Baanbrekende nieuwe behandeling leidt tot beter herstel na hersentrauma bij muizen

Onderzoekers hebben een gerichte therapie ontworpen die ontsteking in de hersenen tegengaat. De aanpak – waarbij doelgericht DNA tot in de hersenen wordt gebracht - blijkt succesvol bij muizen met een hersenletsel, beroerte of multiple sclerose

Kort & bondig:

• Onderzoekers hebben een gerichte therapie ontworpen die ontsteking in de hersenen tegengaat. De aanpak – waarbij doelgericht DNA tot in de hersenen wordt gebracht - blijkt succesvol bij muizen met een hersenletsel, beroerte of multiple sclerose. 
• De behandeling bestaat er in het aantal regulatoire T-cellen, die de anti-inflammatoire respons van het immuunsysteem reguleren, te verhogen in de hersenen.  
• Door het aantal regulerende T-cellen in de hersenen te verhogen, konden de onderzoekers het afsterven van hersenweefsel bij muizen na verwonding voorkomen en deden de muizen het beter bij cognitieve testen. 
• Voor patiënten met een traumatisch hersenletsel zijn er momenteel weinig opties om schadelijke neuroinflammatie te voorkomen. De nieuwe resultaten zijn dus erg hoopgevend. 

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Onderzoekers uit Leuven en uit het Verenigd Koninkrijk publiceren vandaag nieuwe resultaten over een therapeutische piste waarbij het immuunsysteem wordt ingezet om hersenbeschadiging te voorkomen. De samenwerking tussen professor Adrian Liston (voorheen VIB en KU Leuven en sinds enkele jaren verbonden aan het Babraham Institute in het VK) en professor Matthew Holt (verbonden aan VIB, KU Leuven en de i3S-Universiteit van Porto) leidde tot een systeem om in de hersenen het aantal gespecialiseerde ontstekingsremmende immuuncellen op te voeren om op die manier hersenontsteking en -beschadiging te beperken. De aanpak bleek alvast in muismodellen tot minder hersenschade te leiden na hersenletsel, beroerte of bij multiple sclerose. Het onderzoek wordt vandaag gepubliceerd in het tijdschrift Nature Immunology. 

Traumatisch hersenletsel, zoals veroorzaakt na een auto-ongeval of een val, is wereldwijd een belangrijke doodsoorzaak. Het kan langdurige en ernstige gevolgen hebben voor mensen die het overleven, onder de vorm van cognitieve problemen en zelfs dementie. Een belangrijke oorzaak van deze cognitieve stoornissen is de ontstekingsreactie op het letsel. Hierbij veroorzaakt zwelling van de hersenen permanente schade. Terwijl ontsteking in andere delen van het lichaam kan worden aangepakt met geneesmiddelen, is dit in de hersenen heel moeilijk door de aanwezigheid van de bloed-hersenbarrière, die voorkomt dat gewone ontstekingsremmende moleculen op de plaats van het (hersen)trauma kunnen komen.  

Prof. Liston: "Ons lichaam heeft zijn eigen ontstekingsremmende respons: regulatoire T-cellen zijn in staat om ontstekingen waar te nemen en een cocktail van natuurlijke ontstekingsremmers te produceren. Helaas zijn er maar heel weinig van deze regulerende T-cellen in de hersenen. Wij probeerden een nieuw therapeutisch middel te ontwikkelen om de hoeveelheid regulerende T-cellen in de hersenen te vergroten. Indien er voldoende regulatoire T-cellen zijn, zo redeneerden we, zouden ze de ontsteking na een letsel kunnen beheersen en de schade beperken." 

Het onderzoeksteam ontdekte dat het aantal regulerende T-cellen in de hersenen laag was door een beperkte aanvoer van het cruciale overlevingsmolecuul interleukine 2, ook bekend als IL2. Het niveau van IL2 is laag in de hersenen vergeleken met de rest van het lichaam omdat het niet doorheen de bloed-hersenbarrière kan.  

Samen bedacht het team een nieuwe therapeutische aanpak waardoor meer IL2 kan worden aangemaakt door hersencellen. De onderzoekers gebruikten een "gene delivery"-systeem op basis van een virale vector: dit systeem kan daadwerkelijk een intacte bloed-hersenbarrière passeren en het DNA afleveren dat de hersenen nodig hebben om meer IL2 aan te maken.  

Prof. Holt: "Jarenlang leek de bloed-hersenbarrière een onoverkomelijke hindernis voor de efficiënte toediening van biologische geneesmiddelen in de hersenen. Ons werk, waarbij we gebruik maken van de nieuwste virale vectortechnologie, bewijst dat dit niet langer het geval is; het is zelfs mogelijk dat de bloed-hersenbarrière onder bepaalde omstandigheden therapeutisch gunstig kan zijn, omdat ze – eenmaal op hun bestemming – het 'lekken' van geneesmiddelen naar de rest van het lichaam verhindert." 

Dankzij hun aanpak waren de onderzoekers in staat de niveaus van de overlevingsmolecule IL2 in de hersenen op te voeren tot dezelfde niveaus als in het bloed. Hierdoor kon het aantal regulerende T-cellen zich in de hersenen opbouwen, tot 10 maal hoger dan normaal. Om de doeltreffendheid van de behandeling te testen in muizen. Wat bleek? Muizen met meer IL2 hadden inderdaad minder hersenschade na een letsel en presteerden ook beter in cognitieve tests.  

Dr. Lidia Yshii, van het team aan KU Leuven, legt uit: "Toen we de hersenen van de muizen zagen na het eerste experiment, was dit een echt 'eureka-moment' - we zagen meteen dat de behandeling het letsel had verkleind."  

De onderzoekers testten ook de doeltreffendheid van hun aanpak in experimentele muismodellen voor multiple sclerose en beroerte—met succes. In een vervolgstudie, die nog aan peer review wordt onderworpen en dus nog niet gepubliceerd is, toont het onderzoeksteam ook aan dat de behandeling doeltreffend was om cognitieve achteruitgang bij ouder wordende muizen te voorkomen.  

"Door de immuunrespons in de hersenen te begrijpen en erop in te spelen, waren we in staat een gen-toedieningssysteem voor IL-2 te ontwikkelen als een potentiële behandeling voor neuro-inflammatie. Met tientallen miljoenen mensen die er elk jaar mee te maken krijgen en met bovendien weinig beschikbare behandelingsmogelijkheden, biedt onze nieuwe aanpak reële mogelijkheden om mensen in nood te helpen. We hopen dat dit systeem binnenkort aan klinische proeven zal worden onderworpen, die essentieel zullen zijn om te testen of de behandeling ook bij patiënten werkt," aldus Prof. Liston. 

Dr. Ed Needham, een neuroloog in het Addenbrooke's Hospital in het VK die geen deel uitmaakte van de studie, gaf commentaar op de klinische relevantie van deze resultaten: "Er is een dringende klinische noodzaak om behandelingen te ontwikkelen die secundair letsel kunnen voorkomen dat optreedt na een traumatisch hersenletsel. Belangrijk is dat deze behandelingen veilig zijn voor gebruik bij kritisch zieke patiënten die een hoog risico lopen op levensbedreigende infecties. De huidige ontstekingsremmende geneesmiddelen werken in op het gehele immuunsysteem en kunnen daardoor de gevoeligheid van patiënten voor dergelijke infecties vergroten. Wat deze studie zo interessant maakt is dat de behandeling niet alleen met succes de door ontsteking veroorzaakte hersenschade kan verminderen, maar dat zij dit kan doen zonder de rest van het immuunsysteem van het lichaam aan te tasten, waardoor de natuurlijke afweer die nodig is om kritieke ziekte te overleven, behouden blijft." 

The genetic underpinnings of severe staph infections

In a large collaborative effort, an international team of researchers describes a genetic mutation that predisposes individuals to severe staphylococcus infections. The research, in collaboration with the Babraham Institute, appears in the latest edition of Science.

Staphylococcus aureus is usually harmless. Many of us host colonies of this bacterium in our noses and on our skin without suffering more than the occasional rash. But some strains of staph—particularly MRSA—can turn deadly, leading to pneumonia and sepsis that claims 20,000 lives in the U.S. each year. Now a new study describes a mutation that predisposes some individuals to severe staph infection.

Babraham Institute researcher Adrian Liston collaborated with Belgian doctors Isabelle Meyts, Rik Schrijvers, and Carine Wouters, to investigate the genetic and immunological cause of the disease.

The research, published in Science, describes a mutation in the OTULIN gene in patients who suffer life-threatening staph infections. “In a collaborative effort, several unrelated patients were identified with identical severe clinical presentations and we found a common genetic cause of the disease”, says Frederik Staels, MD, and PhD student at the University of Leuven in Belgium.

"We have characterized severe Staphylococcus aureus infection at the genetic, cellular, immunological, and clinical levels," says Dr. András Spaan, a clinical microbiologist working at The Rockefeller University in New York, who was one of the coordinators of this large international effort. "By integrating these levels, we have been able to establish causality and provide clues for future pharmaceutical interventions."

The study indicated that about 30 percent of people with this OTULIN mutation develop severe disease. This risk was reduced in patients that had acquired specific anti-staph antibodies, while patients without such neutralizing antibodies remained at very high risk of developing severe infections. “This is a potential path to protecting this at-risk patients”, explains Prof Adrian Liston, “the protected patients had acquired anti-staph antibodies through natural exposure, with each exposure being a high-risk gamble for life-threatening infection. If these patients can be identified and vaccinated, the anti-staph antibodies they gain through vaccination may protect them from serious illness”.

"Studies on these disorders can act as a compass," Prof Humblet-Baron, University of Leuven, says, “They bring new mechanistic insights about the interaction between hosts and pathogens, which can also benefit the general population with better understanding about staph infection pathogenesis.”

“From a clinical point of view, this work is of great relevance to physicians confronted with patients manifesting severe, life-threatening episodes of skin and/or lung inflammation, necessitating prompt recognition and treatment,” says Prof. Wouters, pediatric rheumatologist at the University of Leuven. 

Read the paper over at Science.

A Cross Entropy test for tSNE by Dr Oliver Burton

The low-dimensional representation of high-dimensional data makes t-SNE an attractive visualisation tool, yet it also has value as an analytical tool. We have developed the Cross Entropy test, a statistical test capable of distinguishing biological differences in single cell t-SNE representations, while being robust against false detection of differences in technical replicates or the seed-dependent variation in t-SNE generation. As the t-SNE algorithm is driven by the cross entropy of the individual cells in the dataset, and the t-SNE fixes the average point entropy, each t-SNE can be considered a distribution of cross entropy divergences. Deriving a distribution of cross entropy divergences per t-SNE plot therefore allows the use of the Kolmogorov-Smirnov test to evaluate the degree of difference between two, or more, t-SNE plots.

The Cross Entropy test is a useful tool for calculating p values on the difference between any two t-SNE or UMAP plots, whether the data comes from flow cytometry, mass cytometry or single cell sequencing. Further, the test generates a quantitative comparison of the extent of differences, allowing you to compare multiple t-SNE or UMAP plots and identify outgroups and clustered samples. See an overview of the Cross Entropy test given by Dr Oliver Burton:

Read the paper on arXiv here, get the GitHub package here or see the tutorial on how to use the tool here.

First post-lockdown lab photo!

Our paper discussed on RheumMadness podcast

The RheumMadness podcast scouted our paper on using machine learning and immunoprofiling to understand juvenile idiopathic arthritis. Their summary?

Future: Future implications for immunophenotyping machine learning include the diagnosis, treatment and prognosis of all rheumatologic conditions. With the increase in potential immunomodulating targeted therapies, along with the classification of disease based on those same immune targets, an exciting possibility of choosing precise individualized treatment plans for our patients exists.

In pediatric rheumatology, we are accustomed to using complicated clinical algorithms to properly diagnose and treat our patients. But is this really the most accurate system? Machine learning and immunophenotyping have the potential to turn the field inside out. 

Chances in the Tournament: As the only pediatric team in play, this team is the dark horse. However, the long-term clinical implications of this team are arguably more far-reaching than any other team in the Machine Region—and the entire tournament. Despite the small number of participants in this study, the exclusion of psoriatic and enthesitis-related JIA, and the lack of attention given to race, ethnicity and environmental factors that could potentially alter immune signatures, we still believe the strengths of this article make it a crucial one. We stand an excellent chance.

Immunophenotyping machine learning has implications for more than just anti-tumor necrosis factor response in RA, like our opponents would argue. Our study shows that its implications stretch far beyond one diagnosis or two therapy choices. In fact, pediatric rheumatologists have just begun to pave the way for better classifying patients in the adult world as well. Could eight subtypes of RA actually exist, and you just don’t know it yet? Immunophenotyping through machine learning could be the disrupter you’ve been waiting for. This study can go all the way.

Listen to the podcast here

Manipulating brain Tregs to protect against neuropathology

From the GlobalImmuno Talks 20222:

2021 Golden Pipette

The Golden Pipette has a long and illustrious record. Awarded at every lab retreat in recognition of a single very cool result, the Golden Pipette has been handed down through generations of talented scientists. This year the Golden Pipette was awarded to.... Ntombizodwa Makuyana, for her exciting new approach to creating an anti-inflammatory environment in the lung. Well done Tombi, for a stunning first year PhD result!

Responding to the COVID crisis

As well as exposing weaknesses in healthcare systems and supply chains, the coronavirus pandemic has underscored the importance of fundamental research and collective effort. During 2020, scientists rose to the challenge of developing new vaccines and effective treatments for Covid-19. Institute immunologists Dr Michelle Linterman and Professor Adrian Liston describe how their labs responded and the lessons we must learn.

In the early days of the coronavirus pandemic, as lockdowns loomed, workplaces closed and travel slowed to a trickle, Dr Michelle Linterman was certain of one thing – she wanted to make her group’s expertise available to the global vaccines effort.

Among those working on a vaccine against SARS-CoV-2 (the coronavirus that causes Covid-19) was Dr Teresa Lambe at the Jenner Institute in Oxford. “I already knew Tess, so once it became clear they had a vaccine candidate, my first instinct was to ask her what we could do to help,” Linterman recalls.

As an immunologist, Linterman’s work focuses on how the immune system responds to vaccines. In particular, she wants to understand why older people respond less well to vaccines, something she studies using human vaccination studies and in aged mice. “I thought the most useful thing was for us to offer something that nobody else could contribute quickly – and that was our ability to use aged mice as a pre-clinical test of how this vaccine is likely to work in an ageing immune system,” she says.

When Lambe said yes, Linterman set up trials to compare immunological responses to the Oxford/AstraZeneca vaccine in young and aged mice, and discovered that although aged mice responded more poorly than young mice to a single dose, after two doses of the vaccine, the immune responses were very good in both groups.

The study helped both institutes. For the Jenner, it showed two doses of the vaccine would give good protection against infection in all adults. For Babraham, it provided new insights into vaccine responses at a cellular and molecular level, expanded research into new vaccine platforms and led to new collaborations. Most importantly, it illustrated the value of publicly-funded research.

“Because we’re funded by the BBSRC – in other words the tax payer – it was incredibly important to use our knowledge and expertise to contribute to vaccine development in the midst of the pandemic,” she says.

Fellow immunologist Professor Adrian Liston also stepped up to the mark, using his research to help clinicians make the best treatment choices for Covid-19 patients and his communication skills to provide accurate information to journalists and the public.

“We need to develop good systems for treating emerging viruses before we know much about them, which is something my lab is working on,” explains Liston. “We are coming up with treatments that are vaccine agnostic, treatments that will work for most viruses with the potential to become pandemic, regardless of the actual virus.”

Liston’s group is also interested in systems immunology – exploring what makes people’s immune systems so different from each other.

 This variation has been graphically illustrated during the pandemic, some people experiencing mild symptoms while others died. “Diversity is intrinsically important to the immune system. It’s the most genetically-diverse system in the human body, and there are other factors at play, such as age, gender and weight,” he explains.

Being so close to events has taught Liston and Linterman many lessons – lessons, they say, that are vital for political leaders to learn. First, zoonoses (diseases spread between animals and humans) with pandemic potential are far from rare events. “They occur every couple of years,” says Liston. “We’ve had coronavirus outbreaks before, like SARS and MERS; they happen like clockwork. In the previous outbreaks we had better luck and better preparation. These are things we must prepare for.”

Secondly, we must guard against complacency. “If we pat each other on the back for a job well done, and then slash science budgets, the next outbreak will be as bad as this one,” he warns. “We must fund surveillance as well as immunology and virology research, because if you scale down this science it takes a decade or more to rebuild that intellectual capital.” This preparation extends to supporting fundamental research in a broad range of areas. “We need to fund fundamental research because you’re never sure which bit of it will save you in the future,” says Linterman.

 Third, a global approach to research, and funding to support this, is essential, because scientific discoveries are not bounded by borders, adds Linterman: “One of the reasons the Oxford vaccine was developed so fast was because of years of work on Ebola and MERS using the same adenoviral vaccine vector.”

As vaccines are rolled out, and countries emerge from lockdown, we might usefully reflect on what we would have done without a vaccine. It’s a scenario that frightens Linterman. “There wasn’t another exit strategy,” she says. “The vaccines are great, far better than we expected. But there are pathogens that we don’t have good vaccines for. For me, that’s the scary thing. We’re lucky the vaccines are so effective – but that doesn’t mean the same will be true for the next pandemic.”

This feature was written by Becky Allen for the Annual Research Report 2019-2020.

Public Engagement award for the VirusFighter team

Congratulations to the VirusFighter team for winning the Babraham Institute Public Engagement Award! VirusFighter is the reincarnation of VirusBreak. Over the last year I've worked with the PhD students in our lab, Amy Dashwood, Ntombizodwa Makuyana and Magda Ali, together with lab alumni David Posner, to create missions for VirusFighter - allowing the player to be Prime Minister of the UK during different virus outbreaks. GameDoctor created the interface, with liason via the PE team here at the Babraham Institute.

Congrats to Amy, Tombi, Magda and David - a huge contribution to scientific communication, and all during the first year of their PhDs!