̽��ֱ�� of Cambridge - Ken Smith

Low iron levels resulting from infection could be key trigger of long COVID

cjb250 — Mon, 04 Mar 2024 10:00:41 +0000

̽��ֱ��discovery not only points to possible ways to prevent or treat the condition, but could help explain why symptoms similar to those of long COVID are also commonly seen in a number of post-viral conditions and chronic inflammation.

Although estimates are highly variable, as many as three in 10 people infected with SARS-CoV-2 could go on to develop long COVID, with symptoms including fatigue, shortness of breath, muscle aches and problems with memory and concentration (‘brain fog’). An estimated 1.9 million people in the UK alone were experiencing self-reported long COVID as of March 2023, according to the Office of National Statistics.

Shortly after the start of the COVID-19 pandemic, researchers at the ̽��ֱ�� of Cambridge began recruiting people who had tested positive for the virus to the COVID-19 cohort of the National Institute for Health and Care Research (NIHR) BioResource. These included asymptomatic healthcare staff identified via routine screening through to patients admitted to Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, some to its intensive care unit.

Over the course of a year, participants provided blood samples, allowing researchers to monitor changes in the blood post-infection. As it became clear that a significant number of patients would go on to have symptoms that persisted – long COVID – researchers were able to track back through these samples to see whether any changes in the blood correlated with their later condition.

In findings published in Nature Immunology, researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), ̽��ֱ�� of Cambridge, together with colleagues at Oxford, analysed blood samples from 214 individuals. Approximately 45% of those questioned about their recovery reported symptoms of long COVID between three and ten months later.

Professor Ken Smith, who was Director of CITIID at the time of the study and will take up a position as Director of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, in April, said: “Having recruited a group of people with SARS-CoV-2 early in the pandemic, analysis of several blood samples and clinical information collected over a 12 month period after infection has proved invaluable in giving us important and unexpected insights into why, for some unlucky individuals, initial SARS-CoV-2 infection is followed by months of persistent symptoms.”

̽��ֱ��team discovered that ongoing inflammation – a natural part of the immune response to infection – and low iron levels in blood, contributing to anaemia and disrupting healthy red blood cell production, could be seen as early as two weeks post COVID-19 in those individuals reporting long COVID many months later.

Early iron dysregulation was detectable in the long COVID group independent of age, sex, or initial COVID-19 severity, suggesting a possible impact on recovery even in those who were at low risk for severe COVID-19, or who did not require hospitalisation or oxygen therapy when sick.

Dr Aimee Hanson, who worked on the study while at the ̽��ֱ�� of Cambridge, and is now at the ̽��ֱ�� of Bristol, said: “Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later.

“Although we saw evidence that the body was trying to rectify low iron availability and the resulting anaemia by producing more red blood cells, it was not doing a particularly good job of it in the face of ongoing inflammation.”

Interestingly, although iron dysregulation was more profound during and following severe COVID-19, those who went on to develop long COVID after a milder course of acute COVID-19 showed similar patterns in the blood. ̽��ֱ��most pronounced association with long COVID was how quickly inflammation, iron levels and regulation returned to normal following SARS-CoV-2 infection – though symptoms tended to continue long after iron levels had recovered.

Co-author Professor Hal Drakesmith, from the MRC Weatherall Institute of Molecular Medicine at the ̽��ֱ�� of Oxford, said iron dysregulation is a common consequence of inflammation and is a natural response to infection.

“When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It’s an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert.

“However, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. ̽��ֱ��protective mechanism ends up becoming a problem.”

̽��ֱ��findings may help explain why symptoms such as fatigue and exercise intolerance are common in long COVID, as well as in several other post-viral syndromes with lasting symptoms.

̽��ֱ��researchers say the study points to potential ways of preventing or reducing the impact of long COVID by rectifying iron dysregulation in early COVID-19 to prevent adverse long-term health outcomes.

One approach might be controlling the extreme inflammation as early as possible, before it impacts on iron regulation. Another approach might involve iron supplementation; however as Dr Hanson pointed out, this may not be straightforward.

“It isn't necessarily the case that individuals don't have enough iron in their body, it's just that it’s trapped in the wrong place,” she said. “What we need is a way to remobilise the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.”

̽��ֱ��research also supports ‘accidental’ findings from other studies, including the IRONMAN study, which was looking at whether iron supplements benefited patients with heart failure – the study was disrupted due to the COVID-19 pandemic, but preliminary findings suggest that trial participants were less likely to develop severe adverse effects from COVID-19. Similar effects have been observed among people living with the blood disorder beta-thalassemia, which can cause individuals to produce too much iron in their blood.

̽��ֱ��research was funded by Wellcome, the Medical Research Council, NIHR and European Union Horizon 2020 Programme.

Reference
Hanson, AL et al. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Imm; 1 March 2024; DOI: 10.1038/s41590-024-01754-8

Problems with iron levels in the blood and the body’s ability to regulate this important nutrient as a result of SARS-CoV-2 infection could be a key trigger for long COVID, new research has discovered.

Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later

Aimee Hanson

Malachi Cowie

A man sitting on a couch holding his head in his hands

̽��ֱ��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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When Symptoms Don't Stop

jg533 — Fri, 22 Jan 2021 08:13:29 +0000

Treating those most severely affected by COVID-19 has necessarily taken priority during the pandemic. But could long COVID be the next wave of the crisis?

Likelihood of severe and ‘long’ COVID may be established very early on following infection

cjb250 — Mon, 18 Jan 2021 12:39:36 +0000

Among the key findings, which have not yet been peer-reviewed, are:

Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID’.

̽��ֱ��immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms. In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.

To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. ̽��ֱ��team take blood samples from patients over several months, as well as continuing to measure their symptoms.

In research published today, the team analysed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.

Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “ ̽��ֱ��NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

Listen to Professor Ken Smith discuss the findings with the Naked Scientists

̽��ֱ��team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back. These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.

In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease. This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.

̽��ֱ��team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms. This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

̽��ֱ��researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.

̽��ֱ��study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

̽��ֱ��team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. ̽��ֱ��more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “ ̽��ֱ��NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

̽��ֱ��research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.

Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765

New research provides important insights into the role played by the immune system in preventing – and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience ‘long COVID’.

Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms

Paul Lyons

NIH Image Gallery

SARS-CoV-2 virus particles are shown emerging from the surface of cells cultured in the lab

̽��ֱ��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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“We’re in it for the long haul”

cjb250 — Wed, 21 Oct 2020 07:46:34 +0000

In late 2019, a new institute opened on the Cambridge Biomedical Campus. Its timing could not have been better - as the COVID-19 pandemic sent Britain into lockdown several months later, the institute found itself at the heart of the ̽��ֱ��’s response to this unprecedented challenge.

150 scientists from new institute join Cambridge fight against COVID-19

cjb250 — Wed, 08 Apr 2020 16:12:03 +0000

Based on the Cambridge Biomedical Campus, the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) is integrated with the NHS both locally, through Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust and the Royal Papworth Hospital NHS Foundation Trust, and nationally, in particular through the National Institute for Health Research (NIHR) BioResource.

CITIID, based in the Jeffrey Cheah Biomedical Centre, opened its doors in September 2019. Following the outbreak of SARS-CoV-2, the virus that causes COVID-19, the institute has redirected all of its research efforts to tackling the pandemic.

“ ̽��ֱ��world is facing an unprecedented challenge, with potentially millions of lives at risk, which is why over 150 of my colleagues at our new institute are focusing their expertise on the fightback against COVID-19,” says Professor Ken Smith, Director of CITIID.

“Together with our partners in the NHS and NIHR, we aim to identify those patients at greatest risk and understand why the coronavirus makes some people so sick while leaving others with only mild symptoms. Ultimately, we hope this will lead to the development of new treatments against this dreadful disease.”

̽��ֱ��Institute last week opened what is believed to be the largest Containment Level 3 Facility in any UK academic institution. These facilities are required for work on dangerous pathogens such as the coronavirus.

“ ̽��ֱ��state-of-the-art facilities and equipment at CITIID will allow us to do essential work on the novel coronavirus in a safe environment,” says Professor Gordon Dougan. “Our institute, positioned as it is on the thriving Cambridge Biomedical Campus, is perfectly suited to lead Cambridge’s response, working with research and health partners locally, nationally and internationally on this urgent problem.”

̽��ֱ��team at the institute has also been instrumental in evaluating and helping set up point-of-care, rapid diagnostic testing for patients at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals (CUH) NHS Foundation Trust, as well as developing tests for frontline healthcare workers treating COVID-19 patients.

“Organising the logistics for testing has been a huge challenge,” says Professor Paul Lehner. “But thanks to a tremendous collaborative effort between CUH and the ̽��ֱ��, we are now testing frontline healthcare workers as well as people who are off work and in isolation due to potential COVID-related contacts.”

Recruitment is already underway of COVID-19 patients at Addenbrooke’s. Researchers aim to recruit all consenting patients infected with SARS-CoV-2 from the hospital.

Once consent has been obtained from a patient, the team will take blood and other samples, which will be processed in the Department of Medicine’s laboratories before being transferred for storage and further study at CITIID. Samples will be taken when the patients first arrive at the hospital and during the course of disease, with the research team also working alongside NHS staff to support patient care.

This study forms part of the COVID-19 BioResource, a collaboration with the NIHR BioResource, and will involve state-of-the-art analysis of the samples, helping the team understand how coronavirus infects us and causes disease and how our immune system fights back. It aims to allow researchers to predict which patients will do well or badly, and to help inform the development of new medicines to tackle the disease.

“A key challenge for the institute is trying to understand how much of the lung disease seen in COVID-19 patients is caused by the virus itself and how much is due to an inappropriate immune response,” explains Professor Lehner. “An answer to this question will help guide how best we treat this devastating condition.”

̽��ֱ�� ̽��ֱ�� recently announced that CITIID would take be taking a leading role in the £20 million COVID-19 Genomics UK Consortium, a major national effort to help understand and control the infection. Its researchers are also leading the evaluation of a new rapid diagnostic test for COVID-19, developed by a ̽��ֱ�� spinout company, which is capable of diagnosing the infection in under 90 minutes.

Visit the Cambridge Fighting COVID website

How you can support Cambridge's COVID-19 research effort

Donate to support COVID-19 research at Cambridge

One of Cambridge’s newest institutes, established to study the relationship between infectious disease and our immune systems, is leading the ̽��ֱ�� of Cambridge’s response to the COVID-19 pandemic, with over 150 scientists and clinicians, the UK’s largest academic Containment Level 3 Facility, and a range of collaborators from across the UK and beyond.

̽��ֱ��world is facing an unprecedented challenge, with potentially millions of lives at risk, which is why over 150 of my colleagues at our new institute are focusing their expertise on the fightback against COVID-19

Ken Smith

geralt

Coronavirus

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Cambridge to spearhead £20million alliance to map spread of COVID-19 coronavirus

cjb250 — Mon, 23 Mar 2020 00:01:10 +0000

Through a £20 million investment administered by the ̽��ֱ��, the COVID-19 Genomics UK Consortium – comprised of the NHS, Public Health Agencies, Wellcome Sanger Institute, and numerous academic institutions – will deliver large-scale, rapid sequencing of the cause of the disease and share intelligence with hospitals, regional NHS centres and the Government.

Samples from patients with confirmed cases of COVID-19 will be sent to a network of sequencing centres which currently includes Belfast, Birmingham, Cambridge, Cardiff, Edinburgh, Exeter, Glasgow, Liverpool, London, Norwich, Nottingham, Oxford and Sheffield.

̽��ֱ�� ̽��ֱ��, together with the Wellcome Sanger Institute, one of the world’s most advanced centres of genomes and data, will coordinate the collaboration between expert groups across the UK to analyse the genetic code of COVID-19 samples circulating in the UK and in doing so, give public health agencies and clinicians a unique, cutting-edge tool to combat the virus.

By looking at the whole virus genome in people who have had confirmed cases of COVID-19, scientists can monitor changes in the virus at a national scale to understand how the virus is spreading and whether different strains are emerging. This will help clinical care of patients and save lives.

Business Secretary Alok Sharma said: “At a critical moment in history, this new consortium will bring together the UK’s brightest and best scientists to build our understanding of this pandemic, tackle the disease and ultimately, save lives.

“As a Government we are working tirelessly to do all we can to fight COVID-19 to protect as many lives and save as many jobs as possible.”

Whole genome sequencing involves reading the entire genetic code of the virus. It will help scientists understand COVID-19 and its spread. It can also help guide treatments in the future and help monitor the impact of interventions.

Government Chief Scientific Adviser, Sir Patrick Vallance said: “ ̽��ֱ��UK is one of the world’s leading destinations for genomics research and development, and I am confident that our best minds, working as part of this consortium, will make vital breakthroughs to help us tackle this disease.”

̽��ֱ��UK Consortium, supported by the Government, including the NHS, Public Health England, UK Research and Innovation (UKRI), and Wellcome, will enable clinicians and public health teams to rapidly investigate clusters of cases in hospitals, care homes and the community, to understand how the virus is spread and implement appropriate infection control measures.

̽��ֱ��Consortium Director will be Professor Sharon Peacock, Chair of Public Health and Microbiology at the ̽��ֱ�� of Cambridge and Director of the National Infection Service, Public Health England.

“This virus is one of the biggest threats our nation has faced in recent times and crucial to helping us fight it is understanding how it is spreading,” said Professor Peacock. “Harnessing innovative genome technologies will help us tease apart the complex picture of coronavirus spread in the UK, and rapidly evaluate ways to reduce the impact of this disease on our society.”

Dr Ewan Harrison from the Department of Medicine will serve as the Scientific Project Manager. Professor John Danesh from the Department of Public Health and Primary Care will serve on the consortium’s Steering Committee

“We are delighted to be leading this important national programme,” said Professor Ken Smith, Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease. “It builds on years of work on pathogen genomics by Professor Peacock and her group, and synergises with other major COVID-19 programmes being driven from Cambridge. ̽��ֱ��size and reach of this study across many centres in the UK will provide unprecedented insight into the biology of COVID-19 and its impact on the population. It will be essential for understand how this virus spreads and why it causes disease, and for monitoring how it evolves, particularly looking at whether it becomes more or less dangerous.”

Professor Sir Mike Stratton, Director of the Wellcome Sanger Institute, added: “Samples from substantial numbers of confirmed cases of COVID-19 will be whole genome sequenced and, employing the Sanger Institute’s expertise in genomics and surveillance of infectious diseases, our researchers will collaborate with other leading groups across the country to analyse the data generated and work out how coronavirus is spreading in the UK. This will inform national and international strategies to control the pandemic and prevent further spread.”

Sir Jeremy Farrar, Director of Wellcome, said: “Rapid genome sequencing of COVID-19 will give us unparalleled insights into the spread, distribution and scale of the epidemic in the UK. ̽��ֱ��power of 21st century science to combat this pandemic is something that those going before us could not have dreamt of, and it is incumbent on us to do everything we can to first understand, and then limit, the impact of COVID-19.”

Professor Fiona Watt, Executive Chair of the Medical Research Council, part of UK Research and Innovation said: “ ̽��ֱ��UK is a leader in cutting-edge genome sequencing science. We are now applying specialist expertise in our fight to slow the spread of Coronavirus and accelerate treatments for those affected.

“ ̽��ֱ��ambitious and coordinated response of our research community to the COVID-19 challenge is remarkable. This investment and the findings from the consortium will help prepare the UK and the world for future pandemics.”

How you can support Cambridge's COVID-19 research effort

Donate to support COVID-19 research at Cambridge

̽��ֱ�� ̽��ֱ�� of Cambridge is to take a leading role in a major national effort to help understand and control the new coronavirus infection (COVID-19) announced today by the Government and the UK’s Chief Scientific Adviser.

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New prognostic test could enable personalised treatment of inflammatory bowel disease

cjb250 — Fri, 03 May 2019 07:12:05 +0000

Ulcerative colitis and Crohn’s disease – collectively known as inflammatory bowel disease (IBD) – are chronic conditions that involve inflammation of the gut. Symptoms include abdominal pain, bloody diarrhoea, weight loss and fatigue. There is currently no cure, but there are a growing number of medicines that aim to relieve symptoms and prevent the condition returning; however, the more severe the case of the IBD, the stronger the drugs need to be and the greater the potential side effects.

Researchers at the Department of Medicine, ̽��ֱ�� of Cambridge, and Cambridge ̽��ֱ�� Hospitals NHS Trust previously showed that a genetic signature found in a certain type of immune cell known as a CD8 T-cell could be used to assign patients to one of two groups depending on whether their condition was likely to be mild or severe (requiring repeated treatment). However, isolating CD8 T- cells and obtaining the genetic signature was not straightforward, making the test unlikely to be scaleable and achieve widespread use.

In the latest study, published in the journal Gut, the researchers worked with a cohort of 69 patients with Crohn’s disease to see whether it was possible to develop a useful, scaleable test by looking at whole blood samples in conjunction with CD8 T-cells and using widely-available technology.

̽��ֱ��team used a combination of machine learning and a whole blood assay known as qPCR – a relatively simple tool used in NHS labs across the country – to identify genetic signatures that re-created the two subgroups from their previous study.

̽��ֱ��researchers then validated their findings in 123 IBD patients recruited from clinics in Cambridge, Nottingham, Exeter and London.

“Using simple technology that is available in almost every hospital, our test looks for a biomarker – essentially, a medical signature – to identify which patients are likely to have mild IBD and which ones will have more serious illness,” says Dr James Lee, joint first author of the study.

“This is important as it could enable doctors to personalise the treatment that they give to each patient. If an individual is likely to have only mild disease, they don’t want to be taking strong drugs with unpleasant side-effects. But similarly, if someone is likely to have a more aggressive form of the disease, then the evidence suggests that the sooner we can start them on the best available treatments, the better we can manage their condition.”

̽��ֱ��accuracy of the test is comparable to similar biomarkers used in cancer, which have helped transform treatment, say the researchers. They found the new test was 90-100% accurate in correctly identifying patients who did not require multiple treatments.

“IBD can be a very debilitating disease, but this new test could help us transform treatment options, moving away from a ‘one size fits all’ approach to a personalised approach to treating patients,” says Professor Ken Smith, senior author and Head of the Department of Medicine.

̽��ֱ��test is now being developed further by PredictImmune, a spinout company co-founded by Professor Smith with support from Cambridge Enterprise, the ̽��ֱ��’s technology transfer arm. ̽��ֱ��team is involved in a £4.2 million trial to see whether using the biomarker to guide treatment at the time of diagnosis can lead to better outcomes for patients.

̽��ֱ��findings have been welcomed by Helen Terry, Director of Research at Crohn’s & Colitis UK, which helps fund the research. “It’s really exciting that we are moving away from a ‘one size fits all’ approach for people with Crohn’s or Colitis. Dr Lee and his team’s latest study is the accumulation of 10 years’ worth of research and we’re now at the stage where this test will be available in the NHS. This could drastically change the lives of people with Crohn’s or Colitis as it means they can be started on the best medication for them sooner.”

Additional funding for the research came from Wellcome, the Medical Research Council and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Later this year, Professor Smith and his team are due to move into the new Cambridge Institute of Therapeutic Immunology and Infectious Disease, to be based in the Jeffrey Cheah Biomedical Centre on the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

Reference
Biasci, D and Lee JC, et al. A blood-based prognostic biomarker in inflammatory bowel disease. Gut; April 2019; DOI: 10.1136/gutjnl-2019-318343

Scientists at the ̽��ֱ�� of Cambridge have developed a new test that can reliably predict the future course of inflammatory bowel disease in individuals, transforming treatments for patients and paving the way for a personalised approach.

This new test could help us transform treatment options, moving away from a ‘one size fits all’ approach to a personalised approach to treating patients

Ken Smith

Dr James Lee

Kate Gray, aged 31, Amersham, living with Crohn’s

Kate was diagnosed with Crohn’s Disease when she was 14 years old having been unwell with symptoms for quite some time.

This meant she needed surgery. “I was told by my consultant I would only need a little bit of a resection and that it’s unlikely I would be bothered by symptoms for decades, giving me the impression that was probably the end of it.”

Within 9 months of her bowel resection, Kate’s symptoms had returned. She tried various medications, including immunosuppressants and steroids but nothing worked, and she kept getting more unwell. She also had some nasty side effects from the drug mercaptopurine, becoming neutropaenic (low on neutrophils), leading to two admissions to hospital.

This pathway continued throughout Kate’s secondary education and once on the drug infliximab, it reached the point where Kate couldn’t eat solid foods. Her bowel was so strictured and damaged that she was told she needed an ileostomy at the age of 20. In the lead-up to this Kate had a nasal-gastric feeding tube which involved long stints in hospital.

When Kate woke up from her operation, she was told that the damage was much more extensive than thought and she would have a permanent stoma.

Following surgery, Kate was started on the biologic drug, Humira and has been on this weekly ever since. “My stoma’s been amazing and bowel wise, my symptoms have been good for the past decade.”

Kate could have benefited hugely from a prognostic test, making her more aware of disease course and allowing her to try stronger treatments earlier.

“I do sometimes wonder what would have happened if I knew my disease was going to be more severe and not mild, as I was told. It’s likely I would have opted for my ileostomy sooner and would have been keen to try stronger drugs earlier as this might have halted to progression of my Crohn’s. It would also have been good to have known what other symptoms I could have expected with more severe Crohn’s, including issues with my joints, uveitis and Crohn’s on the skin at the site of my surgery scars.”

Kate's story courtesy of Crohn's and Colitis UK

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̽��ֱ��self-defence force awakens

cjb250 — Tue, 04 Jul 2017 16:50:17 +0000

An army of cells constantly patrols within us, attacking anything it recognises as foreign, keeping us safe from invading pathogens. But sometimes things go wrong: the soldiers mistake benign cells for invaders, turning their friendly fire on us and declaring war.

̽��ֱ��consequences are diseases like multiple sclerosis (MS), asthma, inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis – diseases that are increasing at an alarming rate in both the developed and developing worlds.

Cambridge will be ramping up the fight against immune-mediated and inflammatory diseases with the opening next year of the Cambridge Institute of Therapeutic Immunology and Infectious Disease, headed by Professor Ken Smith. ̽��ֱ��Institute will work at the interface between immunity, infection and the microbiome (the microorganisms that live naturally within us). “We’re interested in discovering fundamental mechanisms that can turn the immune system on or off in different contexts, to modify, treat or prevent both inflammatory and infectious diseases,” says Smith.

But while diseases such as Crohn’s and asthma have long been understood to be a consequence of friendly fire, scientists are starting to see this phenomenon give rise to more surprising conditions, particularly in mental health.

In 2009, Professor Belinda Lennox, then at Cambridge and now at Oxford, led a study that showed that 7% of patients with psychoses tested positive for antibodies that attacked a particular receptor in the brain, the NMDA receptor. This blocked a key neurotransmitter, affecting communication between nerve cells and causing the symptoms.

Professor Alasdair Coles from Cambridge’s Department of Clinical Neurosciences is working with Lennox on a trial to identify patients with this particular antibody and reverse its effects. One of their treatments involves harnessing the immune system – weaponising it, one might say – to attack rogue warriors using rituximab, a monoclonal antibody therapy that kills off B-cells, the cells that generate antibodies.

“You can make monoclonal antibodies for experimental purposes against anything you like within a few days,” explains Coles. “In contrast, to come up with a small molecule – the alternative sort of drug – takes a long, long time.”

̽��ֱ��first monoclonal antibody to be made into a drug, created here in Cambridge, is called alemtuzumab. It targets both B- and T-cells and has been used in a variety of autoimmune diseases and cancers. Its biggest use is in MS, where it eliminates the rogue T- and B-cells that attack the protective insulation (myelin sheath) around nerve fibres. Licensed in Europe in 2013 and approved by NICE in 2014, it has now been used in tens of thousands of MS patients.

As well as treating diseases caused by the immune system, antibody therapies are now widely used to treat cancer. And, as Professor Gillian Griffiths, Director of the Cambridge Institute for Medical Research, explains, antibody-producing cells are not the only immune cells that can be weaponised.

“T-cells are also showing great promise,” she says. “They are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.”

But cancer cells are able to trick T-cells by sending out a ‘don’t kill’ signal. Antibodies that block these signals, which have become known as ‘checkpoint inhibitors’, are proving remarkably successful in cancer therapies. “My lab focuses on what tells a T-cell to kill, and how you make it a really good killer, using imaging and genetic approaches to understand how these cells can be fine-tuned,” Griffiths explains. “This has revealed some novel mechanisms that play key roles in regulating killing.”

A second, more experimental, approach uses souped-up cells known as chimeric antigen receptor (CAR) T-cells programmed to recognise and attack a patient’s tumour.

Neither approach is perfect: antibody therapies can dampen down the entire immune system, causing secondary problems, while CAR T-cell therapies are prohibitively expensive as each CAR T-cell needs to be programmed to suit an individual. But, says Griffiths, “the results to date from both approaches are really rather remarkable”.

One of the problems that’s dogged immunotherapy trials is that T-cells only have a short lifespan. Most of the T-cells transplanted during immunotherapy are gone within three days, nowhere near long enough to defeat the tumour.

This is where Professor Randall Johnson comes in. He’s been working with a molecule (2-hydroxyglutarate), which he says has “become trendy of late”. It’s an ‘oncometabolite’, believed to be responsible for making cells cancerous, which is why pharmaceutical companies are trying to inhibit its action. Johnson has taken the opposite approach.

He’s shown that a slightly different form of the molecule plays a critical role in T-cell function: it can turn them into renewable cells that hang around for a long time and can reactivate to combat cancer. Increasing the levels of this molecule in T-cells makes them stay around longer and be much better at destroying tumours. “Rather than creating killer T-cells that are active from the start, but burn out very quickly, we’re creating an army of cells that can stay quiet for a long time, but will go into action when necessary.”

This counterintuitive approach caught the attention of Apollo Therapeutics, who recognised the enormous promise and has invested in Johnson’s work, which he carried out in mice, to see if it can be applied to humans.

But T-cells face other problems, particularly in pancreatic cancer, explains Professor Duncan Jodrell from the Cancer Research UK Cambridge Institute, which is why immunotherapy against these tumours has so far failed. ̽��ֱ��problem with pancreatic cancer is that ‘islands’ of tumour cells sit in a ‘sea’ of other material, known as stroma. As Jodrell and colleagues have shown, it’s possible for T-cells to get into the stroma, but they go no further. “You can rev up your T-cells, but they just can’t get at the tumour cells.” They are running a study that tries to overcome this immune privilege and allow the T-cells to get to the tumour cells and attack them.

Tim Eisen, Professor of Medical Oncology at Cambridge and Head of the Oncology Translational Medicine Unit at AstraZeneca, believes we can expect great advances in cancer treatment from optimising and, in some cases, combining existing checkpoint inhibitor approaches.

Eisen is working with the Medical Research Council to trial checkpoint inhibitor antibody therapies as a complement – ‘adjuvant’ – to surgery for kidney cancer. Once the kidney is removed, the drug is used to destroy stray tumour cells that have remained behind. But even antibody therapies, which are now widely used within the NHS, are not universally effective and can cause serious complications. “One of the most important things for us to focus on now is which immunotherapeutic drug or particular combination of drugs might be effective in destroying tumour cells and be well tolerated by the patient.”

T-cell therapies – and, in particular, CAR T-cell therapies – are “very exciting, futuristic and experimental,” he says, “but they’re going to take some years to come in as standard therapy.”

̽��ֱ��problem is how to make them cost-effective. “It’s never going to be easier to engineer an individual person’s T-cells than it is to take a drug off the shelf and give it to them,” he says. “ ̽��ֱ��key is going to be whether you can industrialise production. But I’m very optimistic about our ability to re-engineer processes and make it available for people in general.”

We may soon see an era, then, when our immune systems become an unstoppable force for good.

Our immune systems are meant to keep us healthy, but sometimes they turn their fire on us, with devastating results. Immunotherapies can help defend against this ‘friendly fire’ – and even weaponise it in our defence.

T-cells are the body’s serial killers, patrolling, identifying and destroying infected and cancer cells with remarkable precision and efficiency.

Gillian Griffiths

̽��ֱ��moment when a T-cell kills

̽��ֱ��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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