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A bit more info on this story.

Secret codes of MS cracked 29 July 2007

Investigators have reported the biggest breakthrough in decades into the genetic drivers for multiple sclerosis, identifying two genes that each boost the risk of developing the disease by up to 30 per cent.

In MS, the immune system attacks myelin, the fatty sheath that protects the cells of the central nervous system, rather like plastic insulation protects electrical cables.

As a result, "short circuits" occur in the body's messaging system, because nerve signals get slowed or blocked. This leads to difficulties in movement and co-ordination, muscle weakness, cognitive impairment, slurred speech and vision problems.

Until now, investigations of the human genome have turned up only a cluster of variants of genes on Chromosome 6, in the so-called Major Histocompatibility Complex, which regulates the immune system.

But these genes were identified in the mid-1970s, leaving frustrated doctors to hunt for other culprits in the complex cascade of processes involved in MS. The new suspects play a role in guiding key immune cells, called T cells, which patrol the body for intruders.

They carry the name of interleukin-7 receptor alpha, or IL7R-alpha, located on Chromosome 5, and interleukin-2 receptor alpha (IL2R-alpha) on Chromosome 10, which has previously been associated with Type 1 diabetes. A single change in the genetic code in IL7-R, and two changes in IL2-R create the dangerous variants.

Each variant appears to boost the risk of MS by between 20 and 30 per cent.

"Our finding is very important, because the genetic factors that are already known to be associated with multiple sclerosis only explain less than half of the total genetic basis for the disease," said Simon Gregory, an Australian-born geneticist at Duke University in Durham, North Carolina, who took part in the IL7-R work.

The two studies, published simultaneously by Nature Genetics and the New England Journal of Medicine, were carried out by two consortiums of scientists, from the US and Cambridge University in Britain.

The genetic variants were unearthed thanks to a comparison of more than 20,000 samples of DNA, provided by patients diagnosed with MS and those without the disease, living in the US and Europe.

"People have been looking for genes involved in MS for 30 years," said David Hafler, a professor of neurology at Harvard Medical School, a lead author on the IL2-R study.

Source: The Australian Copyright 2007 News Limited. (29/07/07)

Great stuff Bromley. This sounds like a significant step in unravelling MS. I looked around a little for more on the IL2R and IL7R and came up with a few things:

This June 2007 presentation from UCSF on MS genetics (IL7R stuff starts on slide #30)
http://www.mscare.org/cmsc/images/pdf/2 ... Hauser.pdf


The abstract below includes a connection between IL2R and FoxP3 t-cells, which are connected to how Neurovax is supposed to work, so I'm suddenly more interested in Neurovax.


Selective availability of IL-2 is a major determinant controlling the production of CD4+CD25+Foxp3+ T regulatory cells.

J Immunol. 2006 Oct 15;177(8):5115-21.
Yu A, Malek TR.
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.

The development and maintenance of T regulatory (Treg) cells critically depend on IL-2. This requirement for IL-2 might be due to specificity associated with IL-2R signal transduction or because IL-2 was uniquely present in the niche in which Treg cells reside. To address this issue, we examined the capacity of IL-7R-dependent signaling to support Treg cell production and prevent autoimmunity in IL-2Rbeta(-/-) mice. Expression of transgenic wild-type IL-7R or a chimeric receptor that consisted of the extracytoplasmic domain of the IL-7R alpha-chain and the cytoplasmic domain of IL-2R beta-chain in IL-2Rbeta(-/-) mice did not prevent autoimmunity. Importantly, expression of a chimeric receptor that consisted of the extracytoplasmic domain of the IL-2R beta-chain and the cytoplasmic domain of IL-7R alpha-chain in IL-2Rbeta(-/-) mice led to Treg cells production in the thymus and periphery and prevented autoimmunity. Signaling through the IL-2R or chimeric IL-2Rbeta/IL-7Ralpha in vivo or the culture of thymocytes from IL-2Rbeta(-/-) mice with IL-7 led to up-regulation of Foxp3 and CD25 on Treg cells. These findings indicate that IL-7R signal transduction is competent to promote Treg cell production, but this signaling requires triggering through IL-2 by binding to the extracytoplasmic portion of the IL-2R via this chimeric receptor. Thus, a major factor controlling the nonredundant activity of the IL-2R is selective compartmentalization of IL-2-producing cells with Treg cells in vivo.

Pubmed link


Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7R alpha-expressing cells.

J Exp Med. 2007 Mar 19;204(3):547-57. Epub 2007 Feb 20.
Dooms H, Wolslegel K, Lin P, Abbas AK.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.

The common gamma chain cytokines interleukin (IL)-2 and IL-7 are important regulators of T cell homeostasis. Although IL-2 is implicated in the acute phase of the T cell response, IL-7 is important for memory T cell survival. We asked whether regulated responsiveness to these growth factors is determined by temporal expression of the cytokine-specific IL-2 receptor (R) alpha and IL-7Ralpha chains. We demonstrate that IL-2Ralpha is expressed early after priming in T cell receptor-transgenic CD4(+) T cells, whereas IL-7Ralpha expression is lost. In the later stage of the response, IL-7Ralpha is reexpressed while IL-2Ralpha expression is silenced. This reciprocal pattern of IL-2Ralpha/IL-7Ralpha expression is disturbed when CD4(+) T cells are primed in the absence of IL-2 signals. Primed IL-2(-/-) or CD25(-/-) (IL-2Ralpha(-/-)) CD4(+) T cells, despite showing normal induction of activation markers and cell division, fail to reexpress IL-7Ralpha late in the response. Because the generation of CD4(+) memory T cells is dependent on IL-7-IL-7Ralpha interactions, primed IL-2(-/-) or CD25(-/-) CD4(+) T cells develop poorly into long-lived memory cells. Retrovirus-mediated expression of IL-7Ralpha in IL-2(-/-) T cells restores their capacity for long-term survival. These results identify IL-2 as a factor regulating IL-7Ralpha expression and, consequently, memory T cell homeostasis in vivo.

Pubmed link

Dignan,

Another article on the same findings. This one mentions Zenapax (Daclizumab).

http://c.moreover.com/click/here.pl?j10 ... 8&w=464753


Ian

Daclizumab, interesting. Here is a relatedpresentation from the 2007 ACTRIMS conference:


Use of Daclizumab in Multiple Sclerosis

B Bielekova
Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA

It is believed that multiple sclerosis (MS) is a T cell mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab, a humanized monoclonal antibody that blocks the IL-2 binding-site on the IL-2 receptor alpha-chain (CD25) is among these novel agents. CD25 is present at very low levels in resting human T cells (with the exception of Tregs), but is significantly upregulated on activated T cells, enabling them to receive a high affinity IL-2 signal. Because it was believed that IL-2 signaling was necessary for T cell function, it was expected that the blockade of CD25 would result in selective functional inhibition of T cell activation. This provided the rational for the use of daclizumab in autoimmune disorders such as MS.

Two phase II, open-label, baseline-versus-treatment crossover trials of daclizumab in MS patients with incomplete therapeutic response to IFN-b have been concluded at NIH (1) and the University of Utah (2). When used in combination with IFN-b or as a monotherapy, daclizumab showed a profound inhibitory effect on brain inflammatory activity (>75% reduction) and subsequent stabilization of disability progression. Both the inhibition of brain inflammation by daclizumab and the reappearance of inflammation after cessation of the therapy developed gradually over a period of 2–3 months, consistent with the hypothesis that daclizumab induced gradual and prolonged immunomodulatory changes in vivo. A multicentric double blinded Phase II trial of Daclizumab in RR-MS patients with incomplete therapeutic response to IFN-b has also been recently concluded and as the news report reflected the daclizumab therapy led to a significant reduction in the number of new or enlarged gadolinium-contrast enhancing lesions at week 24 as compared to placebo.

We recently reported immunological studies supplementing the two Phase II NIH trials of daclizumab in MS (3). In contrast to the putative mechanism of action of daclizumab, we did not observe any significant inhibition of T cell activation or function during in vivo administration of the drug. However, we did observe profound expansion of CD56bright natural killer (NK) cells during daclizumab therapy, which correlated with the treatment outcome. CD56bright NK cells represent a minute population of lymphocytes (approx 1%) in human peripheral blood. These cells have been labeled “immunoregulatory” because they are expanded under situations that assume immunoregulation, such as pregnancy or bone-marrow transplantation. Additionally, CD56bright NK cells home to lymph nodes and affect T cell priming by production of cytokines and by killing of autologous immature dendritic cells.

In our studies, we observed a slow but gradual decline in absolute numbers of CD4+ and CD8+ T cells during daclizumab therapy (by approx 10%) and a statistically significant correlation between expansion of CD56bright NK cells and reductions in T cell numbers in vivo. Extensive in vitro experiments demonstrated that daclizumab-expanded CD56bright NK cells are capable of killing activated autologous CD4+ and CD8+ T cells in a perforin-dependent manner. This data suggests an unexpected and novel mechanism of action of daclizumab via a regulatory circuit between innate and adaptive immune responses.

http://www.nationalmssociety.org/docs/H ... rogram.pdf

While it doesn't make connections to potential treatments, here's the version from the New York Times. Front page news at the moment!

July 29, 2007
Advances Cited in Research on Multiple Sclerosis
By NICHOLAS WADE
Medical researchers have made a significant advance in understanding multiple sclerosis, a common neurological disease that causes symptoms ranging from muscle weakness to paralysis.

The disease is one in which the body’s immune system mistakenly attacks the electrical insulation of nerve fibers. The cause is part genetic and part environmental, but researchers trying to identify the relevant genes have endured repeated frustration. Their approach has been to guess what genes might be involved and see if patients have abnormal versions.

This guesswork has produced more than 100 candidate genes in recent years, none of which could be confirmed except for long-known variants in the mechanism used by immune system to recognize proteins that are foreign to the body.

In three articles published online today in The New England Journal of Medicine and Nature Genetics, three teams of researchers say they have identified, by separate routes, new genetic variants that contribute to the disease.

One team used a new, advanced gene-hunting method called Whole Genome Association, which has racked up a string of successes with major diseases in the last few months. The other teams used the candidate gene approach, but because all three teams identified the same gene, the researchers say they are confident that have opened a new window into the cause and possible treatment of multiple sclerosis.

The gene makes a substance called the interleukin-7 receptor, a protein that enables cells of the immune system to respond to a control agent. Researchers believe the receptor is part of a biochemical pathway involving many genes; defects in any of these genes may lead to the disease. It is now possible to explore the pathway, they say, in the hope of devising treatments to correct the disease-causing process.

The new research is the product of several large teams at universities in the United States and abroad who have coordinated their publications and pooled their data for analysis.

The leaders of the Whole Genome Association Study include David A. Hafler of Brigham and Women’s Hospital in Boston Stephen L. Hauser of the University of California at San Francisco and Jonathan L. Haines of Vanderbilt University Medical Center in Nashville. The two candidate gene studies were headed by Dr. Haines and Jan Hillert of the Karolinska Institute in Stockholm.

“This is a very good beginning,” said Kári Stefánsson, chief executive of Decode Genetics, a company based in Reykjavik, Iceland, that has led the search for genetic causes of common diseases. Dr. Stefánsson, a neurologist, said he had studied multiple sclerosis for 20 years but had been unable to explore its genetic basis because there are too few patients in Iceland for a statistically valid analysis.

Because the course of the disease is unpredictable, clinical trials are very hard to conduct. “But once you have an ironclad discovery, as I believe the interleukin-7 receptor is, then you have the motivation to endure the expense of a long clinical trial,” Dr. Stefánsson said.

Do you guys really think this means anything? It just doesn't seem like it will lead to anything. The chances aren't really set in stone that if you have IL2, or IL7 variants that you will develop MS, just a chance that you will, and even then, how sound is the research? I am just not that excited by this, but as you guys already know I am kind of cynical. What are your thoughts on this?

Brock

Good question Brock, I don't really know if this will prove to be really important. I think it's a good sign though--in that they have been looking for different genetic culprits since the 1970s and this is first new one they have come up with about which they they sound confident. An interesting bit from the "Time" coverage of this news puts it in perspective:



As exciting as the discovery is, it's a small part of the story: the new genes account for less than 1% of the risk of developing MS. In addition, about 70% of the normal, non-MS affected population has the same variants. "Every single time we have looked for genes for MS, the genes turn out to have a very small effect," says Dr. Moses Rodriguez, professor of immunology at the Mayo Clinic and a leading MS researcher." That suggests that either the disease is not genetically controlled in a significant way, or that if it is, that there are at least a 100 or so more genes that account for the entire disease process."

Hafler acknowledges that these findings are only the first step. Uncovering additional genes will require analyzing an even larger pool of MS patients and their families — Hafler is hoping to find at least 9,000 more patients. He calculates that with that much DNA, he'll be able to tease out 90% of the genetic culprits involved in MS. "These first genes give us a working hypothesis for what may be causing MS," says Hafler, "and a lot more work needs to be done. But we have finally begun."

http://www.time.com/time/health/article ... 40,00.html

Brock,

It's certainly good news for gene researchers.

This disease is such a complex one (many genes / unknown environmental factor) that even small advances in knowledge are to be welcomed. The good news is that (i) no mice were involved and (ii) the techniques / methods used can be taken forward so that the other genes can be identified quickly.

http://news.bbc.co.uk/1/hi/health/6919613.stm

I put this story alongside some of the other advances we are seeing: treatments that can pretty much stop relapses; treatments which are being trialled to see if they can stop nerves degenerating (such as sodium channel blockers); work underway looking at repair (perhaps using stem cells etc); research on the benefits of hormones (including Vit D). These are all little steps against the same enemy, and the work on genes may be another addition to the armoury.

Ian

PS tell me if you get the chocolate I sent. Given that you are 330 pounds I'm feeling a bit guilty - perhaps an English apple would have been better.

Dignan, Ian,

Thank you for your responses. I cued in on this:



and figured, "How important or relevant is this really?"..

Ian, which drug are you speaking of that will stop relapses? Rituxan?

Brock

P.S. No reason to feel guilty, it is 330lbs of pure muscle, no doubt. Besides, my wife will probably take it from me, and she probably needs it more than I since she is only 130 lbs, thanks again!!!!!

Also, do you think your new PM, Mr. Brown will be able to talk our, uh, president in to pulling out of Iraq?

-B

Brock--I am a "cynic" too (as you well know!) All I see here is yet again, years and years of "research" into a finding that will probably not make much of a difference, especially for the posters at this site.

BTW--my daughter continues to thrive. I choose to focus on that! Chris

Thanks for bringing us all down to earth Chris. You're right - nothing is going to make any difference. Best if we stop all the trials, switch off the MRIs and sack the neuros [I'm guessing that you were one of the people in 1960 that said we'd never put a man on the moon].

I think one has to place this kind of discovery into perspective when it comes to what it will or won't do for MS patients around the world.

Like Ian stated, it is wonderful news for genetic scientists who have to spend countless months and months at trying to decipher the human genetic code. This kind of breakthrough for them is a major accomplishment.

But what does it mean for the MS patient? Immediately, pretty much next to nothing because this kind of discovery from now to a viable treatment would likely take 10 years or more. For someone who is going to be diagnosed with the disease in the next five years it would certainly offer a glimmer of tangible hope. It might even lead to a vaccine that would possibly go a long way in preventing a person from getting MS in the first place.

My big concern with announcements like this is that they tend to make some believe that a treatment involving a gene therapy of some kind is just around the corner. Many of us know that while this discovery is a big step, there is a ton of work ahead and that work is going to take a very long time.



I don't want to speak for Chris but I don't think she meant for her statement to be taken in a manner which brought this response. I'll let her address that if she wants but it's only my opinion.

Harry

Yes Harry--you are absolutely correct! I do not ever want to burst anyone's bubble! And the manner in which you expressed your perspective could not have been said better or more eloquently! It was basically what was in my head---just didn't flow very well through my mouth!

Like you, I also find these breakthoughs to be frustrating for current MSers. Guess that was where I was coming from. I really care about all of you--so much! I do not have this hideous disease and, for me anyway, I want news that might have an impact on those currently afflicted.

Okay, so I am selfish for not caring about all the "future" diagnosed! In the end, I am sure God will get me for that!

Seriously, thank you for your moderation, clarity and again, excellent perspective! Chris

Just like clock work..

_________________
Had ms for over 19 years now.