The leukemia drug Campath (aka alemtuzumab) has been shown in clinical trials to have impressive efficacy against MS. It kills off large numbers of various immune cells circulating in the body; these cells then regenerate over time. One downside of the drug that was seen in the MS trials is that it increases the risk of certain autoimmune conditions that target the thyroid and blood components. A team of scientists studied factors that might influence the development of these conditions and found that higher levels of the signalling molecule IL-21 may be to blame (open access article -- read it here!).
The team analyzed serum samples taken from people on the trial and analyzed IL-21 levels from those who did and didn't develop autoimmunity. They found that in samples taken both before and after treatment with alemtuzumab, those who did develop autoimmunity had higher IL-21 levels than those who did not. They also found certain variants in the IL-21 gene that appear to increase IL-21 levels, so it may be that whether someone develops autoimmunity after immune cell depletion is genetically determined.
The team also found that:
The authors conclude that higher levels of IL-21 boosts T cell turnover, thereby increasing the risk that a person will generate auto-reactive T cells and develop new forms of autoimmunity. They suggest that these findings could be developed further into a method for providing advice to people with MS concerning use of Campath. An interesting question raised by this study is why IL-21 increases the risk of thyroid autoimmunity and not other types of autoimmune disease -- the authors speculate that IL-21 may drive some disease activities but not others.
Interferon beta drugs are a mainstay of MS treatment, but one of their drawbacks is that they have to be injected at least every week, if not more frequently depending on formulation. Biogen Idec, maker of Avonex (interferon beta-1a), is hoping to make this drug easier to take by creating a new version that doesn't have to be injected as often. This version, named "BIIB017," has been chemically altered (pegylated) to help it avoid targeting by the immune system and therefore remain in the body's circulation for longer. Biogen Idec has now begun enrollment for a phase III clinical trial of this drug. You can get more information about the trial and participating sites on www.clinicaltrials.gov.
The trial period is two years, and participants will inject themselves every two weeks with either (a) the pegylated interferon, (b) a placebo injection, or (c) alternating pegylated interferon and placebo (to test the efficacy of a monthly injection schedule). If safety and efficacy results are positive, then interferon beta users may have the option of a less burdensome injection schedule in the future.
[P.S. Thanks to Stephanie S. for the pointer to this study -- and all MSNews readers should feel free to send me their own pointers by clicking on my name above.]
Infiltration of T cells into the brain and spinal cord is part of the immune response seen in MS. Once in the central nervous system, T cells emit molecules that perform functions such as signaling other cells. First, however, T cells must be activated. Activation happens when the T-cell receptor (a molecule extending from the surface of the T cell) successfully binds to a protein fragment that is also bound to an HLA molecule extending from the surface of another cell. The HLA molecules and T-cell receptors that are expressed by a person's cells bind only to specific protein fragments; therefore learning what these particular fragments are in people with MS could help us better understand the disease. Previous research has given some idea of the central nervous system proteins that might be involved in the MS immune response, but technology has now evolved to the point of being able to show the exact fragments that T cells might "see" in the MS brain.
A team of researchers, using autopsy brain samples from 8 people with MS, were able to separate out the HLA molecules in the tissue and were then able to determine which segments of which proteins those HLA molecules were binding. They identified 174 proteins all together. Not surprisingly, most of the MS subjects had HLA molecules that bound a fragment of MBP (myelin basic protein), which is an abundant protein in myelin and a known target of T cells. Other fragments identified belonged to proteins that are involved in remyelination, neurodegeneration, cell death (apoptosis), astrocyte scarring, cell signaling, etc. Further analysis of the results of this study (and similar studies that may be published in the future) could lead to a better understanding of the immune response in MS and perhaps even targeted therapies that block the immune reaction to specific proteins.
This study is interesting because it reveals a new aspect of the actual state of affairs in MS. Unfortunately, it requires actual brain tissue samples and so its applicability will be limited to autopsy cases and rare biopsy tissue samples.
Here's an interesting study that takes advantage of recorded parentage data from people with MS with mixed-race parents to see what effect different ancestries may have on risk of MS. A research team searched a gigantic database of 30,000 MS families and found 58 families where people with MS had one Native American parent and one Caucasian parent. The team performed some comparisons between the 27 families where the father was Native American and the mother Caucasian, and the 31 families where the ancestry was reversed. They found no difference in the ratios of female:male children overall; however, in just the children with MS, the female:male ratio was much higher when the mother was Caucasian and the father Native American than when the parentage was reversed (7:1 vs. 2:1). No differences between the two groups was seen in terms of clinical course or age at onset.
Why would the ethnicity of the parents affect the MS sex ratio in these interracial families? The authors didn't have an answer for that but suggested that it might be due to different exposures to environmental factors, and/or how these interact with genetic factors.
Results from a clinical trial published last year suggested that people with MS who are on IFN-b therapy may increase their risk of relapse or MRI lesions if they also take statin drugs. This study was small, however, with only 26 subjects total, so another group of scientists decided to see whether the same effect could be replicated in another data set. They analyzed relapse and MRI outcome data from the SENTINEL trial, a study that compared Tysabri plus IFN-b to IFN-b alone. The scientists found that of the 582 subjects in the "IFN-b alone" arm, 40 had taken statins during the trial while the others had not. Comparison of the relapse and MRI data from the statins and no-statins subjects revealed no significant difference between the two groups. Lab experiments were also conducted to see if the presence of statins affected IFN-related gene expression in cells; no effect was seen.
One difference between this study and the one published last year that may account for the discrepancy in the findings is that in this study, people in the statins group were on different statin drugs at doses that were usually 20 mg or less per day, whereas in the previous study, subjects were given atorvastatin at 40 or 80 mg. The authors conclude that at usual therapeutic doses, statins don't appear to interfere with the disease-modifying effects of IFN-b.
It's been a little while since we've seen any large-scale collaborative MS genetic study results -- but this week makes up for it with two such studies being published. First, a consortium from Australia and New Zealand conducted a whole-genome screen using DNA samples from nearly 10,000 MS and control subjects. They confirmed several genetic associations that had already been found, and identified two additional variants on chromosomes 12 and 20 that appeared to differ in frequency between the MS and control groups. These locations have also been associated with other autoimmune diseases. The next step will be to more finely map these regions to see exactly which gene variants are involved in MS.
In the second study, an international team of researchers combined data from past genome-wide screens in order to conduct a meta-analysis of all the results, and also replicated key findings from that analysis in a new cohort of 2,215 MS subjects and 2,116 controls. They demonstrated strong associations with MS for variants in three genes (TNFRSF1A, IRF8, and CD6), as well as associations with other genes that have been associated with inflammatory diseases in past studies. They also showed that the variant in IRF8 that was associated with MS appears to affect the expression of interferon pathway genes in MS subjects. (I'm happy to note that 632 of the DNA samples used in this study came from the Accelerated Cure Project repository!)
It's well established that women with MS who become pregnant often have fewer relapses while they are pregnant, but are at a higher risk of relapse after giving birth. A few studies have looked at whether breastfeeding can affect relapse rate also, with mixed results, but none of them have asked whether breastfeeding only (no formula) makes a difference. Recently a research team followed 32 women with MS who had given birth, collecting information about whether they breastfed and if so, for how long and whether they also supplemented with formula. They found that only 36% of those who breastfed exclusively for at least two months had a relapse in the year after childbirth, compared with 87% of those who didn't breastfeed or combined it with bottle feeding during those first two months. The results were similar after adjusting for factors such as disease severity and pre-pregnancy relapse rate which may affect whether women with MS choose to breastfeed or not. Exclusive breastfeeding also delayed resumption of menstrual cycles, so perhaps hormonal levels underlie the link found between breastfeeding and reduced relapse rate. Those women who supplemented breastfeeding with bottle feeding resumed their menstrual cycles sooner than those who only breastfed.
Women with MS sometimes choose not to breastfeed for very long or at all because they want to resume taking their MS medications. However, these results (while based on small numbers and therefore needing to be confirmed) suggest that they might be better off breastfeeding instead and holding off on MS therapies for a while longer.
P.S. My apologies for not being as tech-savvy as Art and not as able to fend off the frequent spam attacks which have required us to limit the functionality of this site for now. I'll do my best to continue posting research that I think you all might want to know about. It probably won't be every day, but maybe once or twice a week. If you're a registered user of this site, you should be able to send me a message by clicking on my name above. Feel free to send me questions, comments, or ideas for things to post!
After 8 years, Art is changing roles from employee to Board Member at Accelerated Cure Project. As such, he will no longer be able to commit time to MSNews on a daily basis.
MSNews will remain as a searchable resource, and Hollie will continue to do periodic postings on things she finds interesting or write-ups from conferences. However, we will shutdown the ability for users to comment and submit stories.
Users getting updates emailed to them will continue to receive MSNews updates, and new users can sign up for them, but user content will have to stop due to lack of bandwidth to police it for spam (of which there is far too much these days).
I thought this article was a good first-person account of one man who got autologous (his own) stem-cell treatment for his MS. It seems well-reasoned and not over-hyped and I like reading about what took place in his own words.
