Tag Archives: multiple sclerosis

UNIGE1.

Overeager immune system cells may be to blame for multiple sclerosis

New research from the University of Geneva in Switzerland is inching in on the causes of multiple sclerosis.

UNIGE1.

In a multiple sclerosis, a cluster of lymphocytes T CD8+ (red) express TOX (green) within the nucleus (blue).
Image credits UNIGE.

Multiple sclerosis (MS) is a debilitating disease that affects roughly 3 in 10.000 people worldwide, and about 0.1% of the population (1 in 1,000 people) in the US. The disease is still as mysterious as ever: we know it involves the breakdown of the myelin sheaths around the tails of neurons in the brain, but not why. Symptoms range from physical or mental to psychiatric — vision problems, impairment of locomotor functions or speech difficulties among others — and they can come about in isolated attacks (relapsing forms) or set in over time (progressive forms). We can help patients manage the symptoms to some extent, but we don’t yet know how to cure the disease.

TOX and MS

Researchers at the University of Geneva (UNIGE), Switzerland, and Geneva University Hospitals (HUG) are investigating into one of the potential culprits behind MS. They have identified one DNA-binding factor named TOX which might play a role in triggering multiple sclerosis — the team reports that TOX enables cells to cause autoimmune damage to brain cells. The team’s findings could help us develop better treatments to both MS and autoimmune diseases in general.

We don’t know why some people develop MS while others don’t. We have observed, however, that the disease is linked with both genetic and environmental risk factors (among the latter being infection and even smoking). To get a better understanding of the processes that underpin MS’s onset, the team decided to look at the role infection factors play in its formation.

“We decided to analyse the infectious factors by studying the auto-immune reactions provoked by different pathogens,” explains Doron Merkler, a Professor at the HUG Clinical Pathology Department. “This was to try to pinpoint an element that might influence the development of multiple sclerosis where there has been an infection”.

The team used with two different pathogens — one viral, the other bacterial — that are known to elicit a response from the immune system. The research was performed using healthy mouse models. According to co-author Nicolas Page, a researcher in UNIGE’s Pathology and Immunology Department, both pathogens elicited a “quantitative identical immune reaction” from one particular type of white blood cells: lymphocytes CD8+ T.

“However, only the mouse infected with the viral pathogen developed an inflammatory brain disease reminiscent to Multiple Sclerosis,” he adds.

The team’s next step was to look at how gene expression levels in CD8+ T varied when different pathogens were used to activate them — which led to the discovery of TOX. This DNA-binding factor expressed only in cells activated by the viral pathogen, they explain. Later, the team confirmed the link between TOX and MS, using mice models in which they eliminating the expression of TOX in CD+ 8 lymphocytes. In this case, the mice didn’t develop the disease despite being infected with the viral pathogen.

However, for all the damage it can do, the team reports that TOX actually means well. Our brains can’t regenerate that well, and relying on tissue regrowth doesn’t guarantee the integrity of function or stored memories — so our body tries to prevent damage to neurons rather than make sure it can easily repair. Our brains are so fragile, however, that they also have to keep out our own immune system cells, which could damage the organ in their relentless fight against pathogens. So, the brain is insulated with barriers that prevent T lymphocytes from entering.

TOX, however, alters the expression of certain key receptors on the surface of CD+ T lymphocytes — the same receptors that receive the “stay away” signals from the brain’s barriers. The defending cells can thus bypass the filters, gain access to the brain, and inadvertently cause the outbreak of the disease, notes the team. Another damning piece of evidence, the team reports, is that TOX was also expressed in T cells present in multiple sclerosis lesions.

“This is an encouraging result for understanding the causes of the disease but there is still lots of work to be done to ascertain what really causes multiple sclerosis in humans,” admits Page.

The researchers now plan to study if and how TOX is involved in other autoimmune diseases, as well as certain cancers.

The paper “Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells” has been published in the journal Immunity.

New STEM cell technology allows scientists to grow retinal nerve cells

Johns Hopkins researchers have discovered a method that allows them to coax stem cells to morph into retinal ganglion cells. This type of nerve cells reside in the retina and transmit visual input from the eyes to the brain. If these cells become damaged or die vision-loss conditions develop, such as glaucoma or multiple sclerosis.

Fluorescence microscopy: Human retinal ganglion cells are shown at day 50.
Image via sciencedaily

“Our work could lead not only to a better understanding of the biology of the optic nerve, but also to a cell-based human model that could be used to discover drugs that stop or treat blinding conditions,” says Donald Zack, M.D., Ph.D., the Guerrieri Family Professor of Ophthalmology at the Johns Hopkins University School of Medicine and lead scientists of the study.

“And, eventually it could lead to the development of cell transplant therapies that restore vision in patients with glaucoma and MS.”

By using a genome editing tool called CRISPR-Cas9, the team grafted a new gene in human embryonic stem cells’ DNA. The gene determined the production of a fluorescent-red protein but would only express when another gene, BRN3B (POU4F2), also became active. Since BRN3B becomes active in mature retinal ganglion cells, once stem cells differentiated to this type they would glow bright red.

“By the 30th day of culture, there were obvious clumps of fluorescent cells visible under the microscope,” says lead author Valentin Sluch, Ph.D., a former student at Johns Hopkins and postdoctoral scholar at Novartis, a pharmaceutical company.

After picking them out under a microscope scientists employed a technique named fluorescence-activated cell sorting to separate the newly formed ganglion cells from the rest if the material. This left the team with a highly purified population of cells that showed the same biological and physical properties as retinal ganglion cells naturally produced by the body, Zack says.

“I was very excited when it first worked,” Sluch says. “I just jumped up from the microscope and ran [to get a colleague]. It seems we can now isolate the cells and study them in a pure culture, which is something that wasn’t possible before.”

Zack is now working with Peter Calabresi, M.D., professor of neurology and director of the Johns Hopkins Multiple Sclerosis Center to develop new treatments for glaucoma and MS based on this new technology.

“We really see this as just the beginning,” adds Zack. In follow-up studies using CRISPR, his lab is looking to find other genes that are important for ganglion cell survival and function. “We hope that these cells can eventually lead to new treatments for glaucoma and other forms of optic nerve disease.”

To use these cells to develop new treatments for MS, Zack is working with Peter Calabresi, M.D., professor of neurology and director of the Johns Hopkins Multiple Sclerosis Center.

The team also found that adding forskolin (a chemical that occurs naturally in plants) to the culture helped improve the cells’ odds of becoming retinal ganglion cells. They do caution that forskolin is not scientifically proven safe or effective for treatment or prevention of blindness or any other disorder however.

The full paper is available online in the journal Nature.

Stem Cell Treatment Offers Hope for MS Treatment

For the first time, scientists have developed a treatment for Multiple Sclerosis (MS) that actually reverses the disability. Dr. Richard K. Burt performed the first hematopoietic stem cell transplant (HSCT) for a multiple sclerosis (MS) patient in the United States at Chicago’s Northwestern Memorial Hospital, and the treatment showed great promise.

Normal cell vs Multiple Sclerosis Cell. Image via American Cryo system.

 

MS is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. It’s not clear what causes it and there is no clear treatment for the disease.

In this trial 151 patients underwent a stem cell transplant. Their immune systems were numbed first with low dose chemotherapy, and then doctors used stem cells previously extracted from the patients to “reboot” their immune systems. After only a few days spent in the hospital, the patients then returned home, reporting no symptoms from the disease and needing no more medication.

Doctors administered several tests to detect any lingering signs of the disease and also asked participants to fill out questionnaires regarding their lives. Four years after the treatment was administered, 80 percent of participants were relapse free, and even those who relapsed showed a significant reduction of symptoms.

Since 1993, the FDA has approved 12 disease-modifying therapies (DMTs) to treat relapsing-remitting MS (RRMS). All of them basically work around suppressing the immune system, and are extremely expensive – costing some $5,000 / months. They must also be taken indefinitely, since if you stop the treatment, there is a high risk for relapse. This treatment is also very expensive – it has a one time cost of $125,000, so it only starts paying for itself after 2 years.

“If you’re doing well on first-line therapies, interferons or Copaxone, good, that’s where you should stay,” Burt added. “But if you’re having frequent relapses, two or more a year despite those therapies … I think that’s the group that, rather than going to Tysabri or Fingolimod, should be given this therapy because it’s so much more beneficial. Plus, if you wait until you’ve had all those other [DMTs] then you increase the risk of this treatment.”

However, there is still much room for improvement with this type of stem cell treatment, and with further research, it might become significantly cheaper. But there are also downsides.

“The caveat,” Burt conceded, “is this is not effective in progressive MS.” He pointed out the tendency among neurologists to try one DMT after another until the patient is out of options before offering HSCT. “But by then [the patient has] entered secondary progressive and most likely nothing will help.”

This was also an observational cohort study, not a randomized controlled study. The journal article states:

Because this is an observational cohort without a control group, inferences about causal effects of HCST cannot be made. Definitive conclusions will require a randomized trial; however, this analysis provides the rationale, appropriate patient selection, and therapeutic approach for a randomized study.

In other words, while promising, this is an initial study with many limitations. A larger, more controlled study will almost certainly lead to better results, and then we can start talking about a treatment for MS.

The team is currently conducting a larger study comparing HSCT to FDA-approved DMTs at three centers worldwide. The trial is currently enrolling, and interested patients can learn more at http://www.stemcell-immunotherapy.com/research_clinical.html.

Journal Reference: Richard K. Burt et al. Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis JAMA. 2015;313(3):275-284. doi:10.1001/jama.2014.17986.

Open access paper.

Photo: University of Utah Health Sciences

Mice with multiple sclerosis walk and run again after human stem cell treatment

In a feat that surprised even the scientists who made the experiment, mice disabled by a condition similar to multiple sclerosis (MS) began to walk and even run again after human stem cells had been transplanted. The findings could potentially offer new means of treating MS, a terribly disease which plagues some 2.3 million people worldwide.

Photo: University of Utah Health Sciences

Photo: University of Utah Health Sciences

Growing stem cells and new legs

University of Utah researchers first transplanted human stem cells with no particular beneficial expectations. The scientists thought the stem cells would be rejected in the first place, like most foreign cells by the host’s immune system, however something much more than this happened. The plagued mice began to walk again within a short period, 10 to 14 days, following the transplant.

“My postdoctoral fellow Dr. Lu Chen came to me and said, ‘The mice are walking.’ I didn’t believe her,” said co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, who began the study with co-first author Chen at the University of California, Irvine.

Multiple sclerosis (MS) is a potentially debilitating disease in which your body’s immune system eats away at the protective sheath (myelin) that covers your nerves. Damage to myelin causes interference in the communication between your brain, spinal cord and other areas of your body. This condition may result in deterioration of the nerves themselves, a process that’s not reversible.

Current treatments and drugs only concentrate on halting any of disease’s progress or ameliorating symptoms; once MS is in a later stage, it can not be reversed and there is no cure. Results from the study demonstrate the mice experience at least a partial reversal of symptoms. Immune attacks are blunted, and the damaged myelin is repaired, explaining their dramatic recovery.

“The way we made the neural stem cells turns out to be important,” said Loring, describing the reason behind the novel outcome.

The human neural stem cells send chemical signals that instruct the mouse’s own cells to repair the damage caused by MS. Experiments by Lane’s team suggest that TGF-beta proteins comprise one type of signal, but there are likely others. This realization has important implications for translating the work to clinical trials in the future.

“Rather than having to engraft stem cells into a patient, which can be challenging from a medical standpoint, we might be able to develop a drug that can be used to deliver the therapy much more easily,” said Lane.

Next, the researchers need to assess the long term effects of the human stem cell transplanted mice.

“We want to try to move as quickly and carefully as possible,” Lane continued. “I would love to see something that could promote repair and ease the burden that patients with MS have.”

Findings appeared in the journal Stem Cell Reports.

Big breakthrough in Multiple Sclerosis – man-first study shows promise

Multiple Sclerosis (MS) is one mean, hard, disease. It’s an autoimmune disease – your body basically fails to identify itself, and starts attacking itself, and treatment is very difficult.

In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be conducted properly and all sorts of problems start appearing – from mild numbness to paralisys.

white blood cell

“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”

Current MS treatments are pretty difficult, basically shutting down pacients’ immune systems, rendering them vulnerable to many other complications, like infections or even cancer. But in this Phase 1 clinical trial, the immune system wasn’t shut down and still managed to reduce patients’ immune systems’ reactivity to myelin by 50 to 75 percent.

“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”

In the trial, white blood cells were filtered out, processed, and then treated with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops.

More info about the study on Northwestern.