Autoimmunity is not just a theory in MS

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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Jan 27, 2012 10:14 am

Also, when I first got sick and started doing a lot of research and read about the latitude gradient in MS and how it was suspected that this may be the result of sun exposure and vitamin D the first question I had to ask myself is why hasn't this been fully investigaged? This theory has been around for almost 30 years and not much has been done about it. I think the National MS Society has really lost sight of what they should be doing.

But here is an interesting video presentation regarding the initiation of clinical trials:

http://youtu.be/a8qh-wXN578
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Sun Jan 29, 2012 12:11 am

Hi CV,

Watched the vitamin D video. Very interesting. I am looking forward to a clinical trial, if/when it ever happens. (Of course the drug companies have no incentive to support such an endeavor).

Of all people, I thought you would like this paper (just in case you haven't seen this specific Mayo Clinic publication before) since it has info beyond just HSCT. . . . .

Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation

http://download.journals.elsevierhealth ... 623884.pdf

- George
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Jan 30, 2012 11:04 am

Hi George,

That is an interesting article in that it suggests that after HSCT the thymus is involute and the T cell reconstruction is due to memory cells that
are remnants after the HSCT treatment:

In adult humans, the thymus is involuted, which suggests that extrathymic differentiation of T-cell progenitors, peripheral expansion of mature T
cells, or both are the principal mechanisms of T-cell reconstitution after transplantation. Dreger et al17 showed a lack of naive CD45RA+ cells after AHSCT, suggesting that most circulating T cells after AHSCT in humans are activated memory CD45RO+ cells rather than naive T cells. The deficient numbers of naive T cells predict the inability to elicit immune responses against new antigens after AHSCT.


I think this article was written before the acceptance of the discovery of regulatory T cells. These cells act as moderators of the immune system and prevent autoimunity from occuring. Here is a pretty good paper that descibes these cells:

http://www.smccd.edu/accounts/digennaroc/biology430/Articles/Regulatory_T-cells.pdf

So, this peaked my interest to see what happens to regulatory T-cells (tregs) after HSCT. According to the paper below, the regulatory T-cell subpopulation quickly becomes normal within 9 months.

http://www.jci.org/articles/view/41072
Prospective monitoring of CD4+ T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4+ lymphopenia.


Granted this is for allogenic HSCT, but it may be that the Treg/Teffector cell population increases after HSCT which would explain why the non-myeoblative procedure works also (note that Tregs are a type of CD4+ cell, but are usually a small proportion, about 5% if memory serves me correctly).

At any rate, it seems people with MS have defective regulatory T cells. http://www.ncbi.nlm.nih.gov/pubmed/17099776

So it could be that the cause of MS is not simply autoreactive T-cells but could be because the role of the regulatory T-cells are deficient in people with MS and allows autoimunity to happen.

Incidentally, to tie this all together, it appears the Vitamin D has the ability to enhance regulatory T-cell function:

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006635
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Re: Autoimmunity is not just a theory in MS

Postby georgegoss » Mon Jan 30, 2012 1:02 pm

All great points that make sense the way you describe them, CV. Also, for up to ten years post-HSCT the CD4+/CD8+ ratio remaining inverted (favoring CD8+ suppressor cells) may also play a factor since there may be a strong bias to supress self-intolerant CD4+ cells during this time.

Interesting that I just noticed that one of the authors of the paper I cited is Prof. Dreger. He was one of the clinical doctors on staff in Heidelberg that made daily rounds in the transplantation treatment ward to check on patients so I saw him nearly every day. A totally humorless guy (I never once saw him smile), but a smart doctor. I had a lot of great scientific discussions with him regarding HSCT for autoimmune diseases in general. He was very conversant on the topic.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Jan 30, 2012 4:14 pm

Yeah most Gemans I have met dont have a sense of humor.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Feb 03, 2012 9:47 am

Here is a good video presentation regarding what is thought causes MS (Vitamin D & EBV as well as genes):

http://youtu.be/yAU3R8hq_2Q

Also, here is an excellent video presentation which talks about genetics, stems cells and why people with MS
have different levels of dissablities:

http://youtu.be/DZwWlDYMTio
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Mon Feb 20, 2012 10:18 am

Here is a good review article about the effect of Vitamin D on the adaptive immune system:

http://www.sciencedirect.com/science/article/pii/S1568997211001042
Epidemiological studies have shown that a poor vitamin D status is associated with an increased risk of several diseases, including autoimmune diseases. The immune regulatory function of vitamin D is thought to have an important role in these associations. Cells of the adaptive immune system have shown to be direct targets of the vitamin D metabolites. Besides being direct targets, cells of the adaptive immune system express the enzymes involved in the metabolism of vitamin D, enabling them to locally convert 25(OH)D into its active metabolite 1,25(OH)2D. In this review, the effects of vitamin D on cells of the adaptive immune system are described. Experimental data in vitro show that vitamin D skews cells of the adaptive immune system toward a more tolerogenic status which might be exploited in the treatment of autoimmune diseases. However, it should be noticed that in vivo effects may differ from in vitro effects due to the cross-talk between different vitamin D sensitive cells, but data support the view that vitamin D is positively involved in maintaining or restoring immune homeostasis. Upcoming vitamin D supplementation trials will further elucidate the in vivo effects of vitamin D on the immune system and its potency to serve as an immune regulating agent in autoimmune diseases.
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Fri Apr 20, 2012 12:29 pm

In regards to the theory that neurdegeneration is secondary to demylination of the axon, here is an interesting paper that
looks at a specific protein at the meylin-axon interface known as myelin-associated glycoprotein or MAG for short:

http://www.jneurosci.org/content/29/3/630.full.pdf

So, it is thought that the process of neurodegeneration begins when enough of the meylin sheath is destroyed and the MAG component is no longer present
to protect the axon.

In this study, they used mice that were breed withouth the MAG protein in their DNA. These are known as MAG knock-out mice. The result is that although there
appeared to be no problems with the meylin sheath, the axonal numbers were reduced by 28% in these mice over a 15 month period compared to healthy mice.

We speculate that the loss of axonal stabilizing and protective effects of MAG may contribute to the late axonal degeneration
seen in demyelinating diseases. Although MAG is not a component of compact myelin,MAG is known to be lost from oligodendrocytes
and Schwann cells that have undergone demyelination. There is a wealth of evidence that axons are liable to both prompt
and progressive late Wallerian-like degeneration after demyelination (Dyck, 1975; Trapp et al., 1998; Scherer, 1999; Berciano et
al., 2000; Krajewski et al., 2000; Bjartmar et al., 2003; Oh et al., 2004).
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Re: Autoimmunity is not just a theory in MS

Postby CVfactor » Sat Apr 28, 2012 2:51 pm

Here is a good article that describes the status of MS reseach including comments by the leading scientists:
http://www.dana.org/news/publications/detail.aspx?id=24568

Included in this group is a description of the work being done by Dr. Burt at Northwestern:

Stem Cells Provide Blank Slate

A team at Northwestern University’s Feinberg School of Medicine, led by Dr. Richard Burt, has been “resetting” the immune system of MS patients by transplanting their own immune stem cells.

In one study, eighteen of twenty-one MS patients with the relapsing-remitting form of the disease improved significantly for twenty-four months after the stem cell transplant, and none got worse.

Most patients with relapsing-remitting MS get progressively worse as irreversible damage to their neurons accumulates.

The procedure involves harvesting immune stem cells from the patient’s bone marrow, and then destroying the immune component of the bone marrow with chemotherapy. When the stem cells are transplanted, the patient develops a new immune system apparently free of disease.

“The stem cells are not immune cells,” Burt said. “They have to be educated. They have to differentiate and grow into immune cells. The reset [after transplantation] results in an immune system like a newborn child’s.”

Burt has applied this technique to other diseases, including type 1 diabetes, lupus, scleroderma, Crohn’s, and a form of vision loss known as autoimmune-related retinopathy and optic neuropathy syndrome, or ARRON.
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