Tesla quantitative susceptibility mapping in COVID-19: brainstem effects and outcome associations.’ Brain (2024). DOI: 10.1093/brain/awae215

Damage to the brainstem – the brain’s ‘control centre’ – is behind long-lasting physical and psychiatric effects of severe Covid-19 infection, a study suggests.

̽��ֱ�� of Cambridge

3D projections of QSM maps on the rendered brainstem

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Scientists identify how fasting may protect against inflammation

cjb250 — Tue, 30 Jan 2024 09:55:30 +0000

In research published in Cell Reports, the team describes how fasting raises levels of a chemical in the blood known as arachidonic acid, which inhibits inflammation. ̽��ֱ��researchers say it may also help explain some of the beneficial effects of drugs such as aspirin.

Scientists have known for some time that our diet – particular a high-calorie Western diet – can increase our risk of diseases including obesity, type 2 diabetes and heart disease, which are linked to chronic inflammation in the body.

Inflammation is our body’s natural response to injury or infection, but this process can be triggered by other mechanisms, including by the so-called ‘inflammasome’, which acts like an alarm within our body’s cells, triggering inflammation to help protect our body when it senses damage. But the inflammasome can trigger inflammation in unintentional ways – one of its functions is to destroy unwanted cells, which can result in the release of the cell’s contents into the body, where they trigger inflammation.

Professor Clare Bryant from the Department of Medicine at the ̽��ֱ�� of Cambridge said: “We’re very interested in trying to understand the causes of chronic inflammation in the context of many human diseases, and in particular the role of the inflammasome.

“What's become apparent over recent years is that one inflammasome in particular – the NLRP3 inflammasome – is very important in a number of major diseases such as obesity and atherosclerosis, but also in diseases like Alzheimer's and Parkinson's disease, many of the diseases of older age people, particularly in the Western world.”

Fasting can help reduce inflammation, but the reason why has not been clear. To help answer this question, a team led by Professor Bryant and colleagues at the ̽��ֱ�� of Cambridge and National Institute for Health in the USA studied blood samples from a group of 21 volunteers, who ate a 500kcal meal then fasted for 24 hours before consuming a second 500kcal meal.

̽��ֱ��team found that restricting calorie intake increased levels of a lipid known as arachidonic acid. Lipids are molecules that play important roles in our bodies, such as storing energy and transmitting information between cells. As soon as individuals ate a meal again, levels of arachidonic acid dropped.

When the researchers studied arachidonic acid’s effect in immune cells cultured in the lab, they found that it turns down the activity of the NLRP3 inflammasome. This surprised the team as arachidonic acid was previously thought to be linked with increased levels of inflammation, not decreased.

Professor Bryant, a Fellow of Queens’ College, Cambridge, added: “This provides a potential explanation for how changing our diet – in particular by fasting – protects us from inflammation, especially the damaging form that underpins many diseases related to a Western high calorie diet.

“It’s too early to say whether fasting protects against diseases like Alzheimer's and Parkinson's disease as the effects of arachidonic acid are only short-lived, but our work adds to a growing amount of scientific literature that points to the health benefits of calorie restriction. It suggests that regular fasting over a long period could help reduce the chronic inflammation we associate with these conditions. It's certainly an attractive idea.”

̽��ֱ��findings also hint at one mechanism whereby a high calorie diet might increase the risk of these diseases. Studies have shown that some patients that have a high fat diet have increased levels of inflammasome activity.

“There could be a yin and yang effect going on here, whereby too much of the wrong thing is increasing your inflammasome activity and too little is decreasing it,” said Professor Bryant. “Arachidonic acid could be one way in which this is happening.”

̽��ֱ��researchers say the discovery may also offer clues to an unexpected way in which so-called non-steroidal anti-inflammatory drugs such as aspirin work. Normally, arachidonic acid is rapidly broken down in the body, but aspirin stops this process, which can lead to an increase in levels of arachidonic acid, which in turn reduce inflammasome activity and hence inflammation.

Professor Bryant said: “It’s important to stress that aspirin should not be taken to reduce risk of long terms diseases without medical guidance as it can have side-effects such as stomach bleeds if taken over a long period.”

̽��ֱ��research was funded by Wellcome, the Medical Research Council and the US National Heart, Lung, and Blood Institute Division of Intramural Research.

Reference
Pereira, M & Liang, J et al. Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting. Cell Reports; 23 Jan 2024; DOI: 10.1016/j.celrep.2024.113700

Cambridge scientists may have discovered a new way in which fasting helps reduce inflammation – a potentially damaging side-effect of the body’s immune system that underlies a number of chronic diseases.

Our work adds to a growing amount of scientific literature that points to the health benefits of calorie restriction

Clare Bryant

Carol Yepes (Getty Images)

Intermittent fasting conceptual image

Yes

Cancer drug could hold hope for treating inflammatory diseases including gout and heart diseases

cjb250 — Wed, 01 Nov 2023 08:00:30 +0000

In a study published on 1 November in the Journal of Clinical Investigation, the researchers have identified a molecule that plays a key role in triggering inflammation in response to materials in the body seen as potentially harmful.

We are born with a defence system known as innate immunity, which acts as the first line of defence against harmful materials in the body. Some of these materials will come from outside, such as bacterial or viral infections, while others can be produced within the body.

Innate immunity triggers an inflammatory response, which aims to attack and destroy the perceived threat. But sometimes, this response can become overactive and can itself cause harm to the body.

One such example of this is gout, which occurs when urate crystals build up in joints, causing excessive inflammation, leading to intense pain. Another example is heart attack, where dead cell build up in the damaged heart – the body sees itself as being under attack and an overly-aggressive immune system fights back, causing collateral damage to the heart.

Several of these conditions are characterised by overactivation of a component of the innate immune response known as an inflammasome – specifically, the inflammasome NLRP3. Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found a molecule that helps NLRP3 respond.

This molecule is known as PLK1. It is involved in a number of processes within the body, including helping organise tiny components of our cells known as microtubules cytoskeletons. These behave like train tracks inside of the cell, allowing important materials to be transported from one part of the cell to another.

Dr Xuan Li from the Department of Medicine at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “If we can get in the way of the microtubules as they try to organise themselves, then we can in effect slow down the inflammatory response, preventing it from causing collateral damage to the body. We believe this could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications.”

But PLK1 also plays another important role in the body – and this may hold the key to developing new treatments for inflammatory diseases.

For some time now, scientists have known that PLK1 is involved in cell division, or mitosis, a process which, when it goes awry, can lead to runaway cell division and the development of tumours. This has led pharmaceutical companies to test drugs that inhibit its activity as potential treatments for cancer. At least one of these drugs is in phase three clinical trials – the final stages of testing how effective a drug is before it can be granted approval.

When the Cambridge scientists treated mice that had developed inflammatory diseases with a PLK1 inhibitor, they showed that it prevented the runaway inflammatory response – and at a much lower dose than would be required for cancer treatment. In other words, inhibiting the molecule ‘calmed down’ NLRP3 in non-dividing cells, preventing the overly aggressive inflammatory response seen in these conditions.

̽��ֱ��researchers are currently planning to test its use against inflammatory diseases in clinical trials.

“These drugs have already been through safety trials for cancer – and at higher doses than we think we would need – so we’re optimistic that we can minimise delays in meeting clinical and regulatory milestones,” added Dr Li.

“If we find that the drug is effective for these conditions, we could potentially see new treatments for gout and inflammatory heart diseases – as well as a number of other inflammatory conditions – in the not-too-distant future.”

̽��ֱ��research was funded by the British Heart Foundation. Professor James Leiper, Associate Medical Director at the British Heart Foundation said: “This innovative research has uncovered a potential new treatment approach for inflammatory heart diseases such as heart failure and cardiomyopathy. It’s promising that drugs targeting PLK1 – that work by dampening down the inflammatory response – have already been proven safe and effective in cancer trials, potentially helping accelerate the drug discovery process.

“We hope that this research will open the door for new ways to treat people with heart diseases caused by overactive and aggressive immune responses, and look forward to more research to uncover how this drug could be could be repurposed.”

Reference
Baldrighi, M et al. PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. JCI; 1 Nov 2023; DOI: 10.1172/JCI162129

A cancer drug currently in the final stages of clinical trials could offer hope for the treatment of a wide range of inflammatory diseases, including gout, heart failure, cardiomyopathy, and atrial fibrillation, say scientists at the ̽��ֱ�� of Cambridge.

We believe [our findings] could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications

Xuan Li

kazuma seki (Getty Images)

̽��ֱ��feet of a man suffering from gout - stock photo

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Inflammation in the brain linked to several forms of dementia

cjb250 — Tue, 17 Mar 2020 00:14:10 +0000

Inflammation is usually the body’s response to injury and stress – such as the redness and swelling that accompanies an injury or infection. However, inflammation in the brain – known as neuroinflammation – has been recognised and linked to many disorders including depression, psychosis and multiple sclerosis. It has also recently been linked to the risk of Alzheimer’s disease.

In a study published today in the journal Brain, a team of researchers at the ̽��ֱ�� of Cambridge set out to examine whether neuroinflammation also occurs in other forms of dementia, which would imply that it is common to many neurodegenerative diseases.

̽��ֱ��team recruited 31 patients with three different types of frontotemporal dementia (FTD). FTD is a family of different conditions resulting from the build-up of several abnormal ‘junk’ proteins in the brain.

Patients underwent brain scans to detect inflammation and the junk proteins. Two Positron Emission Tomography (PET) scans each used an injection with a chemical ‘dye’, which lights up special molecules that reveal either the brain’s inflammatory cells or the junk proteins.

In the first scan, the dye lit up the cells causing neuroinflammation. These indicate ongoing damage to the brain cells and their connections. In the second scan, the dye binds to the different types of ‘junk’ proteins found in FTD.

̽��ֱ��researchers showed that across the brain, and in all three types of FTD, the more inflammation in each part of the brain, the more harmful build-up of the junk proteins there is. To prove the dyes were picking up the inflammation and harmful proteins, they went on to analyse under the microscope 12 brains donated after death to the Cambridge Brain Bank.

“We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other,” said Dr Thomas Cope from the Department of Clinical Neurosciences at Cambridge.

Dr Richard Bevan Jones added, “There may be a vicious circle where cell damage triggers inflammation, which in turn leads to further cell damage.”

̽��ֱ��team stress that further research is needed to translate this knowledge of inflammation in dementia into testable treatments. But, this new study shows that neuroinflammation is a significant factor in more types of dementia than was previously thought.

“It is an important discovery that all three types of frontotemporal dementia have inflammation, linked to the build-up of harmful abnormal proteins in different parts of the brain. ̽��ֱ��illnesses are in other ways very different from each other, but we have found a role for inflammation in all of them,” says Professor James Rowe from the Cambridge Centre for Frontotemporal Dementia and a Fellow of Darwin College .

“This, together with the fact that it is known to play a role in Alzheimer’s, suggests that inflammation is part of many other neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease. This offers hope that immune-based treatments might help slow or prevent these conditions.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, Association of British Neurologists, Patrick Berthoud Charitable Trust, and the Lundbeck Foundation.

Reference
Bevan-Jones, WR & Cope, TE et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain; 17 Mar 2020; DOI: 10.1093/brain/awaa033

Inflammation in the brain may be more widely implicated in dementias than was previously thought, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��researchers say it offers hope for potential new treatments for several types of dementia.

We predicted the link between inflammation in the brain and the build-up of damaging proteins, but even we were surprised by how tightly these two problems mapped on to each other

Thomas Cope

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Inflammation links heart disease and depression, study finds

cjb250 — Tue, 19 Mar 2019 00:01:32 +0000

While inflammation is a natural response necessary to fight off infection, chronic inflammation – which may result from psychological stress as well as lifestyle factors such as smoking, excessive alcohol intake, physical inactivity and obesity – is harmful.

̽��ֱ��link between heart disease and depression is well documented. People who have a heart attack are at a significantly higher risk of experiencing depression. Yet scientists have been unable to determine whether this is due to the two conditions sharing common genetic factors or whether shared environmental factors provide the link.

“It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs – the cardiovascular system and the brain,” says Dr Golam Khandaker, a Wellcome Trust Intermediate Clinical Fellow at the ̽��ֱ�� of Cambridge. “Our work suggests that inflammation could be a shared mechanism for these conditions.”

In a study published today in the journal Molecular Psychiatry, Dr Khandaker and colleague Dr Stephen Burgess led a team of researchers from Cambridge who examined this link by studying data relating to almost 370,000 middle-aged participants of UK Biobank.

First, the team looked at whether family history of coronary heart disease was associated with risk of major depression. They found that people who reported at least one parent having died of heart disease were 20% more likely to develop depression at some point in their life.

Next, the researchers calculated a genetic risk score for coronary heart disease – a measure of the contribution made by the various genes known to increase the risk of heart disease. Heart disease is a so-called ‘polygenic’ disease – in other words, it is caused not by a single genetic variant, but rather by a large number of genes, each increasing an individual’s chances of developing heart disease by a small amount. Unlike for family history, however, the researchers found no strong association between the genetic predisposition for heart disease and the likelihood of experiencing depression.

Together, these results suggest that the link between heart disease and depression cannot be explained by a common genetic predisposition to the two diseases. Instead, it implies that something about an individual’s environment – such as the risk factors they are exposed to – not only increases their risk of heart disease, but at the same time increases their risk of depression.

This finding was given further support by the next stage of the team’s research. They used a technique known as Mendelian randomisation to investigate 15 biomarkers – biological ‘red flags’ – associated with increased risk of coronary heart disease. Mendelian randomisation is a statistical technique that allows researchers to rule out the influence of factors that otherwise confuse, or confound, a study, such as social status.

Of these common biomarkers, they found that triglycerides (a type of fat found in the blood) and the inflammation-related proteins IL-6 and CRP were also risk factors for depression.

Both IL-6 and CRP are inflammatory markers that are produced in response to damaging stimuli, such as infection, stress or smoking. Studies by Dr Khandaker and others have previously shown that people with elevated levels of IL-6 and CRP in the blood are more prone to develop depression, and that levels of these biomarkers are high in some patients during acute depressive episode. Elevated markers of inflammation are also seen in people with treatment resistant depression. This has raised the prospect that anti-inflammatory drugs might be used to treat some patients with depression. Dr Khandaker is currently involved in a clinical trial to test tocilizumab, an anti-inflammatory drug used for the treatment of rheumatoid arthritis that inhibits IL-6, to see if reducing inflammation leads to improvement in mood and cognitive function in patients with depression.

While the link between triglycerides and coronary heart disease is well documented, it is not clear why they, too, should contribute to depression. ̽��ֱ��link is unlikely to be related by obesity, for example, as this study has found no evidence for a causal link between body mass index (BMI) and depression.

“Although we don’t know what the shared mechanisms between these diseases are, we now have clues to work with that point towards the involvement of the immune system,” says Dr Burgess. “Identifying genetic variants that regulate modifiable risk factors helps to find what is actually driving disease risk.”

̽��ֱ��research was funded by Wellcome and MQ: Transforming Mental Health.

Dr Sophie Dix, Director of Research at MQ, says: “This study adds important new insight into the emergence and risk of depression, a significantly under researched area.

“Taking a holistic view of a person’s health – such as looking at heart disease and depression together – enables us to understand how factors like traumatic experiences and the environment impact on both our physical and mental health.

“This research shows clearly the shared biological changes that are involved. This not only opens opportunities for earlier diagnosis, but also create a solid foundation for exploring new treatments or using existing treatments differently. We need to stop thinking about mental and physical health in isolation and continue this example of bringing sciences together to create real change.”

Reference
Khandaker, GM et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Molecular Psychiatry; 19 March 2019; DOI: 10.1038/s41380-019-0395-3

People with heart disease are more likely to suffer from depression, and the opposite is also true. Now, scientists at the ̽��ֱ�� of Cambridge believe they have identified a link between these two conditions: inflammation – the body’s response to negative environmental factors, such as stress.

It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs – the cardiovascular system and the brain

Golam Khandaker

Mitchell Hollander

Man

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MRC, GSK and five leading UK universities collaborate to crack difficult disease areas

cjb250 — Wed, 15 Jul 2015 09:00:15 +0000

̽��ֱ��Experimental Medicine Initiative to Explore New Therapies (EMINENT) network will be coordinated by ̽��ֱ�� College London (UCL) and will bring together teams of researchers from the Universities of Cambridge, Glasgow, Newcastle, Imperial College London and UCL, with GSK researchers to study the fundamental biological mechanisms responsible for a range of inflammatory diseases. Professor Edwin Chilvers, Professor of Respiratory Medicine, will be leading the ̽��ֱ�� of Cambridge’s involvement, and his colleagues Professors Arthur Kaser and Ken Smith and Dr David Jayne will be leading research themes.

It is hoped that combining the disease biology expertise of these academic scientists with GSK’s drug development expertise and resources will ultimately lead to breakthroughs in understanding that could accelerate the development of innovative treatments for patients.

Drug development is a lengthy, costly and risky process, with the majority of promising treatments failing in clinical trials and hence never reaching patients as medicines. This is because the biological processes that underlie many diseases are still not fully understood.

By gaining a better understanding of the inflammatory process in diseases such as Chronic Obstructive Pulmonary Disease (COPD) and fibrosis, the collaboration aims to improve the success rate for discovering new potential treatments for these and other diseases.

Through the unique EMINENT network, MRC funding of up to £8m over five years will support academic costs. This will be matched with GSK in-kind contributions, including access to a portfolio of currently available medicines, experimental compounds, screening facilities and the company’s drug discovery and development in-house expertise. While GSK will retain ownership of the intellectual property covering these medicines and compounds, joint project teams of GSK and academic researchers will be able to use these as investigational tools to help answer scientific questions about human disease – which in turn could provide starting points for the development of next generation treatments for patients.

̽��ֱ��initiative aims to support up to ten experimental medicine projects over the five year period. ̽��ֱ��academic research teams that are awarded funding by the MRC will work alongside their industry colleagues at both GSK and university facilities, with a view to building a legacy of expertise in translational and experimental human research across academia and industry. It is anticipated that the network will grow beyond the first five academic partners.

Information and new discoveries will be readily communicated across the network, and beyond, in a spirit of open innovation. This will help enable breakthroughs in understanding to be applied across a spectrum of diseases, maximising the potential of the initiative to bring real benefits to patients.

Minister for Life Sciences George Freeman said “Networks of biomedical researchers from hospitals, industry and universities are key to unlocking the biomedical breakthroughs that are transforming our understanding of the mechanisms of disease and developing new diagnostics and treatments for patients.”

Professor Sir John Savill, Chief Executive at the Medical Research Council, said: “Despite major progress made over the last 20 years in many disease areas, some hard-to-treat conditions still carry high morbidity and mortality. Addressing these challenges successfully requires close, flexible, collaboration across a range of disciplines with complementary methodological expertise and disease understanding which is why initiatives such as this are so important to the MRC. We believe this innovative approach could be applied in other areas to combine the work of academia and industry.”

GSK’s president of pharmaceuticals R&D, Patrick Vallance, said: “At GSK, we believe that alongside the cutting-edge research our own scientists are leading, we also have much to learn from researchers outside our walls. We believe that by sharing our resources and research during the early stages of research we can stimulate innovation within the scientific community, strengthen our understanding of human disease and accelerate the development of new treatments for patients. We need to embrace opportunities to work together and share information about our successes and failures.

“ ̽��ֱ��MRC’s EMINENT initiative is a great way for us to do precisely this, allowing us to work alongside scientists from five top UK universities to drive forward our collective understanding of inflammatory disease, and we’re confident this unique approach will make us better able to develop innovative new treatments in the future.”

An independent panel of experts will assess the applications submitted by EMINENT collaborators. Projects will be assessed against the same criteria as any other MRC-funded research, based on the quality of the science. An oversight group, the Joint Steering Committee (JSC), reporting to the MRC, will ensure robust governance and alignment with MRC’s strategic priorities.

̽��ֱ��collaboration will also be supported by the NIHR Biomedical Research Centres at Cambridge, Newcastle, Imperial and UCL.

Cambridge has been part of a successful £16 million bid to work with the MRC, GSK and four other UK universities in a unique open innovation research initiative aiming to improve scientists’ understanding of inflammatory diseases that present a serious burden to patients.

James Heilman, MD

A chest X-ray demonstrating severe COPD (cropped)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Million man study examines long-term effects of blocking inflammation

cjb250 — Thu, 26 Feb 2015 00:00:11 +0000

̽��ֱ��finding is one of the outcomes of research using a powerful new genetic tool that mimics the behaviour of certain anti-inflammatory drugs. ̽��ֱ��technique allows researchers to study the effects of inhibiting interleukin-1, a master regulator of inflammation, on a range of different outcomes not yet investigated in clinical trials.

Interleukin-1 plays a central role in regulating the body’s inflammatory response, setting off a cascade of signals within the body against infection and other damage. Certain drugs, such as anakinra, reduce inflammation by blocking interleukin-1. This action also occurs naturally in individuals who carry particular genetic variants.

Although inflammation is meant to be protective, a disproportionate response can be damaging to the body – for example, causing potentially life-threatening symptoms seen in severe cases of influenza infection. It also plays a crucial role in a number of autoimmune diseases such as rheumatoid arthritis. Although scientists suspected that it would also be likely to increase risk of cardiovascular disease, until now little evidence existed to confirm or disprove this suggestion.

To examine the long-term implications of blocking this pathway, researchers from the Interleukin-1 Genetics Consortium developed a ‘genetic score’ to combine the effects of two of these natural genetic variants. They looked at the effect of this score on key biological indicators of inflammation, comparing it to the effect of anakinra. They investigated this score in relation to several medical conditions including rheumatoid arthritis and coronary heart disease by analysing data from over a million individuals.

̽��ֱ��researchers found that individuals who carried the genetic variants – in other words, had naturally-occurring interleukin-1 inhibition – showed a decreased risk of developing rheumatoid arthritis. This was as anticipated: anakinra is one of the drugs used to treat the condition. ̽��ֱ��variants had no impact on the risks of developing type 2 diabetes or ischaemic stroke.

Surprisingly, however, blocking interleukin-1 increased an individual’s risk of developing coronary heart disease: the risk of a heart attack was 15% higher in people who inherited a greater tendency to block interleukin-1. ̽��ֱ��researchers also observed raised levels of LDL-cholesterol – so-called ‘bad cholesterol’ – in these individuals, which may explain some of this increased risk.

Blocking interleukin-1 also increased an individual’s risk of developing abdominal aortic aneurysm, a swelling of the main blood vessel that leads away from the heart, down through the abdomen to the rest of the body; one in 50 deaths amongst men over 65 years of age is due to such an aneurysm rupturing.

Although anakinra has been tested in clinical trials and shown to be effective in treating symptoms of rheumatoid arthritis, there has been little research into its effect on coronary heart disease. This is, in part, because of the complexity of studying heart disease and the number of individuals and length of study required in order for an effect to become apparent. By studying naturally-occurring interleukin-1 inhibition, the researchers have been able to infer that the drug could potentially elevate the risk of coronary heart disease and abdominal aortic aneurysms.

Professor John Danesh from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, who leads the consortium, says: “Drugs such as anakinra are licensed for the treatment of inflammatory conditions including rheumatoid arthritis, but we know little about the long-term health consequences of blocking interleukin-1.

“Our approach was to use ‘nature’s randomised trial’ to get answers currently beyond the resolution of drug trials. Our genetic analysis suggests, surprisingly, that blocking interleukin-1 over the long-term could increase the risk of cardiovascular diseases.”

Dr Daniel Freitag, lead author of the study, also at the ̽��ֱ�� of Cambridge, adds: “ ̽��ֱ��common view is that inflammation promotes the development of heart disease – we’ve shown that the truth is clearly more complicated. We need to be careful that drugs like anakinra that aim to tackle rheumatoid arthritis by inhibiting interleukin-1 do not have unintended consequences on an individual’s risk of heart disease.”

Professor Peter Weissberg, Medical Director at the British Heart Foundation, which helped fund the study, said: “It is important to remember that this is not a study of an anti-arthritis drug but a gene that can mimic its effects. ̽��ֱ��effects of a gene are lifelong, whereas a drug only affects a person while it is being taken.

“Nevertheless the study suggests that patients who are prescribed anakinra should have their cardiovascular risk factors carefully managed by their doctor.”

̽��ֱ��research was funded by the Medical Research Council, the British Heart Foundation, the National Institute of Health Research (NIHR), the NIHR Cambridge Biomedical Research Centre, the European Research Council and the European Commission Framework Programme.

Reference
̽��ֱ��Interleukin-1 Genetics Consortium. Cardiometabolic consequences of genetic up-regulation of the interleukin-1 receptor antagonist: Mendelian randomisation analysis. Lancet Diabetes and Endocrinology. 26 February, 2015.

Inflammation – the body’s response to damaging stimuli – may have a protective effect against cardiovascular disease, according to a study published today in the journal Lancet Diabetes and Endocrinology.

̽��ֱ��common view is that inflammation promotes the development of heart disease – we’ve shown that the truth is clearly more complicated

Daniel Freitag

Gabriela Pinto

Heart pulse

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