Tag: multiple sclerosis

Categories : Regenerative Medicine Skeletal SystemTags : Leave a comment

Repurposed Multiple Sclerosis Drug Could Help Bones Heal Faster

On By ModernMedia
Photo by Tima Miroshnichenko on Pexels

Researchers at the University of Arizona College of Medicine – Tucson found evidence that a drug that improves the ability to walk in people with multiple sclerosis can also make bone fractures heal faster.

The findings help further the understanding of specific factors involved in the bone healing process, and potentially open avenues for new therapeutic approaches.

“Broken bones are typically slow to heal in many people, and they can impact lives for months and in different ways. People lose time at work and daily activities at home with family and friends are impacted,” said senior author John Elfar, MD, professor, surgeon and chair of the Department of Orthopaedic Surgery at the U of A College of Medicine – Tucson. “This drug has the potential to change that.” 

Elfar partnered with Prem Kumar Govindappa, PhD, DVM, an assistant professor in the department, on the preclinical study that showed treatment with the drug 4-aminopyridine, or 4-AP, resulted in leg fractures healing faster and stronger than without the drug. The paper was published in The Journal of Bone and Joint Surgery.

“Mice with bone fractures healed quicker and were stronger after they healed after treatment with 4-AP,” said Elfar said, who is a member of the university’s BIO5 Institute. “We saw more bone mass and less intermediate cartilage, meaning there was accelerated bone healing.” 

The drug is approved for use in chronic neurological conditions, where it helps with walking by improving how signals from the brain and spinal cord reach limbs.

The team also saw improvements in bone mass and the ability to bear weight after treatment with 4-AP. Collagen deposition and bone mineralization, both of which are necessary for bone healing, also received a boost. Collagen forms the structural foundation of bones. In bone mineralization, minerals like calcium and phosphate join the newly forming bone matrix, strengthening and hardening the bone.

“We found that every fine-tuned measure of the strength of bone was better after administering 4-AP to mice,” Elfar said. “We also found more BMP2 protein in bone-forming cells at the fracture site, which again told us we found something that could accelerate the process.”

Examining human bone cells exposed to 4-AP in a dish, the scientists saw increased production of bone morphogenetic protein, or BMP2, a bone-building substance used clinically to help with some kinds of bone repair. BMP2 prompted the production of stem cells that become cells called osteoblasts, which are essential to form new bone.

The research team also measured 4-AP’s effects on human bone narrow mesenchymal stem cells and human osteoblast cells in the lab. 4-AP increased the conversion of the stem cells into osteoblasts and the latter’s ability to migrate and grow, which are essential to the healing process.

Elfar said that 4-AP’s role in driving BMP2 gene and protein activity is key to its bone healing effects, and using 4-AP to prompt BMP2 production in the body could be especially important.

“BMP2 is a hormone the body makes to accelerate bone healing,” Elfar said. 

BMP2 is known to modulate bone healing and is approved for use in certain medical procedures, including spinal fusion and sinus reconstruction surgery. An artificial version that has orthopedic medicine uses can have side effects, though, including bone resorption and cervical spine swelling. Finding a way to channel naturally produced BMP2 could improve bone healing while avoiding such problems.

The scientists previously showed that 4-AP could prevent bone and muscle loss in a mouse model of nerve damage. Similarly, they saw indications of 4-AP’s healing effects for wound, nerve and limb injuries. 

The researchers plan to eventually test 4-AP’s potential use in healing bones in a clinical trial. They also want to better understand the drug’s effects on BMP2 production, and more broadly, on the biology of healing bone.

Source: University of Arizona

Categories : Neurodegenerative DiseasesTags :

Mitochondrial Failure Contributes to Neuron Death in Multiple Sclerosis

On By ModernMedia
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Multiple sclerosis (MS) affects some 2.3 million people worldwide, with 80% experiencing inflammation in the cerebellum, a brain region crucial for movement and balance. This inflammation can lead to tremors, poor coordination, and motor control issues, which often worsen over time due to the loss of healthy brain tissue.

Researchers at the University of California, Riverside, have made a significant discovery about the underlying mechanisms of cerebellar degeneration in MS. Their study, published in PNAS, suggests that mitochondrial dysfunction may play a key role in the progressive loss of Purkinje cells and worsening motor impairments.

Purkinje cells are essential for coordinating smooth movements and balance. In MS, these cells can be damaged, leading to problems with coordination and movement, known as ataxia. The study found that Purkinje cells in MS patients had fewer branches, lost myelin, and experienced mitochondrial problems, resulting in a failing energy supply.

“Our study, conducted by my graduate student Kelley Atkinson, proposes that inflammation and demyelination in the cerebellum disrupt mitochondrial function, contributing to nerve damage and Purkinje cell loss,” said Seema Tiwari-Woodruff, a professor of biomedical sciences in the UC Riverside School of Medicine, who led the research team. “We observed a significant loss of the mitochondrial protein COXIV in demyelinated Purkinje cells, suggesting that mitochondrial impairment contributes directly to cell death and cerebellar damage.”

The research team used a mouse model of MS to investigate mitochondrial alterations during disease progression. They found that the mice lost Purkinje cells over time, similar to people with MS. The loss of energy seemed to be a key part of MS, with cells only dying later.

“Our research looked at brain tissue from MS patients and found major issues in these neurons: they had fewer branches, were losing myelin, and had mitochondrial problems – meaning their energy supply was failing,” Tiwari-Woodruff said. “Because Purkinje cells play such a central role in movement, their loss can cause serious mobility issues. Understanding why they’re damaged in MS could help us find better treatments to protect movement and balance in people with the disease.”

The study suggests that targeting mitochondrial health may be a promising strategy to slow or prevent neurological decline and improve quality of life for people living with MS.

The researchers plan to further investigate whether mitochondrial impairment affects other brain cells, such as oligodendrocytes and astrocytes. This research has the potential to open the door to finding ways to protect the brain early on, such as boosting energy in brain cells or aiding repair of the myelin sheaths.

Source: University of California, Riverside

Categories : Immune SystemTags :

Multiple Sclerosis Drug Ocrelizumab Works by Reshaping the Immune System

On By ModernMedia
Myelin sheath damage. Credit: Scientific Animations CC4.0

When ocrelizumab became the first FDA-approved treatment for early forms of multiple sclerosis (MS) in 2017, it offered patients immense hope. The long-awaited drug is a monoclonal antibody that depletes B cells – the immune cells that drive MS progression. Exactly how ocrelizumab does this, however, remains unclear.

In a new study published in The Journal of Clinical Investigation, Yale scientists begin to answer this question. By using single-cell RNA sequencing, a technique that provides a window into the gene expression in individual cells, the researchers laid out a detailed view of how ocrelizumab achieves its therapeutic effects.

“The surprise was that the drug doesn’t work at all the way we thought it was working,” says David A. Hafler, MD, Professor of Neurology at Yale School of Medicine, who led the study. “We knew what the end result was and that the drug was enormously effective in patients. But what’s driving the drug’s action is a type of white blood cell in the central nervous system. No one would ever hypothesise that.”

The roles of T cells and B cells in multiple sclerosis

B and T cells have closely intertwined roles in the immune system. B cells are critical cells that recognise foreign objects, bind them, and present them to T cells, which then signal other immune cells to take action. But this relationship goes awry in disease.

Scanning electron micrograph of a B cell. Credit: NIH

In MS, abnormally active B cells trigger T cells to attack the myelin sheath, the protective layer of nerve fibres, leading to neurological symptoms, such as loss of vision, muscle weakness, and cognitive impairment. More than two decades ago, Hafler and his team discovered this was due to defects in regulatory T cells, which normally put the brake on immune responses, but when defective, unleash immune cells that mistakenly target the body’s own tissues.

In the early stages of MS, both B and T cells are deemed to be the drivers of the disease. Once the disease progresses to a neurodegenerative stage, other inflammatory processes become more prominent.

“Once you enter the neurodegenerative phase of the disease, it is much more difficult to stop the process,” Hafler says. “What we’ve learned is that the earlier you treat the disease, the better the outcome.”

Ocrelizumab binds to the surface of B cells, leading to their destruction. And especially for people in the early stages of MS, it can be quite effective. “The drug works incredibly well,” Hafler says. But Hafler and his team found that ocrelizumab was doing far more than just controlling B cells.

In the new study, the researchers analysed the blood and cerebrospinal fluid of 18 patients, all of whom had an early-onset form of multiple sclerosis in which patients cycle between periods of disease remission and relapse. The scientists measured the cell type-specific changes in protein expression before and after the patients received six months of ocrelizumab, in an effort to identify immune molecules that might change in response to the drug.

They discovered that the reduction in B cells driven by ocrelizumab led to an increase in the pro-inflammatory molecule TNF-α. This was unexpected because TNF-α has been shown to trigger the immune system and exacerbate inflammation in certain diseases. In fact, medications that block the activity of TNF-α are typically used for treating various autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

As they looked further, the researchers found that by inducing TNF-α, ocrelizumab led to an increase in a specific type of regulatory T cell. This, in turn, curbed the circulation of T cells that attack the myelin.

“This unpredicted increase in TNF-α shows that ocrelizumab works in a paradoxical way,” says Hafler.

Understanding the cause of multiple sclerosis

One of the current working models of MS suggests that the disease originates from the Epstein-Barr virus. “How the Epstein-Barr virus triggers the disease is a point that we don’t yet understand,” Hafler says. However, there is a strong body of evidence to show that the virus infects B cells. Therefore, understanding how a B cell-depleting drug affects T cell activity may lead to further explanations.

The current finding also explains why a fifth of the genes linked to MS risk involve the TNF pathway and why many of those genetic changes are protective in other diseases, such as inflammatory bowel diseases.

“This shows that biology has a richness to it,” Hafler says. “When these molecules are made, where they’re made, and what cell they’re working on have very different effects.”

Hafler suspects that ocrelizumab might be acting through other mechanisms as well, an inkling that motivates his lab to continue their investigation. “For something to work that well, there must be other things going on,” he says.

The team is now beginning to study the pathogenesis of MS in a large cohort of women who have at least one parent with the disease. By following the genetic evolution of the disease, the scientists are hoping to better understand how B cells change the immune landscape in real time.

“This study is only one piece of the puzzle,” Hafler says. “We’ll continue to look for other pieces.”

Source: Yale School of Medicine

Categories : New Compounds and TreatmentsTags :

New Cannabis Formula will Help Epilepsy, Multiple Sclerosis Sufferers

On By ModernMedia
Photo by Kindel Media on Unsplash

Scientists at the University of South Australia have come up with an innovative solution to improve the effectiveness of cannabidiol to treat epilepsy, multiple sclerosis and other neurodegenerative diseases.

Cannabidiol (CBD), a non-psychoactive cannabis compound, is widely prescribed for its analgesic, anti-inflammatory and neuroprotective properties, but its clinical applications to date have been limited by its poor water solubility and absorption in the human body.

By developing a phospholipid complex – a class of lipids (fats) that contain phosphorus – UniSA researchers have increased the solubility of cannabidiol by up to six times and improved its absorption in the gastrointestinal tract.

Lead researcher Professor Sanjay Garg says the breakthrough, reported in the International Journal of Molecular Sciences, means that patients could experience more consistent and effective results with lower doses of oral CBD medications.

Currently, only a small fraction of orally ingested CBD reaches the bloodstream, limiting its therapeutic effects.

“For this reason, a number of different formulations have been explored, including the production of synthetic CBD, self-emulsifying delivery systems, and encapsulating CBD in gelatine matrix pellets, but all of them have only resulted in minor improvements in bioavailability,” Prof Garg says.

His research team identified the optimal phospholipid composition to form nanosized CBD-PLC particles. Compared to pure CBD, the phospholipid complex improved dissolution rates from 0% to 67.1% within three hours, demonstrating a significant enhancement in drug release.

In cellular uptake studies, CBD-PLC exhibited 32.7% higher permeability than unmodified CBD, ensuring greater absorption through the intestinal wall.

Another critical advantage of this new delivery system is its stability. Traditional CBD formulations degrade over time when exposed to heat, light or oxygen, reducing potency and shelf life.

However, testing over 12 months showed that CBD-PLC retained its performance under varied storage conditions, making it a more reliable option for pharmaceutical applications.

The study’s first author, UniSA PhD candidate Thabata Muta, says the discovery has significant implications for the future of CBD-based therapeutics.

“Improved bioavailability means that lower doses can achieve the same therapeutic effect, potentially reducing side effects and making treatment more cost effective,” Thabata says.

The research team believes that this innovation could be applied beyond CBD, providing a blueprint for enhancing the absorption of other poorly water-soluble drugs.

With the global CBD market projected to grow from USD 7.59 billion in 2023 to USD 202.45 billion by 2032, the findings of this study come at a crucial time, according to the study authors.

The team is now exploring opportunities for commercialisation and clinical trials to validate their new formulation.

Source: University of South Australia

Categories : Neurodegenerative Diseases PaediatricsTags :

More Sunshine as a Baby Linked to Less Disease Activity for Children with MS

On By ModernMedia
Photo by Anders Jilden on Unsplash

Getting at least 30 minutes of daily summer sun in the first year of life may mean a lower relapse risk for children who are diagnosed with multiple sclerosis (MS) later, according to a study published in Neurology® Neuroimmunology & Neuroinflammation, an official journal of the American Academy of Neurology. The study also found if a child’s biological mother had at least 30 minutes of daily sun during the second trimester of pregnancy, the child had a lower risk of MS relapses.

The study does not prove that sun lowers relapse risk for children with MS, it only shows an association. “It is important not to spend too much time in the sun without sun protection, however greater exposure to sun has been tied in previous research to a lower risk of developing MS in childhood,” said Gina Chang, MD, MPH, of The Children’s Hospital of Philadelphia and member of the American Academy of Neurology. “It’s encouraging that our study found that greater sun exposure during early development may also be beneficial in helping to reduce disease activity in children who are later diagnosed with MS.”

For the study, researchers looked at health records from 18 MS clinics across the United States to identify 334 children and young people with childhood-onset MS age four to 21. Participants were within four years of experiencing their first symptoms. The median follow-up time was 3.3 years. To determine sun exposure, participants’ parents or guardians completed questionnaires that asked how much time the participant and their biological mother had spent in the sun at various periods of life, what kind of clothing they typically wore and how often they used sunscreen.

Of the total group, 206, or 62%, experienced at least one relapse during the study. Relapses were defined as new or returning symptoms lasting for at least 24 hours and separated by at least 30 days from the last MS attack, without a fever or infection. They found that of 75 participants who had 30 minutes to an hour of daily summer sun during their first year of life, 34 children, or 45%, had a relapse.

Of the 182 participants who had less than 30 minutes of daily summer sun during their first year of life, 118 children, or 65%, had a relapse. After adjusting for factors such as tobacco exposure in the first year of life, season of birth, the type of MS medication taken and use of sun protection such as sunscreen, hats and clothing, researchers found that 30 or more minutes of daily summer sun during the first year of life was associated with a 33% lower risk of relapse compared to less than 30 minutes of daily summer sun.

Researchers also looked at sun exposure for the biological mothers of the children. They found that 30 minutes or more of daily sun during the second trimester of pregnancy was associated with a 32% reduced risk of relapse for their child with MS.

“Our findings suggest that sun exposure in early childhood may have long-lasting benefits on the progression of childhood-onset MS,” said Chang. “Future studies should look at how time in the sun at other time periods before and after MS diagnosis affects disease course, to better guide sun exposure recommendations for children with MS and to help design potential clinical trials.” A limitation of the study was that it relied on participants’ parents or guardians reporting their sun exposure and use of sun protection, which they may not have remembered accurately.

Source: American Academy of Neurology

Categories : Mental Health NeurologyTags :

A Multiple Sclerosis Drug may Help with Poor Working Memory

On By ModernMedia
This is a pseudo-coloured image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Fampridine is currently used to improve walking ability in multiple sclerosis. A new study shows that it could also help individuals with reduced working memory, as seen in mental health conditions like schizophrenia or depression.

Working memory allows a memory to be actively retained for a few seconds, for cognitive tasks such as remembering an email address to save it, or participating in a conversation. Certain conditions, such as schizophrenia or depression, as well as ADHD, impair working memory. Those affected lose track in conversations and struggle to organise their thoughts.

Fampridine is a drug that could help in such cases, as shown in a study led by Professors Andreas Papassotiropoulos and Dominique de Quervain at the University of Basel. The team has reported their findings in the journal Molecular Psychiatry.

Effective only if working memory is poor

In their study, the researchers tested the effectiveness of fampridine on working memory in 43 healthy adults. It was in those participants whose baseline working memory was at a low level that fampridine showed a more pronounced effect: after taking the active substance for three days, they scored better in the relevant tests than those who took the placebo. In contrast, in people who already had good baseline working memory, the drug showed no effect.

The researchers also observed that fampridine increased brain excitability in all participants, thus enabling faster processing of stimuli. The study was randomized and double-blind.

Established drug, new application

“Fampridine doesn’t improve working memory in everyone. But it could be a treatment option for those with reduced working memory,” explains Andreas Papassotiropoulos. Dominique de Quervain adds: “That’s why, together with researchers from the University Psychiatric Clinics Basel (UPK), we’re planning studies to test the efficacy of fampridine in schizophrenia and depression.”

The drug is currently used to improve walking ability in multiple sclerosis (MS). Particularly in capsule form, which releases the active ingredient slowly in the body, fampridine has shown effects on cognitive performance in MS patients: for some, it alleviates the mental fatigue that can accompany MS.

The researchers did not select the drug at random: this study followed comprehensive analyses of genome data in order to find starting points for repurposing established drugs. Fampridine acts on specific ion channels in nerve cells that, according to the researchers’ analyses, also play a role in mental disorders such as schizophrenia.

Source: University of Basel

Categories : Neurodegenerative DiseasesTags :

A New Era of Treating Neurological Diseases at the Blood-brain-immune Interface

On By ModernMedia
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

The question of what causes complex neurological diseases such as Alzheimer’s or multiple sclerosis continues to confound scientists and doctors, with the unknowns standing in the way of early diagnoses and effective treatments.

Even among identical twins who share the same genetic risk factors, one may develop a particular neurological disease while the other does not.

That’s because unlike diseases such as cystic fibrosis or sickle-cell anaemia, which are caused by a single gene, most neurological disorders are associated with many, sometimes hundreds, of rare genetic variants. And on their own, these variants can’t predict who will develop disease, as neurological conditions are also strongly influenced by environmental factors and vascular risks such as high blood pressure, aging, heart disease, or obesity.

But there’s one often-overlooked thread that connects most neurological diseases, says Katerina Akassoglou, PhD, a senior investigator at Gladstone Institutes: They’re marked by a toxic immune reaction caused by blood that leaks into the brain through damaged blood vessels.

“Interactions between the brain, blood vessels, and the immune system are a common thread in the development and progression of many neurological diseases that have been traditionally viewed as very different conditions,” says Akassoglou. “Knowing that leaked blood is a key driver of brain inflammation, we can now approach these diseases from a different angle.”

She and her collaborators share their insights on this topic in a commentary article published in Cell’s 50th anniversary “Focus on Neuroscience” issue. 

Neutralising the Culprit

Akassoglou and her lab have long investigated how blood that leaks into the brain triggers neurologic diseases, essentially by hijacking the brain’s immune system and setting off a cascade of harmful often-irreversible effects that result in damaged neurons.

One blood protein in particular, fibrin, normally involved in blood coagulation, is responsible for setting off this detrimental cascade. The process has been observed in conditions as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, premature birth, and even COVID-19. However, Akassoglou and her team found that the process could be prevented or interrupted by “neutralising” fibrin to deactivate its toxic properties – an approach that appears to protect against many neurological diseases when tested in animal models.

“As a first step, we know that neutralizing fibrin reduces the burden posed by vascular dysfunction,” Akassoglou says. Regardless of what initially caused the blood leaks, be it a head injury, autoimmunity, genetic mutations, brain amyloid or infection, neutralizing fibrin appears to be protective in multiple animal models of disease.

The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. This fibrin-targeting immunotherapy has shown, in mice, to protect from multiple sclerosis and Alzheimer’s, and to treat neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio, a biotech company launched to advance discoveries from Akassoglou’s lab.

A New Era of Brain Research

In the Cell commentary, Akassoglou and her colleagues make the case that seemingly disparate neurological diseases must be viewed differently in light of new research on the blood-brain-immune interface.

They say that in the coming decade, scientific breakthroughs will emerge from collaborative networks of immunologists, neuroscientists, haematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These partnerships, forged across academia, industry, and foundations, will catalyse innovation in drug discovery and transform medical practice for neurological diseases.

“This is a new opportunity for drug discovery that goes beyond addressing genes alone or environmental factors alone,” Akassoglou says. “To usher in this new era, we must leverage new technologies and embrace an interdisciplinary approach that accounts for the important roles of immune and vascular systems in neurodegeneration.”

Source: Gladstone Institutes

Categories : Neurodegenerative DiseasesTags :

Epstein-Barr Virus: How does a Common Infection Trick the Immune System into Attacking the Brain in People with MS?

On By ModernMedia
An electron micrograph showing three Epstein-Barr virus (EBV) particles colourised red-orange. Credit: NIAID

Olivia Thomas, Karolinska Institutet; Graham Taylor, University of Birmingham, and Jill Brooks, University of Birmingham

Almost 3 million people worldwide have multiple sclerosis (MS) – an autoimmune disease caused by the immune system mistakenly attacking the brain and central nervous system.

While treatments for MS have improved over the years, there’s still no cure. This is largely because researchers still don’t fully understand what goes wrong in the immune system to cause MS. But our latest research has revealed new insights into the way certain immune cells behave in people with MS. This discovery brings us closer to understanding why some people get MS – and may also be a crucial step in developing better treatments and even cures.

Although the causes of MS aren’t fully understood, we know that genetics, lifestyle and environment factors can all influence MS risk. But the biggest risk factor for developing MS appears to be a common virus called Epstein-Barr virus (EBV).

EBV typically infects people during childhood without causing any symptoms – so most early infections go unnoticed. But if the infection occurs during adolescence, it may cause glandular fever (infectious mononucleosis) which, although debilitating in the short-term, usually has no long-term effects.

Most viral infections are rapidly cleared by the body’s immune system, but EBV is cleverer than most viruses. Although the immune system controls the infection, it is unable to completely eradicate the virus as it hides inside a type of immune cell called a B cell (which normally produce antibodies that bind to and destroy invading viruses or bacteria). Once you’re infected with EBV you carry it for life – although for most people this causes no problems.

By adulthood about 95% of people are infected with EBV, but in people with MS nearly 100% are infected. Large epidemiological studies have shown that EBV infection increases the risk of developing MS over 30-fold. For people who have had glandular fever the risk is even higher. Research has also shown that in people with MS, EBV infection occurs before the very earliest stages of disease.

Many researchers now believe being infected with EBV is more than a risk factor in MS – it’s essential.

But how does EBV cause MS – and why does a common virus only cause MS in a few people? Several theories are currently being investigated.

One theory is that in some people the immune cells activated by EBV mistakenly attack parts of the brain and central nervous system. This process, called molecular mimicry, also occurs in other autoimmune diseases, such as Guillain-Barré syndrome. This could explain why drugs which prevent immune cells from entering the brain are shown to dramatically improve MS symptoms.

Research into EBV molecular mimicry in MS has mainly focused on the viral protein EBNA1. Without EBNA1 EBV cannot live in B cells, and MS patients have higher levels of antibodies towards EBNA1.

But EBV makes over 80 different proteins during its life cycle. In our latest work we investigated immune responses to these other viral proteins in people with MS.

Altered immunity

We compared the immune responses of 31 people with MS, 33 healthy people and 11 people who had recently recovered from glandular fever. We wanted to see if each group reacted to EBV infections differently.

We found that antibodies targeting EBNA1 and another viral protein called VCA were higher in people with MS compared to the other groups. People with MS were also more likely to have antibodies targeting several other viral proteins. This suggests EBV antibodies are more altered in MS than previously thought – but it isn’t certain whether these antibodies are fighting infection or if they have a role in MS disease.

Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID

Antibodies aren’t the full story. Previous research has suggested another type of immune cell, called a T cell, may also play an important role as they’re found in high numbers in MS brain lesions. As such, we wanted to understand whether T cells which fight EBV were different in people with MS.

By analysing blood samples we found that, although EBV T cell numbers were similar in MS and healthy people, these cells behaved differently in people with MS. T cells from people with MS produced slightly higher amounts of an inflammatory substance called interleukin-2. The body normally produces this substance in response to injury or infection, but too much interleukin-2 can cause chronic disease.

We also looked at molecular mimicry, wondering whether EBV T-cells mistakenly target brain proteins rather than fighting the virus.

Surprisingly, we found that in both people with MS and healthy people, their EBV T cells reacted to multiple proteins found in the brain. Notably, most people had EBV T cells that targeted a protein called myelin oligodendrocyte glycoprotein, or Mog, which surrounds the nerves.

Looking at one person with MS in more detail, we found individual T cells that directly recognised both EBNA1 and Mog. This means that, rather than just fighting infection, some EBV T cells could also target nerve cells in the brain.

This widespread misdirection between EBV T cells and the brain goes some way to suggest how infection with this common virus can lead to MS. But its presence in healthy people is slightly confusing. One possible explanation could be that EBV T cells are better able to cross the blood-brain barrier (a tight-knit lining of cells that protect the brain) in people with MS. This idea is something we’re keen to explore in future research.

While there’s still much we don’t know about these misdirected EBV T cells in the brain, our latest findings provide fresh evidence for researchers and hopefully will lead to the development of new, targeted treatments for MS.

Olivia Thomas, Assistant Professor, Department of Clinical Neuroscience, Karolinska Institutet; Graham Taylor, Associate Professor in Viral and Tumour Immunology, University of Birmingham, and Jill Brooks, Research Fellow, Institute of Cancer and Genomic Sciences, University of Birmingham

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : Cancer Neurodegenerative DiseasesTags :

MS Associated with an Increased Risk of Certain Cancers

On By ModernMedia
This is a pseudo-coloured image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.

Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

A new study has found some cancers to be slightly more frequent in people with multiple sclerosis (MS) than in people without MS. The study is published online in Neurology®, the medical journal of the American Academy of Neurology. Types of cancers found to have a small increased risk include bladder, brain and cervical cancers.

“People with MS undergo an increased number of tests to monitor MS, making it more likely to detect other diseases,” said study author Emmanuelle Leray, PhD, of Rennes University in France. “We found an association between some types of cancer and MS which may have different explanations depending on a person’s age and the types of cancer. Overall, our study found the increased risk of cancer was quite small.”

For the study, researchers reviewed 10 years of data in the French national health care database. Researchers identified 140 649 people with MS and matched them for factors such as age, sex and residence to 562 596 people without MS. All participants were cancer free three years before the study. They were followed for an average of eight years.

During the study, 8,368 people with MS and 31,796 people without MS developed cancer.

Researchers determined there were 799 cancers per 100 000 person-years for people with MS and 736 cancers per 100 000 person-years for people without MS. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

Researchers found people with MS had a 6% increased risk of developing any type of cancer regardless of age, sex and residence. They also found cancer risk was higher in those under 55 and lower in people 65 and older when compared to people without MS.

Researchers then looked at cancer types. People with MS had a 71% increased risk for bladder cancer, a 68% increased risk for brain cancer and a 24% increased risk for cervical cancer. However, they also had a 20% lower risk of prostate cancer, a 10% lower risk of colorectal cancer and a 9% lower risk of breast cancer.

“While our study found a higher risk for brain cancer, it may be due in part to earlier detection in those with MS since they regularly have brain scans which may detect cancers earlier, before a person has symptoms,” said Leray. “Frequent urinary tract infections in people with MS and the use of immunosuppressant drugs may contribute to their higher risk of bladder and cervical cancers.”

Leray added, “The lower risk for colorectal and breast cancers may be due in part to fewer people with MS getting screened for cancer in older age when they may be experiencing more MS symptoms. More research is needed, including studies that look at more closely at how cancer screenings may play a role.”

A limitation of the study was that researchers were unable to adjust for factors such as education, income, smoking and alcohol consumption since this information was not available in the national database.

Source: American Academy of Neurology

Categories : Immune System Neurodegenerative DiseasesTags :

New Approach to MS ‘Teaches’ Immune Cells not to Attack

On By ModernMedia
Myelin sheath damage. Credit: Scientific Animations CC4.0

Researchers from have found a potential new way to improve the treatment of multiple sclerosis (MS) using a novel combined therapy. The results, published in the Journal of Clinical Investigation, builds on two harmonised Phase I clinical trials, focusing on the use of Vitamin D3 tolerogenic dendritic cells (VitD3-tolDCs) to regulate the immune response in MS patient.

Multiple Sclerosis (MS) is a long-term disease where the immune system mistakenly attacks the protective myelin sheath around nerve cells. This leads to nerve damage and worsening disability. Current treatments, like immunosuppressants, help reduce these harmful attacks but also weaken the overall immune system, leaving patients vulnerable to infections and cancer. Scientists are now exploring a more targeted therapy using special immune cells, called tolerogenic dendritic cells (tolDCs), from the same patients.

TolDCs can restore immune balance without affecting the body’s natural defences. However, since a hallmark of MS is precisely the dysfunction of the immune system, the effectiveness of these cells for auto transplantation might be compromised. Therefore, it is essential to better understand how the disease affects the starting material for this cellular therapy before it can be applied.

In this study, researchers from Barcelona’s Germans Trias i Pujol Institute and Josep Carreras Leukaemia Research Institute, examined CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-treated tolerogenic dendritic cells (VitD3-tolDCs) from MS patients who had not yet received treatment, as well as from healthy individuals. The clinical trials (NCT02618902 and NCT02903537) are designed to assess the effectiveness of VitD3-tolDCs, which are loaded with myelin antigens to help “teach” the immune system to stop attacking the nervous system. This approach is groundbreaking as it uses a patient’s own immune cells, modified to induce immune tolerance, in an effort to treat the autoimmune nature of MS.

The study, led by Dr Eva Martinez-Cáceres and Dr Esteban Ballestar, with Federico Fondelli as first author, found that the immune cells from MS patients (monocytes, precursors of tolDCs) have a persistent “pro-inflammatory” signature, even after being transformed into VitD3-tolDCs, the actual therapeutic cell type. This signature makes these cells less effective compared to those derived from healthy individuals, missing part of its potential benefits.

Using state-of-the-art research methodologies, the researchers identified a pathway, known as the Aryl Hydrocarbon Receptor (AhR), that is linked to this altered immune response. By using an AhR-modulating drug, the team was able to restore the normal function of VitD3-tolDCs from MS patients, in vitro. Interestingly, Dimethyl Fumarate, an already approved MS drug, was found to mimic the effect of AhR modulation and restore the cells’ full efficacy, with a safer toxic profile.

Finally, studies in MS animal models showed that a combination of VitD3-tolDCs and Dimethyl Fumarate led to better results than using either treatment on its own. This combination therapy significantly reduced symptoms in mice, suggesting enhanced potential for treating human patients.

These results could lead to a new, more potent treatment option for multiple sclerosis, offering hope to the millions of patients worldwide who suffer from this debilitating disease. This study represents a significant step forward in the use of personalised cell therapies for autoimmune diseases, potentially revolutionising how multiple sclerosis is treated.

The team is now preparing to move into Phase II trials to further explore these findings.

Source: Josep Carreras Leukaemia Research Institute