nandixon
Senior Member
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I have an idea for a different mechanism for immune dysfunction in ME/CFS to what Drs. Fluge and Mella suggest in their recent paper:
B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment [2015]
and as a result, also a suggestion to investigate the possibility of using very low dose cyclophosphamide (CTX) as potentially an equally effective treatment to what those doctors have seen so far with both rituximab (RTX) and "normal" (i.e., high) dose CTX infusions, and with greater safety than standard oral dosing of CTX.
The authors state in the paper:
(My bracketed italics.)
If I understand correctly, Drs. Fluge and Mella have more recently found that CTX gives a much more rapid response than RTX. I think this tends to argue away somewhat from an autoimmune hypothesis (Option 1), although it doesn't rule it out by any means. One reason is that CTX is even less likely than RTX to affect the long-lived plasma cells responsible for the presumed lingering autoantibody production after RTX treatment.
Instead, I think it's possible that a reduction in pathological regulatory T cell (Treg) activity (an Option 2 possibility) could be behind the favorable response seen with both RTX and CTX. This would tend to make some variant of immune suppression more likely as a potential underlying cause of ME/CFS as opposed to autoimmunity.
(There's also the possibility for a sort of hybrid of Options 1 and 2, for example an agonistic autoantibody that increases Treg activity via a Treg cell receptor.)
If I understand correctly, depending on the background of the disease being treated, RTX has a sort of "dual" ability to potentially either reduce Tregs where a state of immune suppression is present (e.g., cancer), or to increase Tregs where there is autoimmunity. (It's not quite so simple but that's the general pattern, I think.)
CTX has the ability to "target" and destroy Tregs. (At normal/high doses it somewhat indiscriminately destroys other cell types as well.) And, as I've mentioned before in the rituximab forum, CTX can do this targeting of Tregs very selectively and at a much lower dose than is commonly used. This is because Tregs lack the p-glycoprotein (ABCB1) transporter capability that clears drugs like CTX from within cells. (See: Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis [2014])
I've been having continuous good success, for a month now, using cimetidine (Tagamet). It's the only substance I've found in 17+ years of having ME/CFS that has been able to partially reverse the disease (although not a cure by any means). (See, e.g., this post.)
Cimetidine is more commonly known as an older stomach acid reducer (an H2 blocker), but its most interesting ability, known to researchers since at least 1980, is its ability to decrease Treg activity in immune suppression states, particularly cancer. (Neither ranitidine nor famotidine affect my ME/CFS, ruling out a general H2 blocker or mast cell-related effect.)
I'm very suspicious that cimetidine is essentially acting as a "weaker" version of CTX. Cimetidine decreases Treg activity (possibly by interfering with an H2 receptor on the cell surface), while CTX actually destroys the Tregs and decreases their number.
I think it is worth investigating whether similar results to what have been seen so far using either RTX or normal (i.e., high) dose CTX infusions in the Norwegian trials can instead be achieved by using what I would term "very low dose cyclophosphamide" - in order to take advantage of the remarkable selectivity CTX has against Tregs at low concentrations (again, because Tregs lack ABCB1 gene expression and therefore lack the drug-clearing p-glycoprotein transporter).
This would be an amount of CTX certainly less than 50 mg (total) per day, given orally. For example, in theory I think 5 or 10 mg (or even less) a day is possibly a sufficient/effective amount for targeting only Tregs. I think that should be significantly safer in terms of potential bladder toxicity compared to standard oral dosing of CTX (e.g., >100 mg/day) and far less expensive than either RTX or the "normal" (i.e., high) dose infusions of CTX currently being studied in Norway. [Note: I'm a former medicinal chemist researcher, not a doctor. Do not try this at home!]
(The greater chance may be that the true problem lies upstream of the Tregs but is significantly impacting them, rather than there being an inherent problem with the Tregs themselves. So if for example the upstream problem lay with dysfunctional B cells, then in that case RTX might be a better choice for the long term than CTX - if RTX was actually capable of achieving a permanent or very sustained remission.)
Interestingly, significant Treg involvement in ME/CFS seems to also fit well with some of the endothelial- and nitric oxide-related observations that the Norwegians have made. See for example:
Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation [2014]
Nitric Oxide Modulates TGF-β–Directive Signals To Suppress Foxp3+ Regulatory T Cell Differentiation and Potentiate Th1 Development [2011]
Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide [2010]
Lastly, my understanding appears different with respect to a few points the authors note in the paper, as follows. They state:
My understanding is that elevated Tregs are actually more generally associated with immune suppression, not autoimmunity. And that more typically, decreased numbers/activity of Tregs are found in autoimmune states.
The authors additionally state:
Again, my understanding is that polarization towards a suppressive phenotype (i.e., increased Treg numbers/activity) tends to be the effect RTX has when it's used in autoimmune cases. I think the opposite (i.e., decreased Tregs) tends to occur when RTX is used in immune suppressed states.
In conclusion, I think an immune suppression state due to pathological Treg activity is a valid alternative explanation to the autoimmune possibility. This would also be more consistent with the yet to be published findings Dr. Jose Montoya of Stanford has mentioned regarding the very close similarity between ME/CFS and Systemic Inflammatory Response Syndrome (SIRS) found in a large gene expression study. (See, e.g., this post.)
Additionally, I believe that very low dose CTX might be useful to determine the extent of Treg involvement in ME/CFS - due to its capability to target Tregs in a highly selective manner - and if we were very lucky might possibly make a far less expensive treatment available sooner to a greater number of patients. To be clear, this is just a hypothetical possibility to explore.
B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment [2015]
and as a result, also a suggestion to investigate the possibility of using very low dose cyclophosphamide (CTX) as potentially an equally effective treatment to what those doctors have seen so far with both rituximab (RTX) and "normal" (i.e., high) dose CTX infusions, and with greater safety than standard oral dosing of CTX.
The authors state in the paper:
The lag time before clinical improvement may be compatible with a mechanism involving reduction of long-lived autoantibodies [Option 1], or some other slow alteration in immune function governed by B-cells [Option 2].
(My bracketed italics.)
If I understand correctly, Drs. Fluge and Mella have more recently found that CTX gives a much more rapid response than RTX. I think this tends to argue away somewhat from an autoimmune hypothesis (Option 1), although it doesn't rule it out by any means. One reason is that CTX is even less likely than RTX to affect the long-lived plasma cells responsible for the presumed lingering autoantibody production after RTX treatment.
Instead, I think it's possible that a reduction in pathological regulatory T cell (Treg) activity (an Option 2 possibility) could be behind the favorable response seen with both RTX and CTX. This would tend to make some variant of immune suppression more likely as a potential underlying cause of ME/CFS as opposed to autoimmunity.
(There's also the possibility for a sort of hybrid of Options 1 and 2, for example an agonistic autoantibody that increases Treg activity via a Treg cell receptor.)
If I understand correctly, depending on the background of the disease being treated, RTX has a sort of "dual" ability to potentially either reduce Tregs where a state of immune suppression is present (e.g., cancer), or to increase Tregs where there is autoimmunity. (It's not quite so simple but that's the general pattern, I think.)
CTX has the ability to "target" and destroy Tregs. (At normal/high doses it somewhat indiscriminately destroys other cell types as well.) And, as I've mentioned before in the rituximab forum, CTX can do this targeting of Tregs very selectively and at a much lower dose than is commonly used. This is because Tregs lack the p-glycoprotein (ABCB1) transporter capability that clears drugs like CTX from within cells. (See: Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis [2014])
I've been having continuous good success, for a month now, using cimetidine (Tagamet). It's the only substance I've found in 17+ years of having ME/CFS that has been able to partially reverse the disease (although not a cure by any means). (See, e.g., this post.)
Cimetidine is more commonly known as an older stomach acid reducer (an H2 blocker), but its most interesting ability, known to researchers since at least 1980, is its ability to decrease Treg activity in immune suppression states, particularly cancer. (Neither ranitidine nor famotidine affect my ME/CFS, ruling out a general H2 blocker or mast cell-related effect.)
I'm very suspicious that cimetidine is essentially acting as a "weaker" version of CTX. Cimetidine decreases Treg activity (possibly by interfering with an H2 receptor on the cell surface), while CTX actually destroys the Tregs and decreases their number.
I think it is worth investigating whether similar results to what have been seen so far using either RTX or normal (i.e., high) dose CTX infusions in the Norwegian trials can instead be achieved by using what I would term "very low dose cyclophosphamide" - in order to take advantage of the remarkable selectivity CTX has against Tregs at low concentrations (again, because Tregs lack ABCB1 gene expression and therefore lack the drug-clearing p-glycoprotein transporter).
This would be an amount of CTX certainly less than 50 mg (total) per day, given orally. For example, in theory I think 5 or 10 mg (or even less) a day is possibly a sufficient/effective amount for targeting only Tregs. I think that should be significantly safer in terms of potential bladder toxicity compared to standard oral dosing of CTX (e.g., >100 mg/day) and far less expensive than either RTX or the "normal" (i.e., high) dose infusions of CTX currently being studied in Norway. [Note: I'm a former medicinal chemist researcher, not a doctor. Do not try this at home!]
(The greater chance may be that the true problem lies upstream of the Tregs but is significantly impacting them, rather than there being an inherent problem with the Tregs themselves. So if for example the upstream problem lay with dysfunctional B cells, then in that case RTX might be a better choice for the long term than CTX - if RTX was actually capable of achieving a permanent or very sustained remission.)
Interestingly, significant Treg involvement in ME/CFS seems to also fit well with some of the endothelial- and nitric oxide-related observations that the Norwegians have made. See for example:
Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation [2014]
Nitric Oxide Modulates TGF-β–Directive Signals To Suppress Foxp3+ Regulatory T Cell Differentiation and Potentiate Th1 Development [2011]
Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide [2010]
Lastly, my understanding appears different with respect to a few points the authors note in the paper, as follows. They state:
Several studies have provided data suggesting autoimmunity as a possible mechanism in a subgroup of ME/CFS. Altered B-cell subtypes compared to healthy controls have been detected [31], also reduced NK-cell activity and elevated T-regulatory cells [32].
My understanding is that elevated Tregs are actually more generally associated with immune suppression, not autoimmunity. And that more typically, decreased numbers/activity of Tregs are found in autoimmune states.
The authors additionally state:
However, other underlying mechanisms than autoimmunity may explain the observed clinical effects of B-cell depletion on ME/CFS symptom maintenance. RTX influences other aspects of immune function than the pronounced effect on CD20 positive B-cells. These include... T-cell polarization to a suppressive phenotype...
Again, my understanding is that polarization towards a suppressive phenotype (i.e., increased Treg numbers/activity) tends to be the effect RTX has when it's used in autoimmune cases. I think the opposite (i.e., decreased Tregs) tends to occur when RTX is used in immune suppressed states.
In conclusion, I think an immune suppression state due to pathological Treg activity is a valid alternative explanation to the autoimmune possibility. This would also be more consistent with the yet to be published findings Dr. Jose Montoya of Stanford has mentioned regarding the very close similarity between ME/CFS and Systemic Inflammatory Response Syndrome (SIRS) found in a large gene expression study. (See, e.g., this post.)
Additionally, I believe that very low dose CTX might be useful to determine the extent of Treg involvement in ME/CFS - due to its capability to target Tregs in a highly selective manner - and if we were very lucky might possibly make a far less expensive treatment available sooner to a greater number of patients. To be clear, this is just a hypothetical possibility to explore.
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