Helminth therapy and HSCT therapy

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Helminth therapy and HSCT therapy

Postby Jasper9 » Sat Aug 13, 2011 6:37 am

Assuming that the autoimmune theory is correct, as all the evidence seems to indicate, what are people's thoughts on the compatibility of the principles of helminthic therapy and HSCT treatment?
Both these treatments seem to have very strong science, clinical trial data, and anecdotal success stories. And both are concerned with somehow modifying the immune response.

For my part I was pretty convinced by the helminth theory, particularly the data from the argentinian study. So I took my first batch of 35 hookworm in April. Early days but so far so good. they pretty much stopped my hayfever this year, so obviously are having some effect. time will tell in regard to my RRMS.

Recently I've been reading up on HSCT thanks largely to george's blog, and am pretty conviced of it's efficacy. It's easy to understand why wiping out the immune system and re-establishing it form self stem cells should halt disease activity, without needing to fully understand the detailed science.
The immune mechanics of helminth therapy is a little trickier for me to understand, though it seems to be modulating or dampening down the self immune response. Can people with more science than me see a correlation between the two approaches??
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Re: CCSVI treatment results?

Postby NHE » Sun Aug 14, 2011 1:47 am

Jasper9 wrote:I had the balloon treatment in Edinburgh last month - no major changes yet but it's still early days and my symptoms are relatively mild.


Last January you shared that you were treated for CCSVI. What were the outcomes of this treatment?


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Postby Jasper9 » Sun Aug 14, 2011 3:33 am

Well nice of you to notice my history, and as you ask the outcome of the CCSVI treatment was absolutely no change. Left jugular and azgous veins were succesfully dilated, but no change in symptoms at all.
Maybe I jumped on the CCSVI bandwagon a bit, but it was surely worth a try. But I've always kept an open mind and since then have delved a bit further into the research. When I found the papers on Helminth immunomodulation I was very impressed and persuaded by the quality of the research to give it a go.
particularly the long term study by Farez/Correale:
http://www.ncbi.nlm.nih.gov/pubmed/17230481

HSCT has always been at the back of my mind, but due to the difficulty of the treatment (time, expense, risk etc) I've not really considered it till now. I suppose I wanted to try the 'easier' stuff first. So in ascending chronological order I try vit D megadosing, LDN, CCSVI, Helminths. Next would be the more serious stuff.

Anyway, as this is the stem cell forum and there is no Helminth forum, any thoughts on the crossover in science with HSCT and helminthinc therapy?
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Postby CVfactor » Sun Aug 14, 2011 3:37 pm

I think this relates to the "Hygiene Hypothesis" which is the thought that because many people in the developed world are not exposed to the amount of pathogens as they were in the past, they develop more autoimmune diseases and allergies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708340/

According to the so-called hygiene hypothesis [7], modern living conditions in the industrialised nations isolate infants and children from many infectious challenges that are required for the development of appropriate immunoregulatory networks. This hypothesis has been advanced to explain the rise in incidence of disease associated with immune dysregulation, including asthma, allergy, autoimmunity and at least some forms of cancer, in the industrially developed world [7]. In addition, the hypothesis suggests strategies for interventions for the prevention of such diseases, as illustrated by studies on the epidemiology of malignant melanoma which indicate that certain vaccinations, BCG, vaccinia and yellow fever, can substitute for the significant protective effect of natural infections [8–11]. As epidemiological investigations on MS strongly indicate that this disease is likewise affected by hygiene-related factors and by a history of infections [3, 6], the challenge is to determine whether there is an underlying distortion of immune responses in this complex disease that could be prevented or corrected by therapeutic intervention.


So, because of this lack of exposure the immune system may develop a propensity for autoimmunity depending on what was encountered in its development (Biography):

The temporal sequence of infections, especially initial and early ones, is crucial to the development of patterns of immune reactivity as prior contacts with other antigens may have induced cross-reactive T-helper cells competing with Tregs. As a consequence Tregs normally induced by the second pathogen may be marginalized or even eclipsed. The latter phenomenon, also known as lateral inhibition, has many parallels in biology, particularly in neurology. The locking of an immune response into an eclipsed state seems to involve an active deletion of clones of T-cells occurring as a result of reinfections or reactivations [28]. In the case of MS, infections such as those with HHV-6 [30, 31] and, possibly, with CP [12, 26] occurring before or at the time of initial or reactivated EBV infection could have such an effect.


I don't know much about the helminthnic therapy, but it appears from the abstract that this develops regulatory T-cells whose function is to control autoimmunity.

So, how does it relate to HSCT? I'm not an expert on this either (maybe George could chime in) but I believe HSCT wipes out the "Biography" of the immune system to start from scratch and I would think the helminithnic therapy probably just modifies your existing system.

But I think this parasite therapy may be in the experimental stages at this point. If I had the money and the doctors would take me I would put my money on HSCT if I began to progress in my disease.
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Postby Jasper9 » Mon Aug 15, 2011 3:34 am

Thanks for the reply CVfactor, and the link on Biography.
Yes Helminth therapy is founded on the hygeine hypothesis. That until the advent of mass hygeine (particularly sewers and shoes) we would have routinely been exposed to a range of 'parasites'. Indeed humans and prehumans have evolved along with such species, in what has likely become a symbiotic relationship.
In order for these helminths to survive in the human host they must in some way modulate our immune response to prevent themselved being killed off. This modualtion protects us from autoimmunity. Without helminths (and presumably with the presence of another 'trigger') the immune system is free to attack self.

The Farez-Correale study is incredible. They followed 12 MS patients who became naturally infected with helminths, and 12 non-infected patients, for 4.6 years. The total number of relapses in all 12 infected patients over the study was 3, compared to 56 in the uninfected group. 9 infected patients remained relapse free over the whole study. Lesoin numbers and change in EDSS also near enough zero.
Further, when some if these patients were later treated to eliminate their helminth infections they experienced a return of MS replases.

This research really struck me, enough to seek out safe helminth infection. I really cant understand why it hasnt received more attention from people.
OK, it was an open label study and small patient numbers, but it's a really robust study with staggering results.

But it's the science behind it (antigens, cytokines, FOXP3.....) that I'm finding hard to understand, and whether this science ties in at all with the science of HSCT.
Clearly HSCT has the potential to reset the immune system and provide a hopefully longlasting 'cure', whereas Helminth therapy seems to offer potential remmision for only as long as the infection is maintained.
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Postby Lyon » Mon Aug 15, 2011 5:27 am

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Postby georgegoss » Mon Aug 15, 2011 11:25 am

Wow. Helminth therapy looks interesting. I had not previously looked at it and therefore know little about it. Although still early, I'm glad to see some trial work being conducted. I'm all for more info, as opposed to less. Especially because the exact root cause of MS is still a mystery.

Lyon I agree with all of your comments. . . . especially the analogy of the "sledgehammer" of HSCT. It's true. Although a very effective therapy, it lacks the specificity of targetting only the abberant misbehaiving immune cells causing the underlying disease progression. This makes it a rather hard therapy on the individual.

I also agree that the Tavoxin work, although not as effective (so far) as HSCT, it does have the advantage of being "targetted." If a targetted-therapy can someday acheive what HSCT has already demonstrated then I would definitely prefer that to the sledgehammer option of HSCT.

Also, your point about the MS initiation being due to both genetic + environmental exposure is well stated. After "autologous" HSCT the immune system is reset, but only from the standpoint of the environmental factor, like turning the immune system's clock back in time to before the environmental exposure occured, whatever that may have been.

Interesting that an "allogeneic" HSCT transplantation procedure would likely correct both the environmental trigger AND the underlying genetic factor (because the donor's hematopoietic stem cells would have a uniquely different genome as compared to the recipient) and would almost certainly confer lifetime protection from MS ever manifesting again. But of course doing allogeneic HSCT for MS is not a very practical therapy because the mortality rate is so high, there would be too many deaths with the treatment. Alas, there is no other way to eliminate the genetic component of the cause of MS.

"perfection will come with time and new methods and products will be developed along the way until only the cells responsible for MS are eliminated and getting rid of MS literally will be an unintrusive trip to the Dr's office entailing little risk.

I think you have to be correct about this statement. The goal we'd all like to see come to fruition.
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Postby CVfactor » Mon Aug 15, 2011 3:24 pm

Jasper9 wrote:But it's the science behind it (antigens, cytokines, FOXP3.....) that I'm finding hard to understand, and whether this science ties in at all with the science of HSCT.


I'll try to explain what I know about the science that I have surmised by reading a lot of research papers. I am not an expert, but I think I have a good grasp of what is involved.

First off there are two types of cells that are of concern when talking about adaptive immunity which is believed to be the mechanism involved in MS.

The first are effector T-cells which are otherwise known as helper T-cells. These cells do not directly cause cell damage, but rather recruit other cells such as machrphages to perform the attack on pathogens and cells that have been taken over by pathogens.

There are three types of helper T-Cells (Th1, Th2 and Th17). I'm not going to go into the details of what each of these cells do, but just remember the cytokine that they produce during a pro-inflamitory response is Gamma Interferon.

The second type of cell is called regulatory T-cells (or Tregs). The purpose of these cells are to monitor the immune system and allow Th cells (as well as B-cells) to function correctly to eliminate pathogens. But they also provide a role in shutting down an immune response when it gets out of control, such as when cells attack the body (autoimmune response).

So all T-cells are first developed in the bone marrow and then go to the thymus (this is why they are called T-cells) where they are conditioned to recognize self antigens (protein fragments of the body) so that they do not attack the self.

This is called central tolerance.

The regulatory T-cells that are developed in the thymus are often called natural regulatory T-cells (nTregs) and express certain proteins on their surface which are CD4+, CD25+ and FoxP3+. The plus sign indicated that these cells express the proteins and it is how they are identified from other cells. So, a naturally occuring regulatory t-cells that is developed in the thymus is reffered to as a CD4+CD25+FoxP3+ t cell.

These regulatory t-cells produce a cytokine known as Interleukin-10 or IL-10. This is a chemical signal that supresses the action of effector cells (helper T-cells) and shuts-down their activity.

So, it appears that some of the Th cells conditioned in the thymus to know self from non-self escape with a propensity for attacking tissues of the human body. The system is not perfect, so it is believed that the natural regulatory t-cells are better at distinguishing the self and prevent autoimmunity by shutting down these Th cells that escape.

Incidentally, there is a human disease called IPEX in which people lack the FoxP3 protein and can die very quickly of a massive autoimmune attack.

So, central tolerance is controlled by conditioning T-cells by conditioning them in the thymus.

However, there also is another mechanism that modulates the immune system which is called peripheral tolerance. This involves T-cells that are induced for normal Th cells at a localized area of inflamation. These cells are also called regulatory T-cells but are referred to as induced regulatory t cells or iTregs. Some of the cells are called Tr1 (regulatory t-cells type 1) and they produce large amounts of the suppressing cytokine IL-10. The cells express CD4+ and CD25+ and are known as CD4+CD25+ regulatory t-cells.

So there is a company trying to actively manipulate these cells as a therapy for many types of autoimmune diseases:

http://www.txcell.com/index.php?option=com_content&task=view&id=61&Itemid=145

So to tie this all together, it appears that people with MS have defficient numbers of Tregs (or they are not as potent):

http://www.ncbi.nlm.nih.gov/pubmed/18200504

But it appears that Vitamin D has the ability to produce Tregs and I have a lot of information on another thread that supports this:

http://www.thisisms.com/ftopic-15479-0.html

So from the link you provided, it looks like that this therapy also promotes development of regulatory T-cells:

During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein-specific responses in peripheral blood showed a significant increase in IL-10 and TGF-beta and a decrease in IL-12 and interferon-gamma-secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein-specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-beta secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-beta.


So, I think this may also be a viable future treatment based on the results showing improved regulatory T-cell function with the treatment group.

But I believe the HSCT therapy probably resets the Tregs so that they revert back to their initial efficacy. I also believe that the reason why it may not work so well in people with primary progressive disease is because there may be a proplem in the thymus which prevents development of natural T-regs. But this is just a guess and I think the scientists are on the right track to find the cause of MS.
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Postby CVfactor » Thu Aug 18, 2011 4:47 pm

In regards to the helper Tcells (Th1, Th2 and Th17) described above, it appears that the recently discovered Th17 variant may play a dominant role in MS:

http://www.ncbi.nlm.nih.gov/pubmed/19132915

And here is a good review article that explains more about the Th17 effector cell as it relates to MS:

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3083.2011.02536.x/full
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Postby Lyon » Thu Aug 18, 2011 8:00 pm

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Postby CVfactor » Fri Aug 19, 2011 3:17 pm

Yes, it seems that researchers are coming to the conclusion that autoimmunity is a function of self tolerance.

http://journals.lww.com/pedresearch/Fulltext/2009/05001/The_Treg_Th17_Cell_Balance__A_New_Paradigm_for.5.aspx
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Re: Helminth therapy and HSCT therapy

Postby CVfactor » Mon Nov 07, 2011 9:56 am

Here is a good review article regarding Autologous hematopoetic stem cell transplantation (HSCT) and autoimune diseases:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817019/

Among the various autoimmune diseases, multiple sclerosis has been the main indication for autologous HSCT. A recent review summarized the data on 400 patients in 12 trials. Patients had either remitting-relapsing or primary progressive disease and conventional immunosuppression had failed. Disease stabilization and improvement occurred in around 70% at least up to 3 years after transplantation. The timing of HSCT in multiple sclerosis may be critical as there is growing evidence that at some stage of the disease neurodegeneration may progress independently of autoreactive processes.


Keep in mind the value of 70% of stabalization and improvement is for both RRMS and PPMS in this study that is cited.

Here is a good graphic from this paper with an overview of what HSCT does:

Image

In particular you can see that HSCT increases regulatory T-cells after treatment. This is also seems to be the case for the Helminth therapy (as discussed above) as well as Vitamin D http://www.thisisms.com/forum/natural-approach-f27/topic15479-45.html.

So, it appears there is a common thread between these three approaches, namely the enhancement of regulatory T-cells or Tregs as they are otherwise known.
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