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Guys Let's Focus on the latest science here

dannybex

Senior Member
Messages
3,561
Location
Seattle
Is there a consensus that this definitely happens with all ME/CFS patients? It is definitely true for me and causes me endless problems with my NHS surgery who won't give me antibiotics when I know I need them. They just tell me its a virus but it's not, usually a throat infection that simmers on and on below the surface making me extremely unwell and unable to do anything butI won't recover until I get an effective antibiotic (often I have had to get these over the Internet because of the attitude of the doctors at my surgery.).

Pam

I don't know if it applies to all patients, as some have clearly benefited from antivirals or Dr. Chia's and other's work.

But I think there's a reason why it used to be called CFIDS -- Chronic Fatigue Immune Dysfunction Syndrome -- because it's extremely rare to hear of a patient getting the flu or an infection -- and then getting a strong, high, prolonged fever which gets rid of the flu or infection, and then recovers and gets their life back.

And on the flip side, there are people who are on antibiotics for years, yet the second they go off them, the infection(s) come roaring back, perhaps because again, the immune system is dysfunctional.

Lastly, some have reported developing ME/CFS after long courses of ABX, suggesting that the microbiome becomes disturbed/depleted as a result...which may bring us back full circle w/the th1/th2 imbalance hypothesis. A lot of this, IMHO comes back to the gut.
 

Kati

Patient in training
Messages
5,497
Has oxymatrine gone through the rigorous process of FDA? Does it have a drug monograph? Has it been tested in clinical trials with a statistically-powered number of patient ? Do we know what it does exactly, for a well established (strict case definition) patient population?

The scary part is that patients can buy this (and it's expensive) and use it without supervison, and other patients counsel about how much to take. To me, it's scary. If takeN in high enough dose, if I remember well it can promote auto-immunity, and when you are at that point, it could be difficult to stop auto-immunity.
 
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Jonathan Edwards

"Gibberish"
Messages
5,256
Thanks for clarifying. In your view is there any merit to the concept of using treatments like oxymartine, interferon, or Nexavir to modulate the immune system into a more balanced state?

I'm new to all of this, but am interested in learning

No, there is no such thing as a balanced state of the immune system. The immune system fights microbes. If you like it has an army, a navy and an air force, but nobody ever talked of having a balance between those. A good commander in chief uses whichever he needs whenever. The idea of imbalance was thought up in the 1980s with no sound basis and has been a centre of immunobabble since.
 

Jonathan Edwards

"Gibberish"
Messages
5,256

Sorry, but to someone who spent thirty years in immunology those papers do not add up to a row of beans. People assume there is a 'TH1 response' and a 'TH2 response' because that is what the mouse people have decided and the human people want to be as savvy, but there is about as much substance here is in certain recent claims by politicians about making countries great etc. This is not real science I am afraid.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
No, there is no such thing as a balanced state of the immune system. The immune system fights microbes. If you like it has an army, a navy and an air force, but nobody ever talked of having a balance between those. A good commander in chief uses whichever he needs whenever. The idea of imbalance was thought up in the 1980s with no sound basis and has been a centre of immunobabble since.

Let me rephrase. Without getting into the underlying dynamics and avoiding models like balance, is it possible these "immunomodulators" help restore healthy function to the immune system?
 
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halcyon

Senior Member
Messages
2,482
Has oxymatrine gone through the rigorous process of FDA? Does it have a drug monograph? Has it been tested in clinical trials with a statistically significant number of patient ? Do we know what it does exactly, for a well established (strict case definition) patient population?

The scary part is that patients can buy this (and it's expensive) and use it without supervison, and other patients counsel about how much to take. To me, it's scary. If takeN in high enough dose, if I remember well it can promote auto-immunity, and when you are at that point, it could be difficult to stop auto-immunity.
Oxymatrine is just a plant based alkaloid, much in the same way caffeine is a plant based alkaloid. Has caffeine gone through these rigorous processes? Is it scary that you can buy enough caffeine over the counter to kill yourself?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Let me rephrase. Without getting into the underlying dynamics and avoiding models like balance, is it possible these "immunomodulators" help restore healthy function to the immune system?

I cannot see any reason or evidence to think so. Immunomodulator is too vague a term to mean anything useful. If a drug does something useful it will be through a specific mechanism that we can define, not through 'immunomodulation'.
 

Kati

Patient in training
Messages
5,497
Oxymatrine is just a plant based alkaloid, much in the same way caffeine is a plant based alkaloid. Has caffeine gone through these rigorous processes? Is it scary that you can buy enough caffeine over the counter to kill yourself?
There are plant based alkaoid which are dangerous like vinca alkaloid as an example, which have been used to make chemotherapies. Cocaine and heroine are other kinds of alkaloids. Not benign.
 

Sushi

Moderation Resource Albuquerque
Messages
19,935
Location
Albuquerque
is it possible these "immunomodulators" help restore healthy function to the immune system?
Immunomodulator is too vague a term to mean anything useful.
Immunomodulator tends to be used in this loose way as general terminology for describing certain medications or substances used in treating ME/CFS by affecting the functioning of the immune system--for instance, LDN.
Low Dose Naltrexone (LDN) may well be the most important therapeutic breakthrough in over fifty years. It provides a new, safe and inexpensive method of medical treatment by mobilizing the natural defenses of one’s own immune system....David Gluck, MD
While this is obviously not explicit terminology, it is in common usage.
 

joshualevy

Senior Member
Messages
158
When people talk about "balanced state of the immune system" these days in the context of an autoimmune disease, they are talking about the ratio of T-reg cells to T-effector cells (which used to be called "killer T cells"). The job of the T-reg cells is to disable broken T-effector cells (ie. those which are mistakenly attacking the body's own cells. This is central to autoimmune diseases of all kinds, and quite different than Th1/Th2 balance. It is a large, active area of research in type-1 diabetes, which is questionably an autoimmune disease. Here is a recent example:
http://www.sanfordhealth.org/promo/the-sanford-project

In type-1 diabetes research the "Immunomodulator" is used to mean any drug which has been found to limit, slow down, or lessen the immune system. That is any drug that increases the number of T-reg cells, or which lower the number of T-effector cells, or which makes the T-effector cells less able to attack other cells. You can find many examples in pubmed, clinicaltrials.gov, etc.
 

nandixon

Senior Member
Messages
1,092
This 2016 paper looked at many of the pathways currently known to be affected by oxymatrine:

The potential signaling pathways involved in the clinical application of oxymatrine might include the TGF-β/Smad, toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor9/TRAF6, Janus kinase/signal transduction and activator of transcription, phosphatidylinositol-3 kinase/Akt, delta-opioid receptor-arrestinl-Bcl-2, CD40, epidermal growth factor receptor, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 signaling pathways, and dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine metabolism pathway.

One thing I noticed is that oxymatrine has some ability to inhibit the Akt/mTORC1 pathway, which (on its own) may not be a desirable trait in many ME/CFS patients since that tends to promote immune suppression (through increased activation of Tregs).

So it seems to make sense that Dr Chia apparently recommends that cimetidine (if I understand correctly) also be taken with oxymatrine. Cimetidine has the opposite effect through the Akt/mTORC1 pathway (i.e., it decreases Treg activity - reference).

I'm not sure if Dr Chia recommends cimetidine for that particular ability, but at least it seems to make sense in that way. Note that other H2 histamine blockers, like ranitidine and famotidine, do not have cimetidine's immunostimulatory ability.

I haven't tried oxymatrine myself.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
Hmm... Fluge and Mella mention a shift toward Th2 in their Phase II Rituximab paper. What do you make of this @Jonathan Edwards? ?

"A recent study investigated cytokine patterns in peripheral blood from ME/CFS patients [35], showing distinct abnormalities of both pro- and anti-inflammatory cytokines early in the course of ME/CFS, which were not present after the first three years. The same research group also showed a disturbed cytokine pattern in cerebrospinal fluid of ME/CFS patients, compared to healthy controls and multiple sclerosis patients. The findings were consistent with an immune activation and a shift towards a Th-2 pattern, which may be associated with autoimmunity [36]."
 
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Jonathan Edwards

"Gibberish"
Messages
5,256
Hmm... Fluge and Mella mention a shift toward Th2 in their Phase II Rituximab paper. What do you make of this @Jonathan Edwards? ?

"A recent study investigated cytokine patterns in peripheral blood from ME/CFS patients [35], showing distinct abnormalities of both pro- and anti-inflammatory cytokines early in the course of ME/CFS, which were not present after the first three years. The same research group also showed a disturbed cytokine pattern in cerebrospinal fluid of ME/CFS patients, compared to healthy controls and multiple sclerosis patients. The findings were consistent with an immune activation and a shift towards a Th-2 pattern, which may be associated with autoimmunity [36]."

I think they were just being polite to Mady Hornig and quoting what she said. These buzz words are deeply embedded in the citation process that goes along with publication these days.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Immunomodulator tends to be used in this loose way as general terminology for describing certain medications or substances used in treating ME/CFS by affecting the functioning of the immune system--for instance, LDN. While this is obviously not explicit terminology, it is in common usage.

Yes, but in science it is important to point out that common usage is often completely counterproductive because it just perpetuates meaningless ideas.
 

Hip

Senior Member
Messages
17,824
When people talk about "balanced state of the immune system" these days in the context of an autoimmune disease, they are talking about the ratio of T-reg cells to T-effector cells (which used to be called "killer T cells").

There is also the T-reg / Th17 cell ratio balance that people talk about in the context of autoimmunity.



No, there is no such thing as a balanced state of the immune system. The immune system fights microbes. If you like it has an army, a navy and an air force, but nobody ever talked of having a balance between those. A good commander in chief uses whichever he needs whenever. The idea of imbalance was thought up in the 1980s with no sound basis and has been a centre of immunobabble since.

I am not disagreeing with what you are saying, but do you think this tendency to devise various immune system "balances" between two immune parameters of supposedly opposing effects relates to the notion of homeostasis in biology?

Although there has been criticism of the homeostasis concept, a lot of biology seems to revolve around homeostasis, because many systems in biology only function properly when they are tightly maintained by homeostatic mechanisms within narrow ranges of operation. Blood pH and body temperature are two well-known examples of parameters that are maintained at near constant values by homeostatic mechanisms.

So perhaps that is why it is tempting for researchers to place two immune parameters that seem to have roughly opposing effects into a "balance" or ratio, in order to conceptually view it as a homeostatic mechanism.

It's easy to understand homeostasis: we are familiar with the concept just from the way our central heating thermostat works; so perhaps that is why researchers create these homeostatic "balance" concepts. Ultimately, these balance concepts may be too simplistic to be of any scientific use, but perhaps they are more a reflection of the limitations of human intelligence than anything else. Mentally, it is easy to think about the balance between two opposing forces, but much more difficult to imagine the complex interaction between the dozens of different immune parameters that are actually in play.

The question in my mind is whether these simplistic immune balances do provide some useful approximation to the truth. To give an example of an approximation to the truth: in physics, we know that strictly speaking, the Newtonian laws of motion are incorrect, and that a more correct description of motion is given by the theory of relativity. However, because relativity is mathematically much more complex, we still use the simpler Newtonian physics in most situations, and fortunately, the nice and simple Newtonian laws of motion provide perfectly adequate calculation results, provided you keep within the areas of Newtonian applicability.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
There is also the T-reg / Th17 cell ratio balance that people talk about in the context of autoimmunity.

I am not disagreeing with what you are saying, but do you think this tendency to devise various immune system "balances" between two immune parameters of supposedly opposing effects relates to the notion of homeostasis in biology?

Although there has been criticism of the homeostasis concept, a lot of biology seems to revolve around homeostasis, because many systems in biology only function properly when they are tightly maintained by homeostatic mechanisms within narrow ranges of operation. Blood pH and body temperature are two well-known examples of parameters that are maintained at near constant values by homeostatic mechanisms.

So perhaps that is why it is tempting for researchers to place two immune parameters that seem to have roughly opposing effects into a "balance" or ratio, in order to conceptually view it as a homeostatic mechanism.

It's easy to understand homeostasis: we are familiar with the concept just from the way our central heating thermostat works; so perhaps that is why researchers create these homeostatic "balance" concepts. Ultimately, these balance concepts may be too simplistic to be of any scientific use, but perhaps they are more a reflection of the limitations of human intelligence than anything else. Mentally, it is easy to think about the balance between two opposing forces, but much more difficult to imagine the complex interaction between the dozens of different immune parameters that are actually in play.

The question in my mind is whether these simplistic immune balances do provide some useful approximation to the truth. To give an example of an approximation to the truth: in physics, we know that strictly speaking, the Newtonian laws of motion are incorrect, and that a more correct description of motion is given by the theory of relativity. However, because relativity is mathematically much more complex, we still use the simpler Newtonian physics in most situations, and fortunately, the nice and simple Newtonian laws of motion provide perfectly adequate calculation results, provided you keep within the areas of Newtonian applicability.

People talk a lot about T reg and TH17 but shifts in these are associated with auto inflammatory states like ankylosing spondylitis and Crohn's disease, not autoimmunity.

I suspect that the idea of 'balance' may indeed reflect a muddled idea about homeostasis. However, the two are quite different concepts. Each innate immune signals has negative feedback systems that are homeostatic. But that has nothing to do with 'balance' between two signals. In some situations you will want not much of either X or Y signal - if all is well. In some situations you may want lots of X but no Y and in some lots of Y and no X and in yet others lots of both. In all cases the amounts will be controlled switch off mechanisms when the job is done. Where does 'balance' come in to that?

The idea that autoimmunity has something to do with shifts in innate signal levels makes no sense epidemiologically or stereochemically. Each autoimmune state is a specific adaptive error. People do not develop a swathe of autoimmune reactions, as might be expected if innate signals were 'out of balance'. The whole business is based on no data at all, other than highly artificial experiments in mice that are designed to get the answer the theorist wants.
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
Sorry, but to someone who spent thirty years in immunology those papers do not add up to a row of beans. People assume there is a 'TH1 response' and a 'TH2 response' because that is what the mouse people have decided and the human people want to be as savvy, but there is about as much substance here is in certain recent claims by politicians about making countries great etc. This is not real science I am afraid.

With all due respect, if assumptions were made, they were tested to see if there was any validity, and not by 'mouse people', but doctors like Nancy Klimas M.D., who has 30+ years of experience not only studying the disease, but treating ME/CFS patients. To compare claims based on her work to those of Donald Trump is bizarre and insulting IMO.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
With all due respect, if assumptions were made, they were tested to see if there was any validity, and not by 'mouse people', but doctors like Nancy Klimas M.D., who has 30+ years of experience not only studying the disease, but treating ME/CFS patients. To compare claims based on her work to those of Donald Trump is bizarre and insulting IMO.

It is the reality of science these days I am afraid. I am not aware that Nancy Klimas has any reason to think there is such a thing as TH1/Th2 balance in humans. Sadly the mythology is almost ubiquitous. I grew up with the people who invented these ideas and they never had any human evidence relating to autoimmunity. I think I can claim to know a bit about autoimmunity having devised one of the major novel therapies based on my understanding.
 

msf

Senior Member
Messages
3,650
Anecdotally, oxymatrine did nothing at all for me... :confused:

I happen to agree with JE on the "Th2 vs Th1" thing, it is an oversimplification. There is no such terminal differentiation. Studies have shown "Th2" T cells can be stimulated by and secrete "Th1" cytokines and vice versa.

The historical Th2/Th1 observations are simply transient cellular adaptations to the microenvironment.

Note that as such, those derived from blood don't necessarily represent what might be going on where there is specific peripheral inflammation.

I realise some might not find this answer satisfactory, so here is a longer answer I've just found, including some history and why the concept is outmoded:

https://www.quora.com/Whats-the-difference-between-Th1-and-Th2-helper-T-cell-subsets

That was an interesting link, thanks. I think it is probably useful to distinguish between the strict Th1/Th2 theory enumerated in the link, and the use of Th1/Th2 to refer to a net inflammatory/antinflammatory cytokine state in certain areas of the body (normally in the blood).