̽��ֱ�� of Cambridge - immune system

Discovery of ‘new rules of the immune system’ could improve treatment of inflammatory diseases, say scientists.

jg533 — Tue, 18 Jun 2024 15:02:29 +0000

This overturns the traditional thinking that regulatory T cells exist as multiple specialist populations that are restricted to specific parts of the body. ̽��ֱ��finding has implications for the treatment of many different diseases – because almost all diseases and injuries trigger the body’s immune system.

Current anti-inflammatory drugs treat the whole body, rather than just the part needing treatment. ̽��ֱ��researchers say their findings mean it could be possible to shut down the body’s immune response and repair damage in any specific part of the body, without affecting the rest of it. This means that higher, more targeted doses of drugs could be used to treat disease – potentially with rapid results.

“We’ve uncovered new rules of the immune system. This ‘unified healer army’ can do everything - repair injured muscle, make your fat cells respond better to insulin, regrow hair follicles. To think that we could use it in such an enormous range of diseases is fantastic: it’s got the potential to be used for almost everything,” said Professor Adrian Liston in the ̽��ֱ�� of Cambridge’s Department of Pathology, senior author of the paper.

To reach this discovery, the researchers analysed the regulatory T cells present in 48 different tissues in the bodies of mice. This revealed that the cells are not specialised or static, but move through the body to where they’re needed. ̽��ֱ��results are published today in the journal Immunity.

“It's difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response,” said Liston.

He added: “Now that we know these regulatory T cells are present everywhere in the body, in principle we can start to make immune suppression and tissue regeneration treatments that are targeted against a single organ – a vast improvement on current treatments that are like hitting the body with a sledgehammer.”

Using a drug they have already designed, the researchers have shown - in mice - that it’s possible to attract regulatory T cells to a specific part of the body, increase their number, and activate them to turn off the immune response and promote healing in just one organ or tissue.

“By boosting the number of regulatory T cells in targeted areas of the body, we can help the body do a better job of repairing itself, or managing immune responses,” said Liston.

He added: “There are so many different diseases where we’d like to shut down an immune response and start a repair response, for example autoimmune diseases like multiple sclerosis, and even many infectious diseases.”

Most symptoms of infections such as COVID are not from the virus itself, but from the body’s immune system attacking the virus. Once the virus is past its peak, regulatory T cells should switch off the body’s immune response, but in some people the process isn’t very efficient and can result in ongoing problems. ̽��ֱ��new finding means it could be possible to use a drug to shut down the immune response in the patient’s lungs, while letting the immune system in the rest of the body continue to function normally.

In another example, people who receive organ transplants must take immuno-suppressant drugs for the rest of their lives to prevent organ rejection, because the body mounts a severe immune response against the transplanted organ. But this makes them highly vulnerable to infections. ̽��ֱ��new finding helps the design of new drugs to shut down the body’s immune response against only the transplanted organ but keep the rest of the body working normally, enabling the patient to lead a normal life.

Most white blood cells attack infections in the body by triggering an immune response. In contrast, regulatory T cells act like a ‘unified healer army’ whose purpose is to shut down this immune response once it has done its job - and repair the tissue damage caused by it.

̽��ֱ��researchers are now fundraising to set up a spin-out company, with the aim of running clinical trials to test their findings in humans within the next few years.

̽��ֱ��research was funded by the European Research Council (ERC), Wellcome, and the Biotechnology and Biological Sciences Research Council (BBSRC).

Reference: Liston, A. ‘ ̽��ֱ��tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program.’ Immunity, June 2024. DOI: 10.1016/j.immuni.2024.05.023

Scientists at the ̽��ֱ�� of Cambridge have discovered that a type of white blood cell - called a regulatory T cell - exists as a single large population of cells that constantly move throughout the body looking for, and repairing, damaged tissue.

It's difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response.

Adrian Liston

Louisa Wood/ Babraham Institute

Dr James Dooley, a senior author of the study, in the laboratory

In brief

A single large population of healer cells, called regulatory T cells, is whizzing around our body - not multiple specialist populations restricted to specific parts of the body as previously thought.
These cells shut down inflammation and repair the collateral damage to cells caused after our immune system has responded to injury or illness.
Tests, in mice, of a drug developed by the researchers showed that regulatory T cells can be attracted to specific body parts, boosted in number, and activated to suppress immune response and rebuild tissue.
Current anti-inflammatory drugs used for this purpose suppress the body’s whole immune system, making patients more vulnerable to infection.
̽��ֱ��discovery could lead to more targeted treatments, with fewer side-effects, for issues from lengthy COVID infections to autoimmune diseases like multiple sclerosis. Clinical trials in humans are now planned.

̽��ֱ��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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CamFest Speaker Spotlight: Professor Adrian Liston

zs332 — Sun, 17 Mar 2024 14:51:12 +0000

Adrian Liston, Professor of Pathology at the ̽��ֱ�� of Cambridge, talks about our extraordinary immune system ahead of his event, Diversity in the immune system on 20th March.

Mito warriors: how T cell assassins reload their weapons to kill and kill again

cjb250 — Thu, 14 Oct 2021 18:00:18 +0000

Cytotoxic T cells are specialist white blood cells that are trained by our immune system to recognise and eliminate threats – including tumour cells and cells infected with invading viruses, such as SARS-CoV-2, which causes COVID-19. They are also at the heart of new immunotherapies that promise to transform cancer treatment.

Professor Gillian Griffiths from the Cambridge Institute for Medical Research, who led the research, said: “T cells are trained assassins that are sent on their deadly missions by the immune system. There are billions of them in our blood, each engaged in a ferocious and unrelenting battle to keep us healthy.

“Once a T cell has found its target, it binds to it and releases its toxic cargo. But what is particularly remarkable is that they are then able to go on to kill and kill again. Only now, thanks to state-of-the-art technologies, have we been able to find out how they reload their weapons.”

Today, in a study published in Science, the team have shown that the refuelling of T cells’ toxic weapons is regulated by mitochondria. Mitochondria are often referred to as a cell’s batteries as they provide the energy that power their function. However, in this case the mitochondria use an entirely different mechanism to ensure the killer T cells have sufficient ‘ammunition’ to destroy their targets.

Professor Griffiths added: “These assassins need to replenish their toxic payload so that they can keep on killing without damaging the T cells themselves. This careful balancing act turns out to be regulated by the mitochondria in T cells, which set the pace of killing according to how quickly they themselves can manufacture proteins. This enables killer T cells to stay healthy and keep on killing under challenging conditions when a prolonged response is required.”

Understanding the details of this basic process could ultimately help in the long-term scientific goal of designing and engineering T cells that are better at killing cancer cells, say the researchers.

To accompany the study, Professor Griffiths and colleagues have released footage showing killer T cells as they hunt down and eliminate cancer cells.

One teaspoon full of blood alone is believed to have around 5 million T cells, each measuring around 10 micrometres in length, about a tenth the width of a human hair. ̽��ֱ��cells, seen in the video as red or green amorphous ‘blobs’, move around rapidly, investigating their environment as they travel.

When a T cell finds an infected cell or, in the case of the film, a cancer cell, membrane protrusions rapidly explore the surface of the cell, checking for tell-tale signs that this is an uninvited guest. ̽��ֱ��T cell binds to the cancer cell and injects poisonous ‘cytotoxin’ proteins down special pathways called microtubules to the interface between the T cell and the cancer cell, before puncturing the surface of the cancer cell and delivering its deadly cargo.

̽��ֱ��research was funded by Wellcome.

Reference
Lisci, M et al. Mitochondrial translation is required for sustained killing by cytotoxic T cells. Science; 14 Oct 2021; DOI: 10.1126/science.abe9977

Cambridge researchers have discovered how T cells – an important component of our immune system – are able to keep on killing as they hunt down and kill cancer cells, repeatedly reloading their toxic weapons.

T cells are trained assassins that are sent on their deadly missions by the immune system. There are billions of them in our blood, each engaged in a ferocious and unrelenting battle to keep us healthy

Gillian Griffiths

T-cell assassins captured on film hunting down cancer cells and ‘reloading’ to kill again

Killer T cell attacking a cancer cell

̽��ֱ��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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Cambridge to lead national consortium examining immune response to SARS-CoV-2 coronavirus

Anonymous — Fri, 28 Aug 2020 13:31:02 +0000

̽��ֱ��study is one of three new UK-wide studies receiving a share of £8.4 million from UK Research and Innovation (UKRI) and the National Institute for Health Research (NIHR).

̽��ֱ��Humoral Immune Correlates of COVID-19 (HICC) consortium will study the humoral immune response - molecules produced by the immune system to fight infection, including antibodies – by focusing on two cohorts: NHS workers - in collaboration with SIREN - to track immunity over 12 months, and hospitalised patients.

It will look in detail at the role of antibodies in immunity to SARS-CoV-2 and characterize the antibody response in people who have mild or asymptomatic infection versus those who develop moderate or severe COVID-19 disease. ̽��ֱ��researchers want to better understand the differences between beneficial - or protective - antibody responses versus those that cause disease. This will help to determine why early indications suggest that people with stronger antibody responses may have had more life-threatening disease and what types of antibody responses are more effective in preventing severe infection.

̽��ֱ��results from the study will help to develop better tests to diagnose protective immunity as well as determine how long protective antibodies persist after exposure to the virus. ̽��ֱ��researchers also hope the study will inform treatments for COVID-19 patients at different stages and with different severities of the disease, including whether targeting the overactivation of the innate humoral immune response – known as the ‘complement system’ – to SARS-CoV-2, could provide a unique approach to reducing severe COVID-19 related disease and death.

̽��ֱ��consortium is a collaboration led by Professor Wilhelm Schwaeble and Professor Jonathan Heeney at the ̽��ֱ�� of Cambridge, and Dr Helen Baxendale at the Royal Papworth Hospital NHS Trust.

“Understanding the role of antibody responses to SARS-CoV-2, and the role that the overactivation of the immediate innate immune response to the virus plays through complement activation in the initiation and maintenance of inflammatory disease, is critical to improve the clinical management of life-threatening cases of COVID-19,” said Dr Baxendale.

“In critical care, we know most patients have high levels of antibody to SARS-CoV-2 however what we don’t know is whether these antibodies are helpful. Pilot data has shown that many of our NHS staff have been exposed to SARS-CoV-2, but we need to find out whether this means they are protected from further infection either in the short or the long term, or may be at risk of disease in the future. Understanding the different types of antibody responses will allow us to determine beneficial antibodies from dangerous ones.

“Collaborating nationally with other UK COVID-19 projects and supported by clinical research networks and scientists across the country, we are delighted to receive this investment to answer these fundamentally important questions.”

HICC has been given urgent public health research status by the Department of Health and Social Care, to prioritise its delivery by the health and care system.

Chief Medical Officer for England and Head of the NIHR Professor Chris Whitty said: “Understanding how our immune systems respond to COVID-19 is key to solving some of the important questions about this new disease, including whether those who have had the disease develop immunity and how long this lasts, and why some are more severely affected.

“This investment by the NIHR and UKRI will help immunology experts to discover how our immune systems respond to SARS-CoV-2, including our T cell response. This is vital information to help prevent and treat the disease.”

Science Minister Amanda Solloway said: “Thanks to the brilliant work of our world-leading scientists and researchers, we continue to gain greater knowledge and understanding of coronavirus, enabling us to rapidly develop new treatments, as well as potential new vaccines.”

̽��ֱ�� ̽��ֱ�� of Cambridge and Royal Papworth Hospital have secured £1.5million of funding as part of the national effort by UK immunologists to understand immune responses to SARS-CoV-2, the coronavirus that causes COVID-19.

Tim Dennell

Sheffield's Women of Steel - COVID-19: We can beat this

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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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'Significant breakthrough' in understanding the deadly nature of pandemic influenza

sjr81 — Tue, 18 Sep 2018 14:59:28 +0000

Influenza is one of the main infectious diseases in humans. Seasonal influenza viruses account for about 650,000 deaths per year, whereas pandemic strains such as the 1918 H1N1 pandemic virus have been linked to 50-100 million deaths worldwide. Highly pathogenic avian influenza viruses such as the H5N1 and H7N9 strains have a mortality rate of about 50% in humans.

̽��ֱ��reasons for difference in disease severity and lethality caused by seasonal influenza viruses on the one hand, and pandemic and highly pathogenic avian influenza viruses on the other hand is still poorly understood. Previous research has indicated that in infections with the 1918 pandemic virus or infections with an H5N1 avian virus, a powerful immune response is established that leads to death.

This led Dr Aartjan te Velthuis of the ̽��ֱ�� of Cambridge and his colleagues Prof Ervin Fodor, Dr Josh Long and Dr David Bauer of the ̽��ֱ�� of Oxford, to ask what viral molecule can trigger this powerful immune response.

̽��ֱ��British groups first looked to how viruses are detected by the cell. Normally, an infected cell spots the presence of a virus by sensing the genetic material of the virus, RNA in the case of flu.

Work by Dr Richard Randall, a co-author on the manuscript from the ̽��ֱ�� of St Andrews, has shown that influenza viruses are good at hiding their RNA. This observation prompted te Velthuis and his colleagues to look for flu RNA that the virus was not able to hide from the cellular pathogen sensing system. What they found was truncated pieces of the viral genome that the virus had produced in error. ̽��ֱ��researchers called these pieces mini viral RNAs.

Fodor and his colleagues next investigated whether different influenza viruses produce mini viral RNAs at different frequencies and whether there was a link with the strong innate immune response that, for instance, the 1918 pandemic virus induces.

A combination of in vitro and in vivo experiments performed at Oxford and Cambridge, as well as by collaborators Leo Poon of the ̽��ֱ�� of Hong Kong, Debby van Riel of the Erasmus Medical Centre, and Emmie de Wit of the Rocky Mountain Laboratories, revealed indeed a strong correlation between the ability of an influenza virus to generate mini viral RNAs and the amount of inflammation and cell death the virus infection caused.

“We think it is a significant breakthrough and that it is particularly exciting that we are finding this factor a hundred years after the 1918 pandemic,” said Dr te Velthuis.

̽��ֱ��research groups are now continuing their efforts to investigate whether there is a causal link between influenza virus mortality and the production of mini viral RNAs. Together with their latest work, these efforts may help us understand better how influenza viruses cause disease, how we can identify dangerous influenza viruses, and how to develop new antivirals against influenza virus infections.

̽��ֱ��work was funded by the Wellcome Trust, Royal Society, Medical Research Council, NIH, and the Netherlands Organization for Scientific Research.

Researchers at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Oxford have discovered a new molecule that plays a key role in the immune response that is triggered by influenza infections. ̽��ֱ��molecule, a so-called mini viral RNA, is capable of inducing inflammation and cell death, and was produced at high levels by the 1918 pandemic influenza virus. ̽��ֱ��findings appeared in Nature Microbiology yesterday (September 17).

We think it is a significant breakthrough and that it is particularly exciting that we are finding this factor a hundred years after the 1918 pandemic.

Aartjan te Velthuis

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Study clears important hurdle towards developing an HIV vaccine

cjb250 — Wed, 13 Sep 2017 07:03:22 +0000

In a study published in 2009, results from a clinical trial carried out in Thailand found that an experimental vaccine against HIV lowered the rate of human infection by 31%. This gave cautious optimism that a vaccine against the virus might be a feasible prospect. A vaccine has obvious advantages over treatment with anti-retroviral drugs in that prevention could lead to eradication.

However, one of the major problems that prevented the vaccine from generating long-lasting protection was that the key immune response it needed to generate was very short-lived. ̽��ֱ��reason has now become clear and researchers have found a potential solution.

When a virus enters the body, its aim is to get into our cells and replicate itself again and again, spreading throughout the body. HIV is especially notorious because a protein on its outer coat specifically targets CD4 T-helper cells, the master regulators of the immune system. These cells produce important signals for other types of immune cell: B-cells, which make antibodies; and T-killer cells, which kill virus-infected cells.

By specifically targeting the CD4 T-helper cells, HIV cripples the command and control centre of the immune system and prevents immune defences from working effectively. HIV does not even need to enter and kill the CD4 T-cells – it can cause a functional paralysis of these cells simply by binding its gp140 with the CD4 receptor, an important molecule on the surface of T-helper cells.

HIV’s envelope proteins are a key component of vaccines to protect against HIV infection. ̽��ֱ��body’s immune system targets this protein and generates antibodies directed at HIV’s outer coat to prevent the virus from entering the cells. If the effects of the vaccine last long enough, then with the assistance of robust helper T-cells, the human body should be able to develop antibodies that neutralise a large variety of HIV strains and protect people from infection.

Previous studies showed that vaccinating using a form of the outer coat protein called gp140 leads to the triggering of B-cells which produce antibodies to the virus, but only for a brief period and insufficient to generate sufficient antibodies that are protective from HIV infection over a long period.

Working with scientists in the UK, France, the USA, and the Netherlands, Professor Jonathan Heeney from the Laboratory of Viral Zoonotics at the ̽��ֱ�� of Cambridge recognised that the binding of gp140 to the CD4 receptor on T-helper cells was probably causing this block, and that by preventing gp140 attaching to the CD4 receptor, the short-term block in antibody producing B-cells could be overcome.

In two back-to-back studies published in the print edition of Journal of Virology, the research team has demonstrated for the first time that this approach works, providing the desired responses that were capable of lasting over a year.

“For a vaccine to work, its effects need to be long lasting,” says Professor Heeney. “It isn’t practical to require people to come back every 6-12 months to be vaccinated. We wanted to develop a vaccine to overcome this block and generate these long-lived antibody producing cells. We have now found a way to do this.”

̽��ֱ��study showed that the addition of a tiny specific protein patch to the gp140 protein dramatically improved B-cell responses by blocking binding to the CD4 receptor and hence preventing the paralysis of T-helper cells early in the key stages of the immune response – like preventing a key from getting stuck in a lock. This small patch was one of several strategies to improve gp140 for an HIV vaccine by a team led by Susan Barnett (now at the Bill and Melinda Gates Foundation).

This modified vaccine approach now better stimulates long-lasting B-cell responses, boosting the ability of B-cells to recognise different contours of the virus coat and to make better antibodies against it. This new finding will allow HIV vaccines to be developed that give the immune system enough time to develop the essential B-cell responses to make protective antibodies.

“B-cells need time to make highly effective neutralising antibodies, but in previous studies B-cell responses were so short lived they disappeared before they have the time to make all the changes necessary to create the ‘silver bullets’ to stop HIV,” adds Professor Heeney.

“What we have found is a way to greatly improve B-cell responses to an HIV vaccine. We hope our discovery will unlock the paralysis in the field of HIV vaccine research and enable us to move forward.”

̽��ֱ��team now hopes to secure funding to test their vaccine candidate in humans in the near future.

̽��ֱ��studies were funded by the National Institutes of Health, USA, and the Isaac Newton Trust Cambridge.

Reference

Bogers, WMJM, et al. Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site. Journal of Virology; DOI: 10.1128/JVI.00811-17.

Shen, X et al. Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques. Journal of Virology; DOI: 10.1128/JVI.00401-17.

An international team of researchers has demonstrated a way of overcoming one of the major stumbling blocks that has prevented the development of a vaccine against HIV: the ability to generate immune cells that stay in circulation long enough to respond to and stop virus infection.

For a vaccine to work, its effects need to be long lasting. It isn’t practical to require people to come back every 6-12 months to be vaccinated

Jonathan Heeney

NIAID

3D print of HIV (edited)

̽��ֱ��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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Leprosy turns the immune system against itself, study finds

cjb250 — Wed, 23 Aug 2017 08:33:57 +0000

Leprosy is an infectious disease that affects the skin and peripheral nerves and is caused by Mycobacterium leprae and, less commonly, Mycobacterium lepromatosis. According to the World Health Organization, there has been a dramatic decrease in the global disease burden in the past few decades: from 5.2 million people with leprosy in 1985 to 176,176 at the end of 2015.

Despite the disease having been known about for thousands of years – many people will have first heard about it through references in the Bible – very little is understood about its biology. This is in part because the bacteria are difficult to grow in culture and there are no good animal models: M. leprae can grow in the footpads of mice, but do not cause nerve damage; the disease causes nerve damage in armadillos, but these animals are rarely used in research.

Now, an international team led by researchers at the ̽��ֱ�� of Cambridge, UK, and the ̽��ֱ�� of Washington, the ̽��ֱ�� of California Los Angeles and Harvard ̽��ֱ��, USA, have used a new animal model, the zebrafish, to show for the first time how M. leprae damage nerves by infiltrating the very cells that are meant to protect us. Zebrafish are already used to study another species of mycobacteria, to help understand tuberculosis (TB).

Scientists have previously shown that the nerve damage in leprosy is caused by a stripping away of the protective insulation, the myelin sheath, that protects nerve fibres, but it was thought that this process occurred because the bacteria got inside Schwann cells, specialist cells that produce myelin.

In new research published today in the journal Cell, researchers used zebrafish that had been genetically modified so that their myelin is fluorescent green; young zebrafish are themselves transparent, and so the researchers could more easily observe what was happening to the nerve cells. When they injected bacteria close to the nerve cells of the zebrafish, they observed that the bacteria settled on the nerve, developing donut-like ‘bubbles’ of myelin that had dissociated from the myelin sheath.

When they examined these bubbles more closely, they found that they were caused by M. leprae bacteria inside of macrophages – literally ‘big eaters’, immune cells that consume and destroy foreign bodies and unwanted material within the body. But, as is also often the case with TB, the M. leprae was consumed by the macrophages but not destroyed.

“These ‘Pac-Man’-like immune cells swallow the leprosy bacteria, but are not always able to destroy them,” explains Professor Lalita Ramakrishnan from the Department of Medicine at the ̽��ֱ�� of Cambridge, whose lab is within the Medical Research Council’s Laboratory of Molecular Biology. “Instead, the macrophages – which should be moving up and down the nerve fibre repairing damage – slow down and settle in place, destroying the myelin sheath.”

Professor Ramakrishnan working with Dr Cressida Madigan, Professor Alvaro Sagasti, and other colleagues confirmed that this was the case by knocking out the macrophages and showing that when the bacteria sit directly on the nerves, they do not damage the myelin sheath.

̽��ֱ��team further demonstrated how this damage occurs. A molecule known as PGL-1 that sits on the surface of M. leprae ‘reprograms’ the macrophage, causing it to overproduce a potentially destructive form of the chemical nitric oxide that damages mitochondria, the ‘batteries’ that power nerves.

“ ̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry,” says Professor Ramakrishnan. “It then starts spewing out toxic chemicals. Not only does it stop repairing damage, but it creates more damage itself.”

“We know that the immune system can lead to nerve damage – and in particular to the myelin sheath – in other diseases, such as multiple sclerosis and Guillain–Barré syndrome,” says Dr Cressida Madigan from the ̽��ֱ�� of California, Los Angeles. “Our study appears to place leprosy in the same category of these diseases.”

̽��ֱ��researchers say it is too early to say whether this study will lead to new treatments. There are several drugs being tested that inhibit the production of nitric oxide, but, says Professor Ramakrishnan, the key may be to catch the disease at an early enough stage to prevent damage to the nerve cells.

“We need to be thinking about degeneration versus regeneration,” she says. “At the moment, leprosy can be treated by a combination of drugs. While these succeed in killing the bacteria, once the nerve damage has been done, it is currently irreversible. We would like to understand how to change that. In other words, are we able to prevent damage to nerve cells in the first place and can we additionally focus on repairing damaged nerve cells?”

̽��ֱ��research was funded by the National Institutes of Health, the Wellcome Trust, and the AP Giannini Foundation.

Reference
Madigan, CA et al. A Macrophage Response To Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage In Leprosy. Cell; 24 Aug 2017; DOI: 10.1016/j.cell.2017.07.030

Leprosy hijacks our immune system, turning an important repair mechanism into one that causes potentially irreparable damage to our nerve cells, according to new research that uses zebrafish to study the disease. As such, the disease may share common characteristics with conditions such as multiple sclerosis.

̽��ֱ��leprosy bacteria are, essentially, hijacking an important repair mechanism and causing it to go awry

Lalita Ramakrishnan

Wellcome Library, London

Hand showing leprosy

̽��ֱ��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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