̽��ֱ�� of Cambridge - transplant

Maintaining heart function in donors declared ‘dead by circulatory criteria’ could improve access to heart transplantation

cjb250 — Thu, 16 Mar 2023 00:55:17 +0000

̽��ֱ��organs are kept functioning by restarting local circulation to the heart, lungs and abdominal organs – but, crucially, not to the brain – of patients whose hearts have stopped beating for five minutes or longer and have been declared dead by circulatory criteria (donation after circulatory death, or DCD).

It is hoped that this technique could increase the number of usable donated hearts by as much as 30% in the future, helping address the shortage of transplant organs. In 2021, 8,409 heart transplants were reported to the Global Observatory on Donation and Transplantation (GODT) by 54 countries. This activity is in contrast with the 21,935 patients who were on a heart waiting list during the year 2021, of whom 1,511 died while waiting and many others became too sick to receive a transplant.

John Louca, a final year medical student at Gonville & Caius College, ̽��ֱ�� of Cambridge, and the study’s first author, said: “Heart transplants are the last bastion for patients with end-stage heart failure. They are successful – patients who receive a transplant live on average a further 13 to 16 years. ̽��ֱ��biggest problem they face is actually getting access to a donated heart: many patients will die before an organ becomes available. That’s why we urgently need to find ways to increase the suitability of donor organs.”

Though the first heart transplant performed at the Groote Schuur Hospital in Cape Town (South Africa) in 1967 was obtained from a DCD donor, this technique was abandoned and replaced by heart transplants obtained from donors confirmed dead using neurological criteria (donation after brain death, or DBD) – in other words, their brain has stopped functioning entirely.

Until recently, heart transplants worldwide were still performed only with organs obtained from DBD donors. However, in recent years, heart transplants from DCD donors have become a clinical reality worldwide thanks to years of research carried out in Cambridge.

DCD is the donation of organs by patients who tragically have a non-survivable illness. These patients are typically unconscious in intensive care in hospital and dependent on ventilation. Detailed discussions between doctors, specialist nurses and the patient’s family take place and if the family agree to organ donation, the process starts.

After treatment is withdrawn, the heart stops beating and it begins to sustain damage to its tissues. After 30 minutes, it is thought that this damage becomes irreversible and the heart unusable. To prevent this damage, at the time of death these non-beating hearts are transferred to a portable machine known as the Organ Care System (OCS) where the organ is perfused with oxygenated blood and assessed to see whether it is suitable for transplantation.

This technique was pioneered by Royal Papworth Hospital NHS Foundation Trust in Cambridge, whose transplant team carried out the first DCD heart transplant in Europe in 2015. Royal Papworth has since become the largest and most experienced DCD heart transplant centre in the world.

DCD heart transplantation started simultaneously in Australia, followed by Belgium, ̽��ֱ��Netherlands, Spain and USA. According to the GODT, 295 DCD heart transplants were performed in these six countries in 2021.

Organ Care Systems are expensive, costing around US$400,000 per machine plus an additional $75,000 for consumables for each perfused organ. An alternative, and much more cost-effective approach, is known as thoraco-abdominal normothermic reperfusion (taNRP). This involves perfusing the organ in situ in the donor’s body and is estimated to cost around $3,000. Its use was first reported in 2016 by a team at Royal Papworth Hospital.

In a study published in eClinical Medicine, an international team of clinical scientists and heart specialists from 15 major transplant centres worldwide, including the UK, Spain, the USA and Belgium, looked at clinical outcomes of 157 DCD donor hearts recovered and transplanted from donors undergoing taNRP. They compared these with the outcomes from 673 DBD heart transplants, which represents the ‘gold-standard’.

̽��ֱ��team found that overall, the use of taNRP increased the donor pool significantly, increasing the number of heart transplantations performed by 23%.

Mr Stephen Large, Consultant Cardiothoracic Surgeon at Royal Papworth Hospital and chief investigator, said: “Withdrawing life support from a patient is a difficult decision for both the families and medical staff involved and we have a duty to honour the wishes of the donor as best we can. At present, one in ten retrieved hearts is turned down, but restoring function of the heart in situ could help us ensure more donor hearts find a recipient.”

Survival rates were comparable between DCD and DBD heart transplantation, with 97% of patients surviving for more than 30 days following taNRP DCD heart transplant, 93% for more than a year and 84% of patients still alive after five years.

Professor Filip Rega, Head of Clinic at the Department of Cardiac Surgery, UZ Leuven, Belgium, said: “This promising new approach will allow us to offer heart transplantation, a last resort treatment, to many more patients in need of a new heart.”

̽��ֱ��researchers say that some of the benefits from taNRP are likely thanks to the reduced amount of time the heart was not receiving oxygenated blood, known as its warm ischaemic time, when compared to direct procurement (that is, when the heart is removed immediately for transplant, and perfused outside the body). ̽��ֱ��median average time was 16.7 minutes, significantly less than the 30 minutes associated with permanent damage to the heart cells.

An added benefit to this approach is that it allows medical teams to simultaneously preserve several organs, such as the liver, pancreas and kidneys, without the need of several organ-specific external machine perfusion devices. This decreases complexity and costs.

Professor Ashish Shah, Head of the Department of Cardiac Surgery at Vanderbilt ̽��ֱ�� Hospitals, Nashville, USA, said: “Heart transplantation has been and always will be a uniquely international effort. ̽��ֱ��current study is another example of effective international collaboration and opens a new frontier, not just in transplantation, but in our basic understanding of how all hearts can be rescued.”

Dr Beatriz Domínguez-Gil, Director General of the National Organisation of Transplantation in Spain, said: “ ̽��ֱ��results of this collaborative study bring hope to thousands of patients in need for a heart transplant every year throughout the world. Its findings reveal that DCD heart transplantation based on taNRP can lead to results at least similar to the gold standard and increase hearts available for transplantation in a manner that contributes to the sustainability of health-care systems.”

Reference
Louca, J et al. ̽��ֱ��international experience of in-situ recovery of the DCD heart: A multicentre retrospective observational study. eClin Med; published online 2 March 2023; DOI: 10.1016/j.eclinm.2023.101887

More donated hearts could be suitable for transplantation if they are kept functioning within the body for a short time following the death of the donor, new research has concluded.

Patients who receive a transplant live on average a further 13 to 16 years. ̽��ֱ��biggest problem they face is actually getting access to a donated heart

John Louca

Sewcream (Getty Images)

Hands holding an image of a heart

̽��ֱ��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 researchers change donor kidney blood type

fpjl2 — Mon, 15 Aug 2022 10:18:07 +0000

Researchers have been able to alter the blood type of deceased donor kidneys using “molecular scissors”.

Llama ‘nanobodies’ could hold key to preventing deadly post-transplant infection

sc604 — Thu, 22 Jul 2021 09:07:34 +0000

Around four out of five people in the UK are thought to be infected with HCMV, and in developing countries this can be as high as 95%. For the majority of people, the virus remains dormant, hidden away inside white blood cells, where it can remain undisturbed and undetected for decades. If the virus reactivates in a healthy individual, it does not usually cause symptoms. However, for people who are immunocompromised – for example, transplant recipients who need to take immunosuppressant drugs to prevent organ rejection – HCMV reactivation can be devastating.

At present, there is no effective vaccine against HCMV, and anti-viral drugs often prove ineffective or have very serious side-effects.

Now, in a study published in Nature Communications, researchers at Vrije Universiteit Amsterdam in the Netherlands and at the ̽��ֱ�� of Cambridge have found a way to chase the virus from its hiding place using a special type of antibody known as a nanobody.

Nanobodies were first identified in camels and exist in all camelids – a family of animals that also includes dromedary, llamas and alpacas. Human antibodies consist of two heavy and two light chains of molecules, which together recognise and bind to markers on the surface of a cell or virus known as antigens. For this special class of camelid antibodies, however, only a single fragment of the antibody – often referred to as single domain antibody or nanobody – is sufficient to properly recognize antigens.

Dr Timo De Groof from Vrije Universiteit Amsterdam, the study’s joint first author, said: “As the name suggests, nanobodies are much smaller than regular antibodies, which make them perfectly suited for particular types of antigens and relatively easy to manufacture and adjust. That’s why they’re being hailed as having the potential to revolutionise antibody therapies.”

̽��ֱ��first nanobody has been approved and introduced onto the market by biopharmaceutical company Ablynx, while other nanobodies are already in clinical trials for diseases like rheumatoid arthritis and certain cancers. Now, the team in ̽��ֱ��Netherlands and the UK have developed nanobodies that target a specific virus protein (US28), one of the few elements detectable on the surface of a HCMV latently infected cell and a main driver of this latent state.

Dr Ian Groves from the Department of Medicine at the ̽��ֱ�� of Cambridge said: “Our team has shown that nanobodies derived from llamas have the potential to outwit human cytomegalovirus. This could be very important as the virus can cause life-threatening complications in people whose immune systems are not functioning properly.”

In laboratory experiments using blood infected with the virus, the team showed that the nanobody binds to the US28 protein and interrupts the signals established through the protein that help keep the virus in its dormant state. Once this control is broken, the local immune cells are able to 'see' that the cell is infected, enabling the host’s immune cells to hunt down and kill the virus, purging the latent reservoir and clearing the blood of the virus.

Dr Elizabeth Elder, joint first author, who carried out her work while at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��beauty of this approach is that it reactivates the virus just enough to make it visible to the immune system, but not enough for it to do what a virus normally does – replicating and spreading. ̽��ֱ��virus is forced to put its head above the parapet where it can then be killed by the immune system.”

Professor Martine Smit, also from from the Vrije Universiteit Amsterdam, added: “We believe our approach could lead to a much-needed new type of treatment for reducing – and potentially even preventing – CMV infectious in patients eligible for organ and stem cell transplants.”

̽��ֱ��research was funded by the Dutch Research Council (NWO), Wellcome and the Medical Research Council, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
De Groof TWM, Elder E, et al. Targeting the latent human cytomegalovirus reservoir for T-cell mediated killing with virus specific nanobodies. Nature Communications (2021). DOI: 10.1038/s41467-021-24608-5

Scientists have developed a ‘nanobody’ – a small fragment of a llama antibody – that is capable of chasing out human cytomegalovirus (HCMV) as it hides away from the immune system. This then enables immune cells to seek out and destroy this potentially deadly virus.

Our team has shown that nanobodies derived from llamas have the potential to outwit human cytomegalovirus

Ian Groves

Jessica Knowlden on Unsplash

Llamas

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Scientists launch a pre-emptive strike on deadly post-transplant infection

ta385 — Tue, 23 Feb 2021 12:45:00 +0000

Around 80% of the UK population is currently infected with human cytomegalovirus (HCMV) and in developing countries this can be as high as 95%. ̽��ֱ��virus can remain dormant in our white blood cells for decades and, if it reactivates in a healthy individual, does not usually cause symptoms. But, for people who are immunocompromised, HCMV reactivation can be devastating.

HCMV reactivation has been identified in COVID-19 patients, though scientists do not yet understand the relationship between the two viruses. Reactivation or re-infection in transplant recipients can lead to severe illness, including organ rejection and, in some cases, death.

More than 200,000 kidney, lung and stem cell transplants take place globally every year and HCMV reactivation occurs in more than half of these cases. For reasons scientists don’t yet fully understand, immunosuppressants appear to encourage the virus to reactivate as well as compromising the patient’s ability to fight it. There remains no effective vaccine against HCMV and anti-viral therapies often prove ineffective or detrimental.

Now, a team from the ̽��ֱ�� of Cambridge’s School of Clinical Medicine has identified a drug type and treatment strategy that could dramatically reduce these devastating reactivation events. ̽��ֱ��study, published in the journal PNAS, describes how scientists exposed HCMV-infected blood samples to a wide-range of ‘epigenetic inhibitors’ – drugs widely used in cancer treatment – hoping to prompt the latent virus to produce proteins or targetable antigen that are visible to our immune system.

They discovered that a particular group of these drugs, ‘bromodomain inhibitors’, successfully reactivated the virus by forcing it to convert its hidden genetic instructions into protein. This then enabled T-cells in the blood samples to target and kill these previously undetectable infected cells.

̽��ֱ��study is the first to identify the involvement of human host bromodomain (BRD) proteins in the regulation of HCMV latency and reactivation but also proposes a novel ‘shock and kill’ treatment strategy to protect transplant patients.

Lead author Dr Ian Groves said: “We’re looking to purge the patient’s viral reservoir before they go into the operating theatre and before they start taking immunosuppressants, when they would become extremely vulnerable to the virus reactivating. In other words, we’re proposing a pre-emptive strike.

“Prior to transplantation, many patients will have a relatively healthy immune system, so when the virus puts its head above the parapet, its cover is blown, and the immune system will see it and kill the cells it’s been hiding in. Ideally, donors would also be treated to avoid re-infecting recipients.”

There are similar drugs in Phase 1–3 clinical trials around the world for other intended uses, mainly in the treatment of cancers but also Type 2 diabetes-related cardiovascular disease.

Dr Groves said: “This would be the first type of treatment to reduce HCMV infection levels pre-transplant in order to lower the chances of virus reactivation during immune suppression after transplantation. Our findings could lead to thousands of lives being saved every year.”

“In addition to the terrible human suffering this virus causes, treating its effects adds enormously to the high costs already incurred by transplantation. It’s a really serious issue for health services in wealthy nations and a desperate one in developing countries. Our findings offer an opportunity to transform this horrible situation.”

̽��ֱ��study builds on over 25 years of extensive research into the molecular biology of HCMV and its immune evasion tactics (funded by the Medical Research Council). ̽��ֱ��researchers hope their study could eventually help doctors fight HCMV on other fronts, including in maternity and neo-natal care. HCMV affects at least 1% of all live births in developed countries, and many more in developing countries. These children can be left with brain damage and hearing loss, but congenital infection during pregnancy can also lead to miscarriage.

Reference

I. J. Groves et al., ‘Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention’. PNAS (2021). DOI: 10.1073/pnas.2023025118

A potential new treatment to protect immunosuppressed patients from human cytomegalovirus (HCMV) has been discovered by scientists at the ̽��ֱ�� of Cambridge. Their study shows that certain epigenetic inhibitors expose and help to destroy dormant HCMV infections, which often reactivate to cause serious illness and death in these vulnerable groups. Subject to clinical trials, their proposed ‘shock and kill’ treatment strategy offers hope to transplant patients across the world.

Our findings could lead to thousands of lives being saved every year

Ian Groves

Sasin Tipchai via Pixabay

Surgeons at work in an operating theatre

Funding

This research was supported by GlaxoSmithKline and the Medical Research Council.

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Lab-grown ‘mini-bile ducts’ used to repair human livers in regenerative medicine first

cjb250 — Thu, 18 Feb 2021 19:00:42 +0000

̽��ֱ��research paves the way for cell therapies to treat liver disease – in other words, growing ‘mini-bile ducts’ in the lab as replacement parts that can be used to restore a patient’s own liver to health – or to repair damaged organ donor livers, so that they can still be used for transplantation.

Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children’s liver transplantations, with no alternative treatments. There is currently a shortage of liver donors: according to the NHS, the average waiting time for a liver transplant in the UK is 135 days for adults and 73 days for children. This means that only a limited number of patients can benefit from this therapy.

Approaches to increase organ availability or provide an alternative to whole organ transplantation are urgently needed. Cell-based therapies could provide an advantageous alternative. However, the development of these new therapies is often impaired and delayed by the lack of an appropriate model to test their safety and efficacy in humans before embarking in clinical trials.

Now, in a study published today in Science, scientists at the ̽��ֱ�� of Cambridge have developed a new approach that takes advantage of a recent ‘perfusion system’ that can be used to maintain donated organs outside the body. Using this technology, they demonstrated for the first time that it is possible to transplant biliary cells grown in the lab known as cholangiocytes into damaged human livers to repair them. As proof-of-principle for their method, they repaired livers deemed unsuitable for transplantation due to bile duct damage. This approach could be applied to a diversity of organs and diseases to accelerate the clinical application of cell-based therapy.

“Given the chronic shortage of donor organs, it’s important to look at ways of repairing damaged organs, or even provide alternatives to organ transplantation,” said Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute. “We’ve been using organoids for several years now to understand biology and disease or their regeneration capacity in small animals, but we have always hoped to be able to use them to repair human damaged tissue. Ours is the first study to show, in principle, that this should be possible.”

Bile duct diseases affect only certain ducts while sparing others. This is important because in disease, the ducts in need of repair are often fully destroyed and cholangiocytes may be harvested successfully only from spared ducts.

Using the techniques of single-cell RNA sequencing and organoid culture, the researchers discovered that, although duct cells differ, biliary cells from the gallbladder, which is usually spared by the disease, could be converted to the cells of the bile ducts usually destroyed in disease (intrahepatic ducts) and vice versa using a component of bile known as bile acid. This means that the patient’s own cells from disease-spared areas could be used to repair destroyed ducts.

To test this hypothesis, the researchers grew gallbladder cells as organoids in the lab. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same tissue architecture, function and gene expression and genetic functions as the part of the organ being studied. They then grafted these gallbladder organoids into mice and found that they were indeed able to repair damaged ducts, opening up avenues for regenerative medicine applications in the context of diseases affecting the biliary system.

̽��ֱ��team used the technique on human donor livers taking advantage of the perfusion system used by researchers based at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation. They injected the gallbladder organoids into the human liver and showed for the first time that the transplanted organoids repaired the organ’s ducts and restored their function. This study therefore confirmed that their cell-based therapy could be used to repair damaged livers.

Professor Ludovic Vallier from the Wellcome-MRC Cambridge Stem Cell Institute, joint senior author, said: “This is the first time that we’ve been able to show that a human liver can be enhanced or repaired using cells grown in the lab. We have further work to do to test the safety and viability of this approach, but hope we will be able to transfer this into the clinic in the coming years.”

Although the researchers anticipate this approach being used to repair a patient’s own liver, they believe it may also offer a potential way of repairing damaged donor livers, making them suitable for transplant.

Mr Kourosh Saeb-Parsy from the Department of Surgery at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, joint senior author, added: “This is an important step towards allowing us to use organs previously deemed unsuitable for transplantation. In future, it could help reduce the pressure on the transplant waiting list.”

̽��ֱ��research was supported by the European Research Council, the National Institute for Health Research and the Academy of Medical Sciences.

Reference
Sampaziotis, F et al. Cholangiocyte organoids can repair bile ducts after transplantation in human liver. Science; 18 Feb 2021

Scientists have used a technique to grow bile duct organoids – often referred to as ‘mini-organs’ – in the lab and shown that these can be used to repair damaged human livers. This is the first time that the technique has been used on human organs.

Given the chronic shortage of donor organs, it’s important to look at ways of repairing damaged organs, or even provide alternatives to organ transplantation

Fotios Sampaziotis

Can we regenerate damaged organs in the lab?

Dr Fotios Sampaziotis and Dr Teresa Brevini, ̽��ֱ�� of Cambridge

Cholangiocyte organoids reconstruct human bile duct

Cambridge Festival: How organoids help us understand ourselves and treat diseases

13:00-14:00 on Monday 29 March 2021

What are organoids? Where do they come from? And how can organoids be used to help us understand and treat human diseases? Kourosh Saeb-Parsy will be taking part in an event as part of the Cambridge Festival, chaired by Richard Westcott, BBC Science Correspondent.

Booking for the Cambridge Festival opens on Monday 22 February. For details visit the Cambridge Festival website.

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Wash cycle: making organs fit for transplantation

cjb250 — Wed, 20 Jul 2016 08:25:59 +0000

In a room in the Department of Surgery, a kidney sits inside a chamber connected to tubes and monitors. Solutions and gases are pumping through it and urine is coming out.

In fact, the chamber in itself is not particularly special – it’s an off-the-shelf machine used for cardiac bypass surgery in children: it’s how it has been adapted and the new uses it has found that make it so significant. This machine is able to rejuvenate kidneys deemed not fit for transplant, making them fit and healthy again – and suitable for a recipient.

Professor Andrew Bradley, Head of the Department of Surgery, is quick to point out that it is his team at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals – particularly Professor Mike Nicholson and Dr Sarah Hosgood – who should take all the credit for this machine, which they refer to as an organ perfusion system.

There is a chronic shortage of suitable organs for transplant and something needs to be done. To help address the problem, in December 2015, Wales became the first country in the UK to make organ donation an ‘opt-out’ system – in other words, doctors would remove the organs from deceased individuals and provide them for use in sick patients unless the individual had explicitly refused consent before their death.

Unfortunately, not every donated organ is suitable for transplant – in the case of kidneys, for example, around 15% are deemed unsuitable. This can be for a variety of reasons, including the age of the donor, their disease history and the length of time the organ has been in cold storage.

“Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye,” says Nicholson. “This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.”

What if there was a way of taking these organs and assessing them systematically? And to take it a step further, could some of them even be rejuvenated? Before coming to Cambridge, Nicholson and Hosgood developed a system while at the ̽��ֱ�� of Leicester that effectively recirculates essential nutrients through the kidney, bringing it back to life.

“We use a combination of red blood cells, a priming solution, nutrients, protective agents and oxygen,” explains Hosgood. “We pump this through the kidney while maintaining a temperature close to our body temperature. It mimics being in the body.”

As the perfusion solution is being circulated, the kidney will begin to function and produce urine. By analysing the contents of this urine and monitoring blood flow, doctors can see how the kidney is performing and whether it might make a viable transplant organ. After just a 60-minute perfusion, the kidneys are resuscitated and are potentially ready for transplantation.

This is no longer just an experiment: since moving to Cambridge, with funding from Kidney Research UK and the National Institute for Health Research, the team has been able to take kidneys rejected from other transplant centres, resuscitate and assess them, then transplant them. In December last year, two individuals on the organ transplant waiting list received the perfect Christmas present courtesy of the Cambridge team: a new kidney.

So far, the team has taken five discarded kidneys and managed to rescue three. “We’re hoping to process another hundred over the next four years,” says Hosgood, who is also working with centres in Newcastle, Edinburgh and at Guy’s Hospital in London, in the hope of replicating their success.

̽��ֱ��current kit, which was not purpose-built for organ perfusion, is bulkier and clumsier than ideal, so the team is currently fundraising to help design a dedicated machine, in collaboration with colleagues from the Department of Engineering. “It’s not very mobile, so we couldn’t use it to help resuscitate organs in transit to other centres.”

Nicholson and Hosgood’s success has spurred on other colleagues. Professor Chris Watson describes himself as “piggybacking” on their work to develop a technique for perfusing livers. ̽��ֱ��situation for liver transplants is even more serious than it is for kidneys: as many as one in five patients on the waiting list will die before a liver becomes available.

So far, his team has taken 12 livers, all but one of which had been rejected by other centres, and successfully resuscitated and transplanted them using a system that builds on the pioneering work of his two colleagues.

“There’s a scene in the Woody Allen film Sleeper where Allen’s character stumbles across a 200-year-old Volkswagen Beetle and manages to start it first time,” he says. “ ̽��ֱ��liver is like that. You take it out of cold storage and expect it to start first time. By first assessing it on our machine, we can be more confident it will work first time.”

In some ways, this has proved more of a challenge than it did for kidneys, he adds. “With kidneys, you can put them in the machine for an hour, resuscitate them and then transplant them. If it doesn’t work immediately, the patient stays on dialysis until it picks up. With a liver, it takes longer to analyse and resuscitate the organ, and if it doesn’t work it’s a disaster for the patient.”

Now that the team has successfully revived and transplanted kidneys and livers, this is by no means the end of the story. There is still much work to be done to further improve the organ – and hence improve the function and prolong survival, says Hosgood.

Once transplanted, organs face a battle with the body’s immune system, which recognises its new occupant as a foreign body. This is one reason why the perfusion system uses only red blood cells, not white – to do so would risk an inflammatory response that could damage the organ.

“Of course, as soon as you transplant the kidney, it will face a similar inflammatory response, but by then it should be in an improved state and able to cope better with what the body throws at it,” she explains. ̽��ֱ��Department is in the process of recruiting 400 patients for a randomised controlled trial to test this technology.

̽��ֱ��perfusion system also enables therapies to be given directly to the kidney. This ensures optimal delivery of the treatment to the targeted organ and avoids any side effects in the patient. One promising avenue of research, in collaboration with Professor Jordan Pober at Yale ̽��ֱ�� (USA), is the use of nanoparticles that target the endothelial cells in the lining of the kidney. These cells play an important role in the inflammatory response after transplantation. “ ̽��ֱ��delivery of nanoparticles in this way may reduce damage to the organ after transplantation,” she adds.

̽��ֱ��shortage of suitable organs is not going away. Not even a UK-wide ‘opt-out’ system is likely to completely eradicate the problem. If anything, the crisis is likely to get worse – the flipside of good news stories such as fewer road traffic fatalities and better medicines that reduce the number of young people dying early. ̽��ֱ��team recognises that the system alone is not the answer, but it brings a new relevance to the old adage “waste not, want not”.

There’s a nationwide shortage of suitable organs for transplanting – but what if some of those organs deemed ‘unsuitable’ could be rejuvenated? Researchers at Addenbrooke’s Hospital have managed just that – and last year gave two patients an unexpected Christmas present.

Grading organs is not an exact science – it’s a mixture of factors about the circumstance in which it became available, its storage and how it looks to a trained eye. This isn’t good enough, particularly if it means we’re losing some potentially suitable organs.

Mike Nicholson

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'Tip Top Stomerij en Wasserette' Linnaeusstraat Amsterdam

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̽��ֱ�� of Cambridge to establish two new Blood and Transplant Research Units

sjr81 — Fri, 14 Nov 2014 15:07:08 +0000

Cambridge has received funding for two units under the £12.1 million scheme. ̽��ֱ��Units will be centres of excellence in human experimental medicine related to blood and transplantation and will have a strong focus on translation. They will support the delivery of objectives and functions of NHS Blood and Transplant, by creating an environment where world-class research, focused on the organisation’s needs, can thrive, and will provide high quality research evidence to inform decision making at NHS Blood and Transplant.

Speaking about the partnership funding awards, Dr Lorna Williamson, Medical and Research Director at NHS Blood and Transplant, said: "I am delighted that the Department of Health, through the NIHR, continues to recognise the importance of blood and transplantation research. This funding supports ambitious experimental research projects that will inform future clinical practice for services that NHS Blood and Transplant provides to the NHS and beyond."

Professor Andrew Bradley, Head of the Department of Surgery at the ̽��ֱ�� of Cambridge, in partnership with Professor Andrew Fisher from Newcastle ̽��ֱ��, will establish a unit focused on organ donation and transplantation. ̽��ֱ��Cambridge/Newcastle unit will focus on understanding how to improve the quality of organs prior to donation and will develop and evaluate novel approaches and technologies that increase the availability of suitable donor organs for transplantation, while improving graft survival.

Professor John Danesh from the Cambridge Institute of Public Health will lead a unit focused on donor health and genomics, a new area of research for NHS Blood and Transplant. ̽��ֱ��Unit will address major questions about the health of blood donors and produce evidence-based strategies to enhance donor safety while ensuring sustainability of blood supply.

̽��ֱ��Units will be based at Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals Partnership, and located within the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

Professor Bradley said: “Blood and transplantation research is vital to improving the quality, safety and availability of donation and transplantation. These two new NIHR units will play an important role in this area and inform NHS policy and practice in the future. They will further add to and capitalise on continuing growth of the Cambridge Biomedical Campus.”

Professor Dame Sally C Davies FRS FMedSci, Chief Medical Officer and Chief Scientific Adviser at the Department of Health, said: “ ̽��ֱ��NHS and its patients rely on an efficient supply of blood and organ donations and, increasingly, stem cells and genomics. We want researchers to explore how to improve the quality and effectiveness of these donations, therapies and technologies. ̽��ֱ��NIHR Blood and Transplant Research Units will involve NHSBT in partnerships with leading university teams so that we can accelerate and translate advances in research into benefits for donors and patients.”

A third unit is due to open at UCL ( ̽��ֱ�� College London), led by Dr Karl Peggs and focused on Stem Cells and Immunotherapies.

̽��ֱ�� ̽��ֱ�� of Cambridge has received £7.9 million from the National Institute for Health Research (NIHR) to fund Blood and Transplant Research Units. Each Unit is a partnership between ̽��ֱ�� researchers and NHS Blood and Transplant, and will begin in October 2015.

Blood and transplantation research is vital to improving the quality, safety and availability of donation and transplantation.

Andrew Bradley

Siringa

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Silent killer

lw355 — Fri, 13 Sep 2013 13:14:24 +0000

To catch the herpes virus human cytomegalovirus (HCMV) you must be exposed to someone who has it. This isn’t difficult: it is carried by around 65% of the population. Once in the body, HCMV persists for life owing to its clever ability to avoid our immune system and to go into hiding inside our cells in a latent state. Now, research is identifying changes in these cells that could lead to a new route to eradicating the virus.

“HCMV can be acquired very early in childhood, and the number of people infected gradually rises throughout life,” said Professor John Sinclair, a molecular virologist in the Department of Medicine. “ ̽��ֱ��active virus can not only be passed from an infected mother to her child in breast milk but can easily be transferred from child to child in saliva – one child puts a toy in their mouth, then it’s passed to another child who does the same, and the virus is passed on. It’s also a sexually transmitted disease, so there’s another increase in infections when people become sexually mature.”

Once acquired, the virus goes into a latent state in the body. If it reactivates in healthy people, their immune responses prevent it from causing disease. But when the immune system is suppressed, active HCMV becomes dangerous. It is a major cause of illness and death in organ and bone marrow transplant patients, who are given drugs to deliberately suppress their immune system and prevent their body rejecting the transplant. With an increasing demand for transplants in the UK, HCMV is set to become a growing problem.

“If it’s not treated well, or it develops resistance to antiviral drugs, HCMV can lead to pneumonitis – inflammation of the lung tissue – and, in the most extreme case, it replicates all over the body and the patient ends up with multiple organ failure,” said Dr Mark Wills, a viral immunologist working alongside Sinclair in the Department of Medicine.

“Tissue from donors carrying the virus often has to be used for transplants because there are so few donors and so many people carrying the virus,” said Sinclair. “By transplanting bone marrow, or an organ from someone with the infection, you’re giving the patient the virus and you’re immune-suppressing them. That’s the worst of both worlds.”

And HCMV is not a worry just for transplant patients. “HCMV is now the leading cause of infectious congenital disease – that is, disease present at birth,” said Sinclair. Women in early pregnancy who are newly infected with HCMV or whose HCMV reactivates are at real risk, and this can lead to disease in their unborn baby. HCMV also targets HIV-AIDS patients, where a progressive failure of the immune system allows this opportunistic infection to thrive.

There is no vaccine to prevent HCMV infection, and the antiviral drugs available to treat it have significant toxicity and only limited effectiveness. In addition to the problem of viral resistance, drugs can only target HCMV in its active state, which means the virus can never be fully eradicated. “You can suppress the virus down to a very low level, but you can never get rid of the latent reservoir with the currently available antiviral drugs,” said Wills.

Sinclair and Wills, who have just received their fifth consecutive five-year grant from the Medical Research Council (MRC), have focused on understanding how the virus maintains this latent infection in specialised cells of the immune system and how the immune system is prevented from eliminating the virus from the body.

“ ̽��ֱ��belief has always been that, in its latent state, HCMV was just sitting there doing nothing, waiting to reactivate,” said Sinclair. “But we’ve started to identify major changes in latently infected cells, and we think these are targetable with novel drugs and immunotherapies.

“One change is in a transporter protein normally used by the cell to pump out things it needs to get rid of,” he added. “If you put the chemotherapy drug vincristine on a healthy cell, the cell will pump it out and survive. Working with Paul Lehner at the Cambridge Institute for Medical Research we found that, during latent infection, this transporter protein is less effective, making the cell more prone to killing by vincristine.” Their results were published in Science in April 2013.

“In addition to treatment with drugs, we’re looking into immunotherapies – treatments based on using the patient’s immune system,” said Wills. “Clearly, the difficulty is that all healthy people have very good immune responses to the virus, yet we all still carry it and can never get rid of it. There must be a problem here – the virus is deliberately trying to evade the immune system by manipulating it.”

Sinclair and Wills are trying to understand how the virus does this while in its latent state. Their findings show that HCMV disrupts the proper activation of the immune system by manipulating small signalling molecules called cytokines and chemokines, which normally help to kick-start the process of removing a foreign invader. “Now we know this, we can start to think about intervening,” said Wills.

“We’ve also found that latently infected cells are producing a number of viral proteins,” added Wills. “That’s a dangerous strategy for the virus, because these proteins could be presented on the surface of the cells they’re hiding in, which would attract immune cells like T cells to kill them. Our initial research showed that there are T-cell responses – so why aren’t the viral cells being eliminated? It’s paradoxical.” In further investigations, they uncovered another mechanism in which the virus was promoting a certain subtype of T cell that suppresses the immune system. “So now we’re working to remove the immunosuppressive component of that immune response by either removing or neutralising the function of the immunosuppressive T-cell subtype, to enable the other components of the body’s immune response to target the infected cells,” added Wills.

By targeting latent infection, this work holds great promise for developing better methods of treatment for HCMV and for the design of a vaccine. “If you intervene just before a transplant, and use this immunotherapeutic technique to target the latently infected cells, in combination with the drugs, you can purge the infected cells,” said Sinclair. “This massively reduces the potential that HCMV will reactivate in the person receiving the transplant, because effectively you’re not giving them the virus,” he added.

They have proved this concept in the laboratory and their new MRC grant will enable them to trial its effectiveness in a model system as a stepping stone to human clinical trials. “A decade ago we couldn’t have even contemplated doing this type of work,” said Sinclair, “but now we have worked out what’s going on during latent infection, we can try to target these changes. Being able to clear the latent infection is key to eradicating much of the disease caused by HCMV that we see in the clinic.”

Many of us are infected with a virus we’ll never clear. While we’re healthy, it’s nothing to worry about, but when our immune system is suppressed it could kill us.

̽��ֱ��virus is deliberately trying to evade the immune system by manipulating it

Mark Wills

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HCMV

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