Saturday, April 26, 2008

DNA Vaccines May Offer Hope In MS

DNA Vaccines May Offer Hope In MS
Authors from the VA North Texas Health Care System Neurology Section and the Department of Neurology at the University of Texas Southwestern Medical Center at Dallas have highlighted the potential benefits for DNA-based vaccine administration in patients with multiple sclerosis (MS).


DNA vaccines may offer hope in multiple sclerosis
News-Medical-Net Thu, 24 Apr 2008 6:14 PM PDT
Authors from the VA North Texas Health Care System Neurology Section and the Department of Neurology at the University of Texas Southwestern Medical Center at Dallas have highlighted the potential benefits for DNA-based vaccine administration in patients with multiple sclerosis (MS).
Accelerating Biomarker Discovery And Disease Research With Tecan's Automated Hybridization Stations
BioresearchOnline Fri, 25 Apr 2008 6:24 AM PDT
Protagen AG, a provider of products, services and software solutions for protein research based in Dortmund, Germany, relies on two Tecan HS 4800 Pro Hybridization Stations for automated processing of its UNIchip protein arrays for antibody characterization, and for discovery of biomarkers relevant to diseases such as multiple sclerosis, rheumatoid arthritis and cancer indications

DNA vaccines may offer hope in multiple sclerosis
News-Medical.net - Sydney,Australia
The authors highlight a recent safety trial with BHT-2009 - the first trial with a DNA vaccine for an autoimmune disease in human patients - which showed it ...
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FSG Media Release: DNA Vaccines may offer hope in MS
PharmaLive.com (press release) - Newtown,PA,USA
The authors, Drs Olaf Stüve, Petra Cravens and Todd Eager, draw attention to recent clinical studies involving BHT-3009, a DNA vaccine encoding full-length ...
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Coronary victim ‘100%’ after stem cell trial
The Herald - Glasgow,Scotland,UK
Earlier this week, The Herald revealed the effects of multiple sclerosis could be reversed within 15 years using stem-cell treatment. ...
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Genentech's Rituxan Fails in MS Trial
FDA news (subscription) - Falls Church,VA,USA
... multicenter study was designed to evaluate the efficacy, safety and tolerability of four courses of Rituxan (rituximab) in 439 patients with PPMS. ...
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Breaking Ground In Discovering How Neurons Generate Movement
When the eye tracks a bird's flight across the sky, the visual experience is normally smooth, without interruption. But underlying this behavior is a complex coordination of neurons that has remained mysterious to scientists.


Critical New Information Added To Nursing Home Compare Web Site
Medicaid beneficiaries and families searching for top quality long-term care services can find critical new information added to the Centers for Medicare & Medicaid Services' (CMS) Web site "Nursing Home Compare.

Thursday, April 24, 2008

BEYOND and PRECISE Results Suggest Equivalence for Multiple Sclerosis Treatments


Susan Jeffrey


April 17, 2008 (Chicago, Illinois) — Final results of the largest multiple sclerosis (MS) trial to date suggest that, in terms of clinical effects, treatment with both 250- and 500-µg doses of interferon beta-1b (Betaferon/Betaseron, Bayer Healthcare Pharmaceuticals) as well as glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) were essentially equivalent in the risk of relapse in patients with relapsing-remitting MS.

Although there was some indication of reduced T2-lesion volume and number with interferon beta-1b, the researchers note, the long-term significance of this difference is unclear.

In a separate presentation, researchers reported full results of a randomized trial of glatiramer acetate vs placebo to prevent conversion to clinically definite MS in patients with clinically isolated syndromes (CIS). They report that fewer patients converted to clinically definite MS with treatment and those who did took longer to do so.

The full results of these studies, the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose (BEYOND) and PRECISE trials, were presented here at the American Academy of Neurology 60th Annual Meeting. Top-line results from the studies, both company-sponsored trials, were previously announced by the companies in October and December of 2007, respectively.

BEYOND Trial

The BEYOND trial compared the efficacy of 2 doses of interferon beta-1b, 250 and 500 µg, given subcutaneously every other day, with glatiramer acetate in patients with relapsing-remitting MS. This trial was funded by Bayer Schering Pharma AG, Berlin, Germany.

"The hypothesis was that the double dose of Betaseron would be more efficacious than the single dose, 500 µg better than 250 µg, in terms of efficacy, with comparable safety and tolerability," Paul O'Connor, MD, from the University of Toronto and St. Michael's Hospital, in Ontario, told Medscape Neurology & Neurosurgery. The 250-µg dose is currently approved in this indication.

A secondary hypothesis was to compare interferon beta-1b in these 2 doses with glatiramer acetate in terms of efficacy, safety, and tolerability, he said.

Patients eligible for the trial were relapsing-remitting MS patients with Expanded Disability Status Scale (EDSS) scores of 5.0 or less and 1 or more relapses in the year prior to study entry; all were treatment naive. A total of 2244 patients were randomized in a 2:2:1 ratio to the 500-µg dose (n=899), to the 250-µg dose (n=899), or to glatiramer acetate in a dose of 20 mg daily (n=448), also given subcutaneously for > 104 weeks. The average time of follow-up in the trial was about 2.3 years, Dr. O'Connor noted. Patients were evaluated clinically every 3 months and received a magnetic resonance imaging (MRI) scan every 12 months.

The primary end point was relapse risk. Results for this end point, he said, "showed that the performance of all 3 drugs was the same in terms of recurrent relapses, whether you did an intent-to-treat analysis or a per-protocol analysis."

The annualized relapse rate (ARR), a supportive end point, fell by almost 80% compared with the year prior to study entry, but without any intergroup differences, the authors note.

Other secondary end points, including time to confirmed disability and progression or change in "black-hole" volume on MRI, again showed no differences between groups, Dr. O'Connor added.

Some MRI end points did show differences favoring the interferon beta-1b treatment, he noted. The cumulative number of T2 lesions up to the last scan was greater with glatiramer acetate than with either the 500-µg dose (P = .001) or the 250-µg dose (P = .017) of interferon beta-1b. The relative increase in T2-lesion volume was also larger in patients on glatiramer acetate than in the 500-µg (P = .001) or the 250-µg groups (P < .001).

However, the authors write, the longer-term significance of these changes, "if any," is "unclear."

Dropout rates were highest in the high-dose interferon beta-1b group, at 19%; lowest with the lower dose, at 13%; and intermediate, at 17%, with glatiramer acetate. Adverse events were similar to the known profiles of these drugs — notably, flulike symptoms were more common with interferon beta-1b, and injection-site reactions including pain and pruritus were more common with glatiramer acetate.

Beyond the minor MRI differences and slightly different profile of adverse events, Dr. O'Connor noted, "the major message is really the similarity in behavior on efficacy measures of the 2 drugs.

"What this does is that it allows the patient and the doctor to decide more on the basis of items such as how often do you want to get injected or what matters more to you, a flulike symptom vs some soreness where you were injected?" he concluded. "In other words, you can choose on the basis of adverse events as differentiating features."

PRECISE Trial

In a separate presentation here, Giancarlo Comi, MD, from Vita-Salute San Raffaele University, in Milan, Italy, presented final results of the PRECISE trial, which examined the efficacy of early treatment with glatiramer acetate vs placebo in delaying the progression to clinically definite MS among patients with clinically isolated syndromes, a first event suggestive of MS. The study was supported by Teva Pharmaceutical Industries.

The trial, a randomized, controlled, multicenter study, randomized 481 patients with a first clinical event and at least 2 T2-weighted brain lesions at least 6 mm in size on MRI to receive 20 mg/day of glatiramer acetate given subcutaneously or placebo.

The primary end point was time to clinically definite MS based on a second clinical attack. A preplanned interim analysis was performed on data accumulated from approximately 80% of the 3-year study exposure. At that point, the data safety monitoring board, chaired by Dr. O'Connor, who presented the BEYOND results, recommended that the double-blind phase of the trial be stopped for efficacy of treatment with glatiramer acetate, and all patients moved onto active treatment.

Results of this interim analysis showed that treatment reduced the risk of developing clinically definite MS by 45% vs placebo: the 25th percentile time to clinically definite MS was prolonged by 115%, to 722 days with treatment from 336 days for placebo.

PRECISE Primary End Point

End Point Hazard Ratio 95% CI P
Time to clinically definite MS 0.55 0.40 – 0.77 .0005

The proportion of patients who converted to clinically definite MS was reduced from 43% of the placebo group to 25% in the treatment group (P < .0001). MRI activity, including the number of enhancing lesions and the number of new T2 lesions, was significantly lower in the glatiramer-acetate group, he added.

"So there are 2 advantages to treatment," Dr. Comi told Medscape Neurology & Neurosurgery. "About half of the patients didn't have a second attack, and those who had the attack had it about 1 year later compared with the others in a 2-year study. So it's a tremendous effect."

The drug was well tolerated, with adverse effects similar to those already known for this drug, with a 16% withdrawal rate at the interim analysis.

The Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, whose 3-year results were reported last year at this meeting and subsequently published (Kappos L et al. Lancet. 2007;370:389-397), showed a benefit from early treatment with interferon beta-1b in this same patient population, Dr. Comi noted. "Now we have a second drug with the same effect in this very early phase."

The patients will continue to be followed per the original protocol out to 5 years, he added. "It will be very interesting to see whether this very early beneficial effect will also lead to advantages in the mid and long term, and this 5-year extension will tell us something about that."

A Choice for Treatment

"There are 2 messages for me" from the combined results of these and the previously published BENEFIT trials, Dr. Comi, who was also a member of the steering committee for the BEYOND trial, told Medscape Neurology & Neurosurgery.

"One is that interferon beta and glatiramer acetate are both doing a very good job," he said. "Of course, some people do better with one, some with the other, and now if you fail with one, you can just try the other, and vice versa."

In addition, both agents have now been shown effective from the beginning of the disease, after first signs, to the end of the relapsing-remitting phase, he noted.

Important Result

Asked for comment on the PRECISE findings, Mark Keegan, MD, from the Mayo Clinic in Rochester, MN, called the result "important, as it shows that glatiramer acetate has a effect in reducing the likelihood of a second attack that is similar to the beta interferons, and it could be recommended in select patients with this presentation."

Similarly, results from the BEYOND study, showing no benefit of implementing a higher dose of interferon beta-1b over the traditional dose of 250 µg. "It also did not show any significant difference in attacks or progression between either dose of interferon beta-1b and glatiramer acetate," Dr. Keegan noted. "The important features are that those patients currently on the traditional dose of interferon beta-1b or glatiramer acetate should not need to alter treatments if they are doing well on their current therapy."

Dr. O'Connor has received compensation for activities with Biogen Idec, Cognosci, Serono, Teva, Berlex Labs, Genentech, Genzyme, Novartis, Roche and Sanofi-Aventis as a consultant. Disclosures for coauthors on the BEYOND trial appear in the abstract. Dr. Comi reports he has received personal compensation for activities with Teva Pharmaceutical Industries, Merck Serono, Bayer-Schering as a consultant and member of the scientific advisory board; Novartis as a consultant; and Sanofi-Aventis and Biogen-Dompé as a consultant and speaker. Disclosures for coauthors on the PRECISE study appear in the abstract. Dr. Keegan reports no conflict of interest.

American Academy of Neurology 60th Annual Meeting: Abstracts LBS.003, LBS.004. Presented April 16, 2008.



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Susan Jeffrey is the News Editor for Medscape Neurology & Neurosurgery and Medscape Psychiatry. Susan has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor for thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at sjeffrey@medscape.net.

Medscape Medical News 2008. © 2008 Medscape


Send press releases and comments to news@medscape.net.

http://www.medscape.com/viewarticle/573185?src=mp&spon=26&uac=60189CV

Stem cells 'to help beat MS in 10 years'

MS Society Comments on Stem Cells Story
Earthtimes - London,UK
Multiple sclerosis is the most common disabling neurological disorder affecting young adults and an estimated 85000 people in the UK have MS. ...
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Stem cells 'to help beat MS in 10 years'
Scotsman - United Kingdom
By HAZEL MOLLISON STEM-cell treatment could be used to help reverse the effects of multiple sclerosis within 10 to 15 years, a leading expert on the disease ...
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Stem cell research should be allowed
Irish Health - Ireland
... disease and multiple sclerosis. Stem cell research generally centres on cells that have been derived from human embryos because unlike adult stem cells, ...
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Scientists still looking for MS cause
Joliet Herald News - Joliet,IL,USA
By Jeanne Millsap special to the herald news Multiple sclerosis is another one of those mysterious diseases of the nervous system. ...
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Micromet Enrolls First Patient In A Phase 1 Clinical Trial With ...
ABN Newswire (press release) - Sydney,NSW,Australia
Additionally, EpCAM has been found on cancer stem cells of colon, breast, prostate and pancreas cancers. Cancer stem cells are believed to cause metastases ...
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Stem cells 'to help beat MS in 10 years'
The Scotsman Wed, 23 Apr 2008 4:01 AM PDT
STEM-cell treatment could be used to help reverse the effects of multiple sclerosis within 10 to 15 years, a leading expert on the disease said today.
Hormone therapy for MS?
WTHR Indianapolis Wed, 23 Apr 2008 2:20 PM PDT
Hormone therapy for menopause is under scrutiny for potentially negative side effects, but researchers are looking at possible benefits for multiple sclerosis patients.
Stem-cell treatment could reverse multiple sclerosis effects ‘within 15 years’
Daily Mail Wed, 23 Apr 2008 7:50 AM PDT
The effects of multiple sclerosis could be reversed with stem-cell treatment within 15 years, a leading expert on the disease said today. Professor Charles ffrench-Constant, the director of a groundbreaking MS research centre in Edinburgh, said the treatment could be used to help patients suffering from the condition that weakens their body’s central nervous system
Health: Pregnancy & Multiple Sclerosis
CBS 3 Philadelphia Wed, 23 Apr 2008 2:09 PM PDT
Paula Lizotte is a proud new mother who for years prior to being pregnant suffered with muscle weakness and pain. Her diagnosis was Multiple Sclerosis.
Stanford Research Shows That Inflammation Triggers Cell Fusions That Could Protect Neurons
Chronic inflammation triggers bone marrow-derived blood cells to travel to the brain and fuse with a certain type of neuron up to 100 times more frequently than previously believed, according to a new study from the Stanford University School of Medicine.

Wednesday's Earnings Downpour
FOXBusiness - USA
Biotechnology company Biogen Idec (BIIB) says its first-quarter profit rose 24 %, boosted by sales of its multiple sclerosis drug. The Cambridge, Mass. ...
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Biogen Idec Reports First Quarter 2008 Results
FOXBusiness - USA
Revenues from AVONEX, one of Biogen Idec's therapies for patients with relapsing forms of multiple sclerosis (MS), increased 19% in the first quarter to ...
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More Studies Show That Sleep Problems Are Likely To Cause Depression And Other Mental Health Problems
Mental Health Awareness Month, observed throughout May in the United States, increases awareness about mental illness such as depression. Mental illness is a significant health concern and, if left untreated, can have serious consequences.

New Campaign Launched During MS Week
The MS Society has launched this week's MS Week 2008 with a series of new adverts featuring images and words of people with multiple sclerosis (MS).The four new adverts encourage people living with the condition to explore the help that is out there, whether through the MS Society's branch network, self management courses, through online support forums, or via personalised care.


New York Times Examines Increasing Prices Of Specialty Drugs Distributed Exclusively By Pharmacy Benefit Managers

Main Category: Pharmacy / Pharmacist
Also Included In: Medicare / Medicaid / SCHIP
Article Date: 22 Apr 2008 - 7:00 PDT
The New York Times on Saturday examined how pharmacy benefit managers in recent years "have built lucrative side businesses ... acting as exclusive or semi-exclusive distributors of expensive specialty drugs." According to the Times, the practice is "seemingly at odds" with their stated intention of helping employers manage prescription drug plans and get drugs at the best prices available.
The prices of specialty drugs -- which treat diseases such as cancer, multiple sclerosis and hepatitis C, and can be regulated as federally controlled substances -- range from about $5,000 annually to about $389,000 annually, and have been rising "much faster" than prices for mainstream drugs, the Times reports. Many large employers say their spending on specialty drugs is growing at more than twice the rate of the rest of their employee drug benefits.
Gerry Purcell, a health benefits consultant serving large employers, said, "We are headed right down into conflict alley with these exclusive arrangements," because PBMs "can raise the prices at will," and "employers will have little chance but to pay the bill." PBMs say providing employers with the best drug prices is still their top priority and have defended their involvement in the pricing of specialty drugs as necessary to keep track of the medications' use (Freudenheim [1], New York Times, 4/19). Effect on Medicare
PBMs also offer coverage through the Medicare prescription drug benefit, "and so are profiting from federal spending on specialty drugs and from Medicare patients' own high out-of-pocket copayments," the Times reports. According to Jack Hoadley of Georgetown University, many Medicare drug plans require enrollees to pay 25 to 33 percent of a drug's price when it is part of a specialty drug tier. Richard Frank and Joseph Newhouse, senior health economists at Harvard University, in a report published in the January issue of the journal Health Affairs wrote that driven in part by specialty drugs, prices of medicines heavily used by the elderly have increased by more than 24% since June 2006. The article stated that the trend does not bode well for "the worrisome future financial health of Medicare" (Freudenheim [2], New York Times, 4/19).
Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
http://www.medicalnewstoday.com/articles/104875.php
Chemotherapy's Damage To The Brain Detailed By Researchers
22 Apr 2008  
A commonly used chemotherapy drug causes healthy brain cells to die off long after treatment has ended and may be one of the underlying biological causes of the cognitive side effects - or "chemo brain" - that many cancer patients experience. That is the conclusion of a study published in the Journal of Biology.
A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.
"This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function," said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. "Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients."

Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.
Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.
While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation's 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.
Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.
The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a "cocktail" with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.
The researchers discovered that months after exposure, specific populations of cells in the central nervous - oligodendrocytes and dividing precursor cells from which they are generated - underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.
Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.
These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients' brains revealed a condition similar to leukoencephalopathy. This demyelination - or the loss of white matter - can be associated with multiple neurological problems.
"It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system," said Noble. "Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects."
Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.
----------------------------
Article adapted by Medical News Today from original press release.
----------------------------
Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center.
Source: Mark Michaud
University of Rochester Medical Center

Article URL: http://www.medicalnewstoday.com/articles/104896.php

Main News Category: Cancer / Oncology

Also Appears In:  Neurology / Neuroscience,  Biology / Biochemistry,
http://www.medicalnewstoday.com/articles/104896.php

Wednesday, April 23, 2008

Stem cell cure hope for MS patients

Stem cell cure hope for MS patients
The Press Association -
Stem-cell treatment could be used to help reverse the effects of multiple sclerosis within 15 years, a leading expert on the disease has said. ...
See all stories on this topic

Scots health pioneers ‘will reverse MS damage in 15 years’
The Herald - Glasgow,Scotland,UK
The effects of multiple sclerosis could be reversed within 15 years using stem-cell treatment, the head of a groundbreaking Scottish research centre said ...
See all stories on this topic

Scots health pioneers ‘will reverse MS damage in 15 years’
The Herald Tue, 22 Apr 2008 4:16 PM PDT
The effects of multiple sclerosis could be reversed within 15 years using stem-cell treatment, the head of a groundbreaking Scottish research centre said yesterday.
Pregnancy hormone may protect MS patients
Belleville News-Democrat Tue, 22 Apr 2008 4:39 AM PDT
When women with remitting-relapsing multiple sclerosis (MS) become pregnant, they often can look forward to a double blessing
New Campaign Launched During MS Week
Medical News Today Tue, 22 Apr 2008 3:13 AM PDT
The MS Society has launched this week's MS Week 2008 with a series of new adverts featuring images and words of people with multiple sclerosis (MS).The four new adverts encourage people living with the condition to explore the help that is out there, whether through the MS Society's branch network, self management courses, through online support forums, or via personalised care.

Active Biotech upgraded to "buy"
newratings.com - Westerburg,Germany
FTY720 is unlikely to get an approval as a first-line treatment, the analysts say. Following this data from Novartis, the peak sales estimate for Laquinimod ...
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Daily Mirror - Colombo,Western,Sri Lanka
Mendis feels that there are other diseases that are neglected in our country which include Cerebral Palsy, Multiple Sclerosis and Alzheimer’s. ...
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ALSO NOTED: Stem cells can treat irregular heartbeats; Gene ...
FierceBioResearcher - Washington,DC,USA
... of new mouse models for autoimmune diseases such as multiple sclerosis and type 1 diabetes, in which the body attacks certain types of its own cells. ...
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Marathon efforts are big boost for charity
Petersfield Today - Petersfield,England,UK
Keith Budge, headteacher of Bedales School, was also running for Higgy’s Heroes, a multiple sclerosis charity charity run by Alastair Hignell, an ex-England ...
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Genentech And Biogen Idec Announce Top-Line Results From A Phase II/III Clinical Trial Of Rituxan In Primary-Progressive Multiple Sclerosis
Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced that a Phase II/III study of Rituxan® (rituximab) for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period.
Potential MS Therapy Advanced By Minnesota Partnership
A production laboratory founded by the Minnesota Partnership has transferred its first potential therapy - a medication for multiple sclerosis - to a processing plant in Minnesota. This step will complete purification of material to fully enable translation from preclinical to clinical development.
Idera Pharmaceuticals Presents Data From Study Of Toll-Like Receptor Antagonist In Preclinical Model Of Multiple Sclerosis
Idera Pharmaceuticals, Inc. (Nasdaq: IDRA), announced the presentation of data from studies evaluating a Toll-Like Receptor (TLR) antagonist in a preclinical model of multiple sclerosis (MS).
Genentech And Biogen Idec Announce Top-Line Results From A Phase II/III Clinical Trial Of Rituxan In Primary-Progressive Multiple Sclerosis
Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced that a Phase II/III study of Rituxan® (rituximab) for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period.
Vaccines 'Golden Era' Is Under Threat
The development of vaccines is on the verge of a 'golden era' - but it may be threatened if the drive to cut costs by governments, including the UK, is carried out regardless of long-term health consequences, a leading academic warned.
Mouse Studies Show Tumors Suppress Cells Responsible For Regulating The Immune System
New research has shown that the function of a type of cell that helps modulate immune responses is impaired inside tumors in mice. Researchers also identified several factors that may contribute to an accumulation of these cells, called T regulatory cells (Tregs), within and around the tumor, which may be how they respond to their loss of functionality.

Tuesday, April 22, 2008

The Immunology of Multiple Sclerosis

The Immunology of Multiple Sclerosis
Medscape (subscription) - USA
ICOS gene haplotypes correlate with IL10 secretion and multiple sclerosis evolution. J Neuroimmunol 2007;186:193-198 Kuchroo VK, Das MP, Brown JA, et al. ...
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Insurance firm offers to help MS sufferer afford needed drug
London Free Press - Canada
By JOHN MINER The owners of a London insurance brokerage have decided to buy an Exeter woman suffering from multiple sclerosis some added time in her battle ...
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Novartis shares soar as first-quarter profits beat forecasts
Pharma Times (subscription) - London,UK
... while filings for FTY720 (fingolimod), which has the potential to become the first oral therapy for multiple sclerosis, are expected at the end of 2009. ...
See all stories on this topic

Novartis reports higher sales and
Ad-Hoc-News (Pressemitteilung) - Germany
FTY720 (fingolimod), with potential to become the first oral therapyfor multiple sclerosis (MS), continued to demonstrate sustainedbenefits in patients with ...
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* Novartis on track in 2008:
Market Wire (press release) - USA
R&D investments rose 8%, with investments made in late-stage trials for development compounds including QAB149, QMF149, FTY720 and ACZ885. ...
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Earnings Preview: Biogen Idec's 1Q depends on MS drug sales
CNNMoney.com - USA
The quarter brought some safety concerns for the company's multiple sclerosis and Crohn's disease drug Tysabri. Biogen and its partner Elan Corp. reported ...
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Idera Pharmaceuticals Presents Data From Study Of Toll-Like Receptor Antagonist In Preclinical Model Of Multiple ...
Medical News Today Mon, 21 Apr 2008 2:15 AM PDT
Idera Pharmaceuticals, Inc. (Nasdaq: IDRA), announced the presentation of data from studies evaluating a Toll-Like Receptor (TLR) antagonist in a preclinical model of multiple sclerosis (MS).


Study on fingolimod shows positive results
PharmaBiz Mon, 21 Apr 2008 5:39 AM PDT
The investigational oral therapy FTY720 (fingolimod) continues to demonstrate sustained benefits in patients with multiple sclerosis (MS) after three years of treatment, according to new clinical data presented from an ongoing phase II study extension.
Potential MS Therapy Advanced By Minnesota Partnership
Medical News Today Mon, 21 Apr 2008 3:13 AM PDT
A production laboratory founded by the Minnesota Partnership has transferred its first potential therapy - a medication for multiple sclerosis - to a processing plant in Minnesota. This step will complete purification of material to fully enable translation from preclinical to clinical development.
Genentech And Biogen Idec Announce Top-Line Results From A Phase II/III Clinical Trial Of Rituxan In ...
Medical News Today Mon, 21 Apr 2008 1:16 AM PDT
Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced that a Phase II/III study of Rituxan® (rituximab) for primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period.

Pipex Pharmaceuticals Inc. drug for fibromialgia going to clinical ...
MLive.com - MI,USA
Pipex's main focus is to treat such diseases as multiple sclerosis, fibromialgia, Alzheimer's disease, Huntington's disease and Wilson's disease. ...
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The Immunology of Multiple Sclerosis

Amit Bar-Or, M.D., F.R.C.P.C.Semin Neurol.  2008;28(1):29-45.  ©2008 Thieme Medical Publishers

Posted

Abstract and Introduction
Abstract

Recent years have witnessed a remarkable growth in literature related to the biology and treatment of multiple sclerosis (MS). The focus of this article is on aspects of the human immune response that have been implicated in the MS disease process and, as a corollary, represent rational targets for the development of safe and effective therapies. Much of the thinking about immune pathophysiology in patients with MS has been shaped by studies in animal models of central nervous system (CNS) inflammation. Translation to the human disease has continued to pose challenges. A simplified model of MS immune pathophysiology is presented to illustrate the basic principles by which peripheral immune activation, as well as compartmentalized immune responses within the CNS, is likely to impact the disease process and to identify the putative sites of action of current and future MS treatments.

Introduction

Clinicians are faced with an ever-growing body of animal and human studies that may, at times, appear to be in conflict. It can be challenging to distinguish between insights into disease mechanisms and/or therapeutic strategies that are plausible based on animal or in vitro studies, and those that emerge from direct observations from patients. Animal studies continue to provide important insights into fundamental mechanisms of immune-neural interaction, and the use of such models, including experimental autoimmune encephalomyelitis (EAE), has become an expected part of the drug development process. Nonetheless, agents applied to multiple sclerosis (MS) clinical trials based on promising animal model data have at times proved ineffective or even harmful. Some potentially useful MS therapies may never be pursued because of a lack of measured benefit in preclinical animal model studies. The translation of findings from animal modeling to understanding mechanisms of human disease and putative therapeutic targets has remained problematic. More effort is being made to study disease biology and treatment responses directly in patients. Even the latter are not foolproof, however, because not all biological responses induced by a therapeutic agent, even if reliably measurable, are necessarily relevant to the disease itself. A further challenge is inherent in our growing appreciation of the biological heterogeneity that exists as part of the MS spectrum, and the notion that the predominant pathophysiological process may differ across patients, or even within a given patient at different times, during their illness.

A more complete understanding of MS pathophysiology requires consideration of the neurobiological aspects of disease and how complex immune-central nervous system (CNS) interactions contribute to both tissue injury and repair—themes that are beyond the scope of this article. Here, we consider some of the more prevalent assumptions regarding immune contributions to the distinct phases of MS. The focus is studies of human immunology and studies in patients with MS, occasionally drawing from animal model findings to underscore principles of immune-CNS interactions that are relevant to the human condition. In this context, we consider how well MS meets the defining requirements of an autoimmune disease.

Initiation of Multiple Sclerosis: How Firm is the Autoimmune Hypothesis?

The normal adaptive immune system (comprising T and B lymphocytes) has the capacity to recognize and develop efficient memory responses to specific antigenic targets. This system must efficiently and reliably discriminate between foreign antigens and components of self, or self-antigens. Within the normal T-cell and B-cell repertoires are cells that can recognize and react to self-antigens. These autoreactive cells are normally kept in check as part of the state of tolerance to self-antigens, and do not mount vigorous immune responses that could be harmful to the host. Why cells that can potentially respond to “self” exist in all healthy individuals remains unknown; it is likely that this normal state of autoimmunity serves important homeostatic functions. Dysregulation of the mechanisms that maintain tolerance to a person's own tissue antigens is considered integral to the emergence and propagation of autoimmune diseases.[1] Why some individuals develop autoimmune disease—and why there is selectivity toward particular target organs—is not known. The prevailing thought (Fig. 1) is that human autoimmune diseases (AIDs), including MS, manifest when certain environmental exposures (such as one or more common viruses) trigger immune dysregulation in genetically susceptible hosts (likely reflecting involvement of multiple risk-conferring and protective genes, each contributing relatively little to the overall susceptibility). The innate immune system, represented by a series of immune response elements capable of sensing and rapidly responding to perturbations in their environment, may be differentially expressed and triggered in different tissues. Innate responses are likely to have important influences on adaptive responses, at both the earliest time points in the disease process, as well as later in disease propagation and within the target organ.

Figure 1.

Immune pathogenesis of multiple sclerosis. An interplay exists between different environmental exposures and multiple genes that influence susceptibility at the levels of both the immune system and the target organ. These complex gene-environment interactions, occurring in early life, ultimately converge and lead to insufficient function of immune regulatory mechanisms, with subsequent loss of tolerance to self-antigens and the development and/or propagation of target-directed autoimmune disease (AID), such as multiple sclerosis (MS).

The classical description of MS pathology involving perivascular immune cell infiltration at sites of CNS injury has long since supported an autoimmune disease etiology for MS. However, because one of the main roles of the normal immune system is to respond to all forms of tissue injury, the mere presence of immune mediators within MS lesions does not necessarily mean that the immune system was responsible for initiating the disease process. For a disease to have a frank autoimmune etiology, several criteria must be met. These include: (1) the presence of immune mediators within sites of pathology in patients who have the illness, (2) the absence of such mediators in persons or tissues without the illness, (3) the ability of the putative immune mediators to adoptively transfer the disease, and (4) the demonstration that removal of these mediators has therapeutic effects. Although MS fulfills the first requirement quite well, relatively few features of MS lesions have been established as specific to the MS pathologic state. Moreover, unlike passive-transfer experiments in myasthenia gravis, in which patient serum can induce disease in recipient animals, similar findings have not been replicated when transferring MS serum or cells into animals. Normal animals do not appear to acquire EAE spontaneously (i.e., without immunization with CNS antigen). Transgenic mice engineered to have all their T cells respond to a specific myelin antigen can develop CNS inflammatory demyelination spontaneously,[2] and this occurs more efficiently when the animals' B cells are also modified to recognize the same antigen.[3] The rather unique circumstance required to observe spontaneous EAE favors a complex, multifactorial etiology for the development of MS in the comparatively nonsterile and out bred human population.

The current ability of immune-directed therapies to favorably impact MS patients lends support for a pathogenic role of immune responses. However, the observation that even aggressive immune suppression or immune ablation does not appear to completely abrogate MS progression invokes pathogenic mechanism(s) that may be relatively independent of peripherally mediated autoimmune responses. These may reflect an important CNS-compartmentalized component of MS pathophysiology (local inflammation and/or degeneration) that can be relatively resilient to peripheral immune intervention and may be particularly dominant later in the disease process (Fig. 2). It has not been firmly established whether the very initial abnormalities in MS are inherent to the immune system or to the target organ.

Figure 2.

Peripherally mediated and central nervous system (CNS)-compartmentalized immune responses in multiple sclerosis (MS)—relationship to MS disease course. The common clinical course in MS (top panel) involves relapses and remissions in the earlier stages of illness, and subsequently progressive worsening occurs without clinically evident relapses and remissions. Imaging parameters applied during the clinical course (bottom panel) can track the accumulation of T2 hyperintense lesion volume (green) as a marker of disease burden, as well as identify time points (arrows) when gadolinium-enhancing lesions are present, reflecting local breach of the blood-brain barrier, a measure of active inflammation. However, an imaging:clinical dissociation exists because later in the disease course progression of disability occurs despite decreased accumulation of further T2 lesion burden and the appearance of fewer new gadolinium-enhancing lesions. This points to the presence of at least two distinct biological mechanisms underlying CNS tissue injury in MS (middle panel). Earlier in disease course, peripherally mediated waves of inflammation prevail, corresponding to some clinically manifest relapses and remissions. Later in disease, ongoing injury predominantly relates to CNS-compartmentalized processes that likely include local (CNS-compartmentalized) inflammatory responses and CNS degeneration.

Thus, although not straightforward indicators that faulty immune regulation is the primary initiating event or a secondary response in MS, the presence of inflammatory mediators at sites of CNS pathology and the observations that immune manipulation in patients can both aggravate or diminish disease activity argue that immune responses do play an important role in MS pathophysiology and are not merely epiphenomena of CNS tissue injury. How such immune mediators may contribute to MS relapses, remissions, and disease progression is considered in the following sections.

Peripheral Immune Activation: The Presumed Trigger of Multiple Sclerosis Relapses

In MS, the immune system is separated from the CNS target by the blood-brain barrier (BBB) (Fig. 3), representing the typical three-compartment model of immune-mediated disease. A key event in the triggering of an MS relapse is thought to be the activation outside the target organ (Step 1) of T cells that can recognize antigens in the CNS. Through a sequence of subsequent events, these activated immune cells then undergo more efficient adhesion to the endothelial barrier (Step 2), attraction (Step 3), and active invasion (Step 4) into the target organ where they may become reactivated (Step 5) and subsequently participate in the disease process (Step 6). The differentiation state and functional response profile of the invading cells (defined in part based on the profile of cytokines they produce, their cytotoxic machinery, etc.) determines whether they contribute to injury or, possibly, counter the injury process. Immune responses may also be propagated within the CNS itself by previously infiltrating peripheral cells that then become chronically activated and/or by chronically activated CNS resident cells such as microglia. Such CNS-compartmentalized inflammation may become relatively independent of ongoing peripheral events. This simplified model is used as a framework to discuss how abnormalities at each of these steps may contribute to the MS process and how targeting one or more of these steps may be of therapeutic benefit.

Figure 3.

Immune responses contributing to multiple sclerosis (MS) propagation. Immune cells activated in the periphery, including T cells, myeloid cells, and B cells, (Step 1) upregulate surface molecules that enable them to more efficiently adhere (Step 2) to the endothelial cells of the blood-brain barrier (BBB) and respond to local chemokine gradients (Step 3). Active secretion of matrix proteases (Step 4) facilitates immune cell invasion into the CNS where they may become reactivated (Step 5) and impact on the biology of central nervous system (CNS) elements (Step 6). These steps also represent rational therapeutic targets for MS therapies. Immune responses may also be propagated within the CNS by previously infiltrating peripheral cells that then become chronically activated and/or by chronically activated CNS-resident cells such as microglia. This CNS-compartmentalized inflammation may take place independent of ongoing peripheral events. Therapeutic targeting requires treatments that result in modulating inflammation within the CNS.

The concept that triggering an autoreactive immune response in the periphery could translate into a CNS inflammatory attack in humans was first considered following Pasteur's introduction of a neural tissue- containing vaccine as a therapy for rabies that resulted in episodes of acute disseminated encephalomyelitis (ADEM) after vaccination.[4] This led to the development of the commonly used EAE model of MS in which peripheral immunization with myelin components (including myelin basic protein [MBP], myelin-oligodendrocyte glycoprotein [MOG], and proteolipid protein [PLP]) can induce inflammatory demyelination of the CNS.[5-7] EAE can also be induced in naïve animals by means of “adoptive transfer” of activated (but not resting) myelin reactive CD4* T cells from animals with established disease.[8] The particular phenotype of EAE, including anatomic predilection (spinal cord or optic nerve) and clinical patterns (relapsing and chronic), depends on the genetic background of the animal strain, the specific antigen selected, and the immunization regimen.[7] The experience with EAE and other animal models established that peripheral activation of CNS autoreactive T cells can result in a CNS inflammatory disease. Based on these animal studies, initiation of the MS process (or at least an MS relapse) is thought to involve activation of auto-aggressive, CNS-directed T cells in the periphery.

To become activated, T cells recognize antigens that bind with sufficient affinity and avidity to their T-cell receptor (TCR). The appropriate antigen fragment must be “presented” to the TCR within the pocket of the major histocompatibility complex (MHC) molecule, expressed on the surface of antigen-presenting cells (APCs) (Fig. 3, Step 1). Effective APCs include dendritic cells, monocyte/macrophage B cells, and CNS microglial cells. Appropriate binding of the antigen-MHC to the TCR delivers an activating signal to the T cell (termed “signal 1”). However, this signal 1 alone is usually not sufficient for full T-cell activation. Costimulatory signals (collectively referred to as “signal 2”) are also required and may be delivered by APCs that express costimulatory molecules on their surface. Typically, a T cell stimulated only via signal 1 (in absence of costimulation) may become anergic, resulting in an inability to subsequently respond to the antigen. In contrast, a T cell receiving both signal 1 and signal 2 may become fully activated, resulting in proliferation, secretion of cytokines and other effector molecules, acquiring cytotoxic capacity, and so forth. These functions may, in turn, impact the target organ directly or through modulation of other immune cell functions. When APCs are exposed to factors such as infectious particles, for example through toll-like receptors (TLRs), various other inflammatory mediators, or injured tissue, they become activated and upregulate their surface expression of costimulatory molecules.[9]

Several families of costimulatory molecules and their receptors are thought to play key roles in regulating immune responses in both health and disease. One important costimulatory pathway is represented by the CD28 or CTLA-4 molecules on T cells, being engaged by the CD80 (B7.1) or CD86 (B7.2) costimulatory molecules expressed on APCs. Engagement of CD28 by B7 molecules stimulates the T cell, while the same B7 molecules engaging CTLA-4 mediates an inhibitory signal. Other costimulatory molecules, with either proinflammatory or antiinflammatory effects, have been described and implicated in MS.[10-19] Whether a T cell becomes productively activated or suppressed depends on the integration of signals mediated by the TCR and the profile of costimulatory molecules available in the particular microenvironment.[20-22] Targeting costimulatory pathways provides an attractive therapeutic approach.[23-25]

The normal immune system has the capacity to generate very different response profiles, depending on the local needs. For example, the same naïve T cells can differentiate into functionally distinct subsets defined based on their distinct effector cytokine responses. In addition to integrating signals mediated by the TCR and the costimulatory profile, the presence of distinct cytokines during T-cell activation provides important contextual cues that can define the subsequent T-cell response. Cytokines released by APCs, including interleukin (IL)-12 and IL-23, can preferentially generate T-helper type 1 cells (Th1) that subsequently secrete IFNγ.[26] These T cells are effective as part of the normal antiviral response.[27-29] T cells that initially become activated in the presence of IL-4 and in the absence of IL-12 or IL-23 subsequently produce cytokines, including IL-4, IL-5, and IL-13. These are defined as “Th2 cells.” As part of the normal immune response, Th2 cells and their effector cytokines are important in containing parasitic infections. Additional types of effector T cells, such as ThIL-17 cells, are being identified based on distinct effector profiles and molecular mechanisms that generate them.[30-32] Furthermore, several CD4 and CD8 regulatory T-cell (Treg) subsets, including thymic-generated natural Tregs (nTregs), inflammation-induced Tregs (iTregs), and human leukocyte antigen-E (HLA-E) expressing CD8 T-cell subsets, are viewed as critical regulators of normal immune responses.[33-41]

As a corollary to the normal functions of the cell subsets noted in the previous paragraph, a dysregulation in the body's normal balance between effector (Th1,Th2, ThIL-17) responses, or deficiencies in regulatory functions, can result in disease states. The roles of natural killer (NK) cells, NK T cells, and γδ T cells in MS are also under investigation.[42,43] Abnormal activation or regulation of Th1, and more recently ThIL-17 responses have been implicated as pathogenic in several target directed autoimmune diseases, including MS and its EAE animal model.[31,44,45] In EAE, proinflammatory CNS-autoreactive T cells can adoptively induce disease, whereas transfer of Th2 cells reactive to the same CNS antigens, or TGFβ-producing Th3 cells, does not usually induce disease. Moreover, the Th2 or Th3 cells may protect the animal from getting the disease. By extension, it has been suggested that in MS, CNS-directed Th1 or ThIL-17 responses may be proinflammatory and cause damage, whereas Th2 or Th3 responses may be antiinflammatory and possibly protective.[24,46-49] Abnormalities in regulatory cell subsets have been implicated in several autoimmune diseases including MS, such as deficiencies in CD25hiFoxP3* CD4 T cells (nTregs),[36,50-52] IL-10-producing T regulatory type 1 (Tr1) cells,[37,53] and HLA-E-restricted CD8 suppressors.[38,39,54]

Several established MS therapies, including β-interferons and glatiramer acetate, are thought to mediate part of their benefit by shifting immune responses in patients from Th1 to Th2 responses (Th2-immune deviation), and/or by promoting function of regulatory immune cells. Similar strategies continue to be pursued.[24,25,55] It should be kept in mind that unchecked Th2 responses may contribute to asthma or atopic conditions, and under certain situations even to exacerbation of CNS inflammation.[56,57] With regards to enhancing regulatory T-cell functions, it is of interest whether such a strategy will impact already differentiated autoaggressive cells.[58,59] Whether CNS antigen-specific regulation can be selectively enhanced in MS is relevant because it also remains to be seen whether over-aggressive induction of broad regulatory immune functions may result in insufficient antiviral or antitumor host responses.

Target-specific regulation of the immune response is predicated on defining the specific CNS antigens involved in the MS disease process. To date, no single CNS antigen has been established as the major MS target. It is likely that the predominant targets differ across patients and, indeed, change within the same individual over time, for example from one relapse to another (epitope spread). Multiple CD4 T-cell targets have been implicated in MS including myelin antigens such as MBP, MOG, and PLP.[60-65] As noted previously, the mere presence of CNS-reactive T cells is not sufficient to cause disease.[66-68] Studies comparing properties of CNS-reactive T-cell responses between MS patients and healthy controls have generally revealed considerable overlap in frequencies and functional profiles. On the average, it appears that myelin-reactive T cells from patients can be found circulating in a higher state of activation,[69,70] require less costimulation,[71,72] tend to be of higher avidity,[70] and preferentially belong to the memory T-cell pool.[73-75] There is also some evidence that MBP-reactive T cells isolated from MS patients are more likely to produce proinflammatory (Th1), rather than antiinflammatory mediators.[76,77] A limitation of such studies in adults with MS relates to the long duration between sampling for immune studies and biological disease onset. Identification of abnormal CNS-directed immune responses in adult patients may, at least in part, be influenced by epiphenomenon of chronic immune dysregulation. Studies in pediatric-onset MS capture a unique and early window of the autoimmune disease pathophysiology. A recent comparison between childhood-onset CNS inflammatory disease and type-1 diabetes (T1D) reveals abnormally enhanced T-cell responses to selected target and environmental antigens. Results suggest that abnormal T-cell responses are not always restricted to disease target antigens, pointing to a more general state of dysregulation. However, a marked degree of specificity is also seen in the study, with abnormal responses to particular mil-antigen peptides in children with one autoimmune disease but not the other.[78]

Much of the focus over the years has tended to center on the role of CNS autoreactive CD4 Th cells, in part because of technical difficulties in maintaining CD8 cytotoxic T cells in culture. Pathologically, however, a prominence of CD8 over CD4 T cells is reported within MS lesions.[79,80] Newer cellular and molecular approaches are being developed.[81,82] It can now be demonstrated that specific CD8 (rather than CD4) T cells are expanded and persist long term within the CNS compartment of patients.[79,83] Higher frequencies of CNS-specific autoreactive CD8 T cells have also been reported in the circulation of MS patients compared with controls.[84-86] It is noteworthy that CNS-reactive T-cell responses may not always be detrimental.[87-91] Indeed, immune responses in MS are not all bad or all good—adaptive response to injury and promotion of repair represent major roles of the normal immune response. The challenge is to appropriately develop and apply immune-modulating therapies that minimize CNS-directed injury and maximize beneficial responses.

The most direct evidence in patients with MS that peripherally activated CNS-autoreactive T cells participate in the disease process is available through careful immune studies of patients treated with an altered peptide ligand (APL) of MBP. The use of APLs represents a form of antigen-specific therapy in which a peptide antigen is altered by replacing one or more of its amino acids. T cells recognizing a particular antigen may also recognize an APL of that antigen, although the T-cell response to the APL may be considerably different than to the native antigen. In EAE, an APL of MBP led to a Th2 shift in MBP reactivity associated with improved clinical outcomes.[92,93] Subcutaneous injection of the same APL in a Phase II placebo-controlled trial of MS was found to induce the anticipated Th2 responses to MBP, and suggested possible benefit on magnetic resonance imaging (MRI) outcomes.[94] However, in another trial, a higher dose of the same APL was associated with significant increases in MRI activity in several patients, with or without clinical correlates.[95] In these patients, elegant immune monitoring identified a strong induction of both APL-reactive T-cell responses and enhanced MBP-directed responses, both in the periphery and in the cerebrospinal fluid (CSF) of patients. These MBP-reactive T cells were notable for their production of high levels of the Th1 cytokine, IFNγ. Although further insights are required to strike the optimal balance of efficacy and safety with APL therapy, these studies provide the most direct evidence that myelin antigens such as MBP are likely targets in MS, and that peripheral modulation of CNS-directed immune responses can translate into modulation of immune responses within the CNS. Indeed, newer antigen-specific approaches are being pursued, including DNA-vaccine technology, that enable presentation of myelin antigens to the immune system of patients in an immune downregulatory context.[96,97] The biological proof-of-principle for an MBP-based DNA vaccine in MS has recently been generated in a Phase I/II study.[98]

Where and how do CNS-reactive T cells become activated in the periphery of patients with MS? Such activation may occur when circulating CNS autoreactive cells encounter fragments of CNS self-antigens that are released, or carried, by APC, for example into the cervical lymph nodes that drain the brain.[99-101] “Molecular mimicry” represents another mechanism by which CNS autoreactive T cells can become activated when they encounter fragments of foreign (nonself) antigens that are sufficiently similar to their cognate CNS self-antigen. Some human MBP-reactive T cells have been shown to respond to antigenic fragments derived from common viruses (including herpes simplex, Epstein-Barr, and influenza viruses) presented by the same MHC molecules.[102] Extending the concept of molecular mimicry is the phenomenon of “structural equivalence,” wherein two different MHC molecules (encoded by the individual's two MHC alleles) bind two distinct antigens (self and foreign), creating two antigen-MHCs that may be sufficiently similar in structure that they are both recognized by the same CNS-reactive T cell.[103] The following sections focus on the molecular mechanisms that regulate the infiltration of peripherally activated immune cells across the BBB and into the CNS.

Immune Cell Interaction with the Blood-Brain Barrier: Adhesion, Attraction, and Invasion

On activation, immune cells upregulate the expression of a series of molecules that are tightly regulated to facilitate cellular migration across endothelial barriers and into the target organ (Fig. 3).[104,105] Upregulated selectins and integrins on the activated immune cells interact with ligands expressed on the endothelial cells of the BBB, resulting in immune cell “rolling” and “tethering/arresting,” respectively (Fig. 3, Step 2). Chemokines are secreted by endothelial cells, by injured tissue, or by the activated immune cells themselves, and can promote integrin activation and further contribute to cell arrest.[106] Chemokines also attract cells expressing the corresponding chemokine receptors toward the source of the chemical gradient (Step 3). Production of tissue lytic enzymes (Step 4), such as the matrix metalloproteinases (MMPs), results in breakdown of the basement membrane and facilitates infiltration of immune cells into the CNS parenchyma.[107] Selected studies implicate these molecular steps in disease pathogenesis and potential therapeutic targets.

Implicating Adhesion Molecules in Multiple Sclerosis. In MS lesions, endothelial cells have been shown to express abnormally elevated levels of adhesion molecules, including intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. These elevated levels correlate with the extent of immune cell infiltration.[105,108-110] Their ligands for these adhesion molecules (lymphocyte function-associated antigen [LFA]-1 and very late antigen [VLA]-4, respectively) have been identified on the perivascular inflammatory cells within MS lesions.[111] These observations and proof-of-principle studies in animal models provided the basis for development of antiadhesion molecule therapies in MS, including the anti-VLA-4 antibody, natalizumab. The clinical trial program of natalizumab confirmed impressive efficacy results with this strategy; however, enthusiasm has been tempered by the emergence of cases of progressive multifocal leukoencephalopathy (PML).[112] Observations in a small number of immune monitoring studies in patients have demonstrated that: (1) the effects of natalizumab infusion do not appear to fully saturate the VLA-4 expressed on circulating immune cells, and that the degree of saturation varies across patients;[113] (2) trafficking of CD4 T cells into the CNS is more significantly impacted than CD8 T cells, resulting in a reversal of the CD4/CD8 ratio in the CSF;[114,115] and (3) natalizumab infusion alters not only the trafficking capacity of immune cells but also their activation threshold.[113] In this regard, it is interesting to note that the adhesion molecules VCAM-1 and LFA-1 are also expressed on glial cells within MS lesions,[116] possibly pointing to additional roles for these molecules in antigen presentation and T-cell costimulation.[111,117,118]

Selective Expression of Chemokines and Chemokine Receptors in Multiple Sclerosis. A complex network of chemokines and chemokine receptors regulates movement of immune cells within and between tissues. Such chemokine-chemokine receptor interactions are also involved in the trafficking of immune cells into the CNS as part of normal immune surveillance, and also in context of the CNS inflammation of patients with MS (Fig. 3, Step 3).[119,120] Studies in both EAE and MS have implicated certain chemokines in the selective CNS recruitment of T cells and monocytes/dendritic cells.[121] In active MS lesions, RANTES (regulated on activation, normal T-cell expressed and secreted) (CCL5), which is chemotactic for lymphocytes and monocytes expressing chemokine receptor (CCR)5, is upregulated at the lesion edge;[122] whereas MCP-1 (CCL2), a chemokine that attracts monocytes expressing CCR2, is expressed by local astrocytes.[123] Compared with neurological controls, MS patients' CSF contains elevated levels of interferoninducible protein (IP)-10 (CXCL10) and CCL5, both of which are chemotactic for activated T cells expressing the chemokine receptor CXCR3.[124] An increased frequency of CD4* and CD8* T cells from the CSF of MS patients were seen to express CXCR3. Tissue-based studies confirmed increased expression of CXCR3 as well as CCR5 on immune cells infiltrating around vessels within MS lesions. Together these observations suggest that CCL2/CCR2, CXCL10/CXCR3, and CCL5/CCR5 interactions may be selectively involved in MS pathogenesis. Some reports suggest preferential contribution of selected chemokines to the trafficking of proinflammatory Th1 T-cell populations,[122,124-127] although this may not always be the case for individual T cells.[128] Careful studies of cell subsets demonstrate that the majority of CSF T cells in MS patients are memory T cells that express CCR7, consistent with a central memory phenotype of cells that participate in immune surveillance. Within the MS lesions themselves, T cells tend not to express CCR7, consistent with an effectormemory phenotype. Many cells with a maturing dendritic cell phenotype (expressing MHC class II, CD68, CD86, and the chemokine receptor CCR7), are present both in the CSF and within the MS lesions.[101] Together, these findings support a model in which the afferent limb of CNS-directed immune responses involves entry of dendritic cells that mature when they capture CNS antigens within MS lesions. The maturing dendritic cells then migrate via the CSF into the deep cervical lymph nodes, where they may present CNS antigens to T cells. The T cells turn into central memory (CCR7*) cells, which infiltrate and participate in the efferent limb of CNS immune responses. On subsequent restimulation by antigen within the CNS compartment, these cells downregulate CCR7 and become CCR7-effector memory T cells that are retained within the MS lesions where they contribute to the disease process.[101,120,129] The chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1) may be particularly relevant in regulating B-cell migration into, and possibly persistence within, the CNS.[130]

Selective Expression of Matrix Proteinases in Multiple Sclerosis. The family of matrix proteinases (MPs) is comprised of tightly regulated proteolytic enzymes, including the MMPs, the related ADAM (a disintegrin and metal-loproteinase) molecules, and tissue inhibitors of matrix proteases (TIMPs). Collectively, these molecules contribute to diverse biological processes such as normal organ development, tissue remodeling, and immune responses. Activated immune cells are able to migrate across barriers such as the BBB and into the extracellular matrix of the CNS, in part, based on the local production of lytic enzymes (Fig. 3, Step 4). Dysregulation of MP molecules may contribute to abnormal tissue invasion by immune cells.[107,131-133] Both MMPs and ADAMs are typically produced as proenzymes requiring proteolytic cleavage to become activated. The TIMPs function to downregulate the MP effects.[134] Expression of MPs is also seen in CNS glial cells such as astrocytes and microglia.[135-137] The MP family molecules may contribute to the MS process by: (1) facilitating infiltration of immune cells by disrupting the BBB basement membrane and extracellular matrix;[134,135] (2) activating membrane-bound proinflammatory cytokines, such as tumor necrosis factor (TNF)α, by cleaving them off the cell surface;[138,139] and (3) directly damaging CNS structures.[140] It should be kept in mind that certain MPs may also be required during processes of repair and regeneration within the CNS.[107,141,142] Increased activity of several CSF MMPs has been reported in MS patients compared with controls;[143,144] gelatinase B (MMP-9) levels are abnormally elevated in both the serum and CSF of MS patients, particularly during acute relapses. A correlation exists between the elevated levels of MMP and the degree of BBB disruption assessed as the number of gadolinium-enhancing MRI lesions.[145,146] Distinct expression profiles of MPs are found in T cells, B cells, and monocytes when purified cell subsets from patients with MS and from controls are examined.[147,148] Of interest, monocytes express a broader range and often higher amounts of different proteolytic enzymes compared with T cells and B cells, which is consistent with the observation that invading monocytes/macrophages are major contributors to the MS inflammatory lesions.[147] Microglia appear to produce even higher amounts of MPs, and this production may in turn regulate their effector cytokine expression.[149]

It is important to keep in mind that the multistep molecular interactions involving adhesion molecules, chemokines, and MPs is fundamental to normal processes of immune surveillance and adaptive immunity. Dysregulated expression and/or function of these molecules may contribute to the pathology of MS. Efforts are aimed at elucidating how targeting these molecular interactions may therapeutically regulate trafficking of particular cell subsets, while minimizing the impact on normal immune functions.

Activation (and Reactivation) of Immune Cells within the Central Nervous System

CNS-reactive T cells may be activated (or reactivated) within the CNS itself (Fig. 3, Step 5). It is well accepted that under normal physiologic conditions, lymphocytes traffic into the CNS.[150-152] Resident CNS microglial cells, both perivascular and parenchymal, have been identified as competent APCs.[7,49,153,154] Antigen presentation could thus be accomplished by resident cells or by invading monocytes/macrophages and dendritic cells.[155-158] Dendritic cells have emerged as important myeloid APCs in the context of CNS inflammation.[159-163] The migration of monocytes across the BBB may be associated with dendritic cell differentiation, which may result in unique APC populations in a subendothelial distribution.[164,165] B cells represent another potential source of APCs capable of presenting antigens to T cells in both the periphery and within the CNS. Studies of CSF and the meninges of MS patients have revealed chronically activated B cells/plasma cells that are organized in structures resembling germinal centers and express high levels of costimulatory molecules.[166] The presence of inflammatory factors produced within the CNS, including cytokines, chemokines, and matrix proteases, can stimulate invading APCs, as well as primed T cells and B cells, in the process called “bystander activation.” Abnormal costimulatory molecule profiles may contribute to the abnormal activation of CNS autoreactive T cells, both within and outside of the CNS. Expression of CD80 (B7.1) is reported to be selectively upregulated in MS plaques,[167,168] and CD80 but not CD86 (B7.2) was found upregulated on immune cells in CSF and peripheral blood of MS patients compared with controls.[169] CD80 and CD86 may preferentially activate Th1 and Th2 responses, respectively, and blockade of CD80 in EAE inhibited disease induction.[20,170,171] Tissue damage may further expose CNS components that can then become targets of subsequent immune attack (epitope spread), possibly contributing to clinical relapses.[172]

Active immune responses could impact on the integrity of CNS myelin, oligodendrocytes (OLGs), and neural elements by several distinct mechanisms (Fig. 3, Step 6, and Table 1 and Table 2 ). CD4 and CD8 T cells can mediate antigen-specific injury to targets that they recognize. Autoreactive antibodies may contribute to antigen-specific injury through complement fixation or antibody-directed cytotoxicity (ADCC). In vitro studies suggest that CD4 and CD8 T cells may also impact the health of neurons by nonspecific cytotoxic mechanisms.[173,174] Injury to neural elements may also be mediated indirectly, for example, efficient killing by NK cells of supporting astrocytes, resulting in secondary compromise to neurons.[175] A variety of soluble factors, including proinflammatory cytokines, glutamate, matrix proteases, nitric oxide, oxygen radicals, and proapoptotic signals may also mediate injury in a non-antigen-dependent way.[49,75,88,176]

Involvement of Antibody-Dependent and -Independent B-Cell Responses in Multiple Sclerosis. As members of the adaptive immune system, B cells, like T cells, have the capacity to recognize particular antigens through their surface B-cell receptors (BCRs). The typical sequence of normal B-cell activation involves encounter with the specific antigen that binds the BCR followed by T-cell help, which involves engagement of CD40 on the B-cell surface by CD40L expressed on the activated T cell. The B cells may then proliferate and differentiate into memory B cells as well as plasma cells that secrete antibodies (immunoglobulins [Igs]), and contribute to the humoral immune response against the stimulating antigen. The potential role of B cells in MS pathophysiology has generally been considered based on their potential to react to particular CNS antigens and subsequently produce CNS-directed auto-antibodies. The CSF of MS patients has long since been known to contain abnormally elevated levels of Ig, typically displaying a pattern of oligoclonal bands (OCBs) on an electrophoretic gel. The presence of deposited Ig and complement molecules is reportedly a common occurrence in MS lesions;[177,178] in both MS and EAE, antibodies bound to fragments of myelin are found within phagocytic cells at sites of demyelination.[179] Consistent with the oligoclonal Ig pattern, somatic hypermutation and clonal analysis of cells found within MS CSF and lesions indicate that particular B-cell clones are expanded in response to antigenic encounter within the CNS compartment. Together, these findings point to contribution of complement-mediated injury and ADCC, mediated by CNS-specific antibodies in MS.[180,181] The antigenic specificity of the OCB in MS has been challenging to elucidate. A series of elegant molecular and cell-based approaches have shown that at least a portion of the CNS Ig appears to bind myelin targets, including MOG.[182-185] Meaningful analysis of serum antibodies against MOG requires assays that use conformationally true epitopes.[183-186] Serum antibodies against CNS myelin components such as MBP appear to be of relatively low affinity.[187] It is not clear whether such antibodies directly contribute to pathogenesis; they may be generated as a consequence of tissue injury and as such, may provide a marker of how aggressive the inflammatory process is.[188,189] It has also been suggested that certain CNS-directed antibodies may actually be beneficial, such as through the support of remyelination[190,191] or by helping to remove debris— including growth inhibitory molecules such as Nogo[192]—thereby providing a more permissive environment for axonal regeneration.

B-cell contributions to MS have also been considered beyond their capacity to become antibody-producing cells. For example, B-cell subsets have been identified that can function as effective APCs to T cells,[193] and normal human B cells are now recognized to actively contribute to the regulation of immune responses through secretion of distinct effector cytokine profiles in a context-dependent fashion.[194-196] In patients with MS, the meninges and CSF are found to contain chronically activated B cells[65] in structures reminiscent of germinal centers that may promote ongoing T-cell activation and propagation of the MS disease activity.[166,197,198] A deficiency in the ability of MS patient B cells to produce the downregulatory cytokine IL-10 has been reported,[199] implicating them directly in the dysregulated MS immune process. Promising results from early-phase MS studies of B-cell depletion with rituximab (anti-CD20 antibody) further support a role for B cells in disease pathogenesis,[200,201] and the rapid onset of action of this strategy (without obvious effects on Ig levels) suggests that antibody-independent functions of B cells likely contribute to the observed therapeutic effect. In the context of B-cell-targeted therapy, it is noteworthy that the molecular interactions that underlie human B-cell entry into the CNS (involving adhesion molecules, chemokines, and MMPs) partially overlap with, but are not identical to, those employed by T cells.[147,148] This becomes relevant when considering the impact of T-cell-directed therapies on B-cell physiology, as well as the optimal approach to the development of B-cell-directed therapies.

Contribution of Immune Responses to Remissions. Recovery from an MS relapse involves both immune and nonimmune mechanisms. Nonimmune mechanisms include redistribution of sodium channels on demyelinated nerve fibers,[202] recruitment of myelinating cells, and remyelination,[203] as well as axonal regeneration and reorganization of networks.[204] Immune mechanisms that contribute to recovery include active resolution and/or suppression of the injurious inflammatory processes and promotion of immune responses that may support protection and repair. Resolving active inflammation requires clearance of infiltrating immune cells from the CNS through either emigration or through in situ apoptosis. This limits further injury and enables reversal of acute edema. The balance between proinflammatory and proretention factors and the profile of proapoptotic and antiapoptotic molecules together determine whether activated immune cells persist within MS lesions and whether they are available to impact on recovery.[88]

As noted previously, active immune responses are not necessarily detrimental during CNS inflammation. Table 2 identifies several ways in which immune mediators may be beneficial in MS. Particular immune responses may suppress or downregulate others: Th2 cytokines are known to inhibit Th1 differentiation, and may thereby limit proinflammatory Th1 responses through “bystander suppression.” Modulation of infiltrating monocytes/macrophages and a resident microglia toward a type-2 APC phenotype could promote antiinflammatory Th2 responses within the CNS.[158,205] Overly aggressive shifts toward Th2 responses may be harmful,[56,57] and, in some settings, Th1 responses have been identified as potentially beneficial, pointing to a possible role for “protective autoimmunity.”[89] Subsets of regulatory T cells (noted earlier)[33-39,50] are thought to actively participate in dampening immune responses, thereby contributing to remission following a relapse. In addition to providing antiinflammatory or down-regulatory signals, immune responses may also be beneficial in the CNS of MS patients by actively contributing to survival and repair of neural elements. This can occur through release of neurotrophic factors,[206,207] cytokines that promote OLG progenitor survival and proliferation (e.g., TNFα),[208] and secretion of particular myelin-directed antibodies that may actually support remyelination.[190,192,209,210] Immune responses are also required to create a more permissive CNS environment through the removal of molecules that otherwise inhibit axonal regeneration such as Nogo and myelin-associated glyco-protein (MAG).[211] Certain immune mediators (e.g., IL-1β, TNFα, apoptotic molecules) may have both detrimental and beneficial effects during CNS inflammation ( Table 1 and Table 2 ). For example, IL-1β can contribute to tissue injury by enhancing the function of certain MMPs and by exacerbating glutamate cytotoxicity. However, IL-1β is also required for the production of ciliary neurotrophic factor (CNTF)[212] and promotes remyelination by inducing production of insulinlike growth factor (IGF)-1.[213] Similarly, TNFα, often considered a Th1 proinflammatory cytokine, may be directly cytotoxic when acting via TNF receptor (R)1, but can support remyelination when acting via TNFR2. This poses particular therapeutic challenges and may explain why anti-TNFα therapies (which work well for patients with rheumatoid arthritis) have been unsuccessful and, indeed, detrimental in MS.

Immune Mechanisms of Disease Progression. Whether and how inflammation contributes to the progressive accumulation of neurological disability in the absence of relapsing/remitting biology remains to be fully elucidated. Failure of the resolution phase of acute relapses due to persistence of proretention and prosurvival cues ( Table 1 ) may play a role in prolonging the injurious impact of infiltrating immune cells. Chronic activation of resident CNS glial cells, such as microglia and astrocytes, as well as persisting immune cells, provides the basis for generation and maintenance of progressive pathologic responses, even in the absence of acute waves of infiltrating inflammatory cells from the periphery. CNS or invading cells may become activated through TLRs or by scavenging the CNS debris itself. Germinal centerlike structures developing within the CNS may provide further nidi for chronic activation.[166,197-199] Collectively, the activated cells residing within the CNS, whether from peripheral or central origin, are likely sources of effector molecules contributing to smoldering tissue injury. This reflects an important CNS-compartmentalized component of MS inflammation that would be relatively resilient to peripheral immune intervention and may be particularly dominant later in the disease process (Fig. 2).

Space precludes detailed discussion of immuneneural interactions and the neurobiology involved in the gradual loss of neural elements and progressive neurological dysfunction over the course of MS. A “multihit” model is likely relevant with initial sublethal injury that renders OLGs and neurons more vulnerable to accumulating insults. For example, in culture, human OLGs chronically exposed to inflammatory cytokines do not die, but do upregulate intracellular p53 that in turn results in upregulation of death receptors, making the cell more susceptible to Fas-ligand and TRAIL (TNF-related apoptosis inducing ligand)-mediated apoptosis.[214] Injury of OLG progenitor cells early in the disease course may lead to their eventual depletion and progressively limit the capacity of CNS remyelination.[215] Axons rely on support from OLG and astrocytes; in their absence, they become more vulnerable to insults that would otherwise have a lesser impact. Combinations of sublethal insults likely contribute to the chronic loss of CNS elements,[216] quite possibly starting in the earliest stages of the MS process. It is not known whether the mechanisms underlying chronic progression in patients with the primary progressive form of MS are identical to those that account for the progression seen later in the course of patients with a relapsing/remitting onset.


Table 1. Immune Mechanisms that Could Contribute to Central Nervous System Injury
Table 1: Immune Mechanisms that Could Contribute to Central Nervous System Injury

Table 2. Immune Mechanisms that Could Contribute to Central Nervous System Recovery, Protection, and Repair
Table 2: Immune Mechanisms that Could Contribute to Central Nervous System Recovery, Protection, and Repair

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Acknowledgements

I wish to thank Claudine McDuff for assistance in preparing the manuscript. This article is dedicated to Mom and Dad—how they shared their worlds, and their world with others.

Funding Information

The author is supported by the Canadian Institutes of Health Research (CIHR), the Multiple Sclerosis Society of Canada (MSSC), and the Immune Tolerance Network (ITN). He is recipient of the Don Paty Career Scientist Award of the MSSC and the FRSQ Chercheur Boursier-Clinicien, and he is awarded a McGill William Dawson Chair.

Reprint Address

Amit Bar-Or, M.D., F.R.C.P.C., Neuroimmunology Unit, Montreal Neurological Institute, 3801 University Street, Room #111, Montreal, Quebec, Canada H3A 2B4. E-mail: amit.bar-or@mcgill.ca .

Amit Bar-Or, M.D., F.R.C.P.C., Experimental Therapeutics Program, Montreal Neurological Institute, Montreal, Quebec, Canada.

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