PHANU Rising II: Dr. Marshall-Gradisnuk Talks on Rituximab, Biomarkers and Chronic Fatigue Syndrome

PHANU is moving to a bigger, better laboratory at Griffith University

PHANU is rising.... Lead by Dr.Sonya Marshall-Gradisnuk and Dr. Donald Staines, the PHANU ME/CFS Australian research team presented more studies at the 2011 Ottawa IACFS/ME conference than any other, scored a major grant from the Mason Foundation, established close ties with Dr. Peterson at the Simmaron Foundation and is moving to a larger laboratory at Griffith University.

This team is moving....Despite being formed just three years ago, PHANU's co-leader, Dr. Staines provided the keynote speech on "New Directions for ME/CFS Research" and Dr. Marshall-Gradisnuk followed that up with a talk on Immunological Biomarkers at the 2011 Invest in ME conference.

Earlier this year Phoenix Rising got to talk with Dr. Marshall-Gradisnuk. The interview revealed a 'quietly confident' and careful researcher.

Background


] Dr. Marshall-Gradisnuk's PHANU research team lit up the Ottawa IACFS/ME Conference

We really appreciate any researcher that takes on chronic fatigue syndrome and you are now deeply immersed in it. You’ve done a lot of work on exercise physiology and the effects of hormones on exercise and the immune system. In retrospect it seems like you would be a good fit for a group of patients with poor exercise ability, poor natural killer cell functioning and hormonal issues. How did you get started with this disorder?

Our collaboration between Bond University and Queensland Health grew from a joint interest in neuroimmunology and public health. In particular there are a number of conditions of public health importance which possibly have a neuroinflammatory or neuroimmune basis. Hence our research interest.

We expect to grow to include not only ME/CFS but perhaps multiple sclerosis, Parkinson’s disease and disorders of ageing. As you have noted it builds upon our strengths in exercise physiology, immunology and public health. (Since this interview was done PHANU has been moving to a bigger lab space in Griffith University)

Rituximab and Autoimmunity in Chronic Fatigue Syndrome


PHANU researchers have long been interested in autoimmunity in ME/CFS and hope to do a Rituximab study

When you accepted the Mason Foundation grant you stated that it would allow you to conduct a Rituximab pilot study. Is that a done deal?

Again this research is in early days. Having only just been notified of this grant there is now much to be done by way of planning and implementing the research programme. We are hoping to link in with other researchers on the Rituximab issue to implement this research as soon as possible. We can’t say for sure at this stage how long it will take.

We know that Rituximab works in many auto-immune diseases and cancer but that it’s also a very powerful drug and, of course, ME/CFS appears to be heterogeneous condition. Dr. Peterson is excited about the drug but he’s also warned that some people with ME/CFS may need their B-cells. If you are doing a pilot trial will you be trying to uncover what types of patients Rituximab works in?

This will be for the study design. We don’t have the fine details on this question yet, however we are finalizing this in the coming months.

Except for yourself and Dr. Staines, not much attention has been given to the potential autoimmune aspects of ME/CFS. In a series of papers over the past few several years you’ve proposed that an autoimmune reaction to the neuropeptides that effect the integrity of the blood/brain barrier might be present in CFS and other disorders. If this enticing theory is true it could account for neuro-inflammation and/or neurodegeneration in a host of ‘neuropsychiatric disorders’ such as multiple sclerosis, Parkinson’s disease, ALS and ME/CFS. Unless I’m wrong, though, work hasn’t been done yet to prove or disprove its efficacy in ME/CFS has it?

As you say this is an enticing theory but still only a theory. Our task is to link researchers with skills in all these areas who may not have worked together before in ME/CFS. Autoimmunity probably has a role in the conditions you mention.

Unfortunately it has not been a prominent part of ME/CFS research except for our group at Bond University. However as awareness of this possibility gradually expands, supported by our research findings, we believe research funding institutions will not wish to neglect developing scientific evidence that ME/CFS may in fact be an autoimmune disorder.

The other side of the coin is that CBT and GET, which we have always been opposed to in ME/CFS, may be shown to have no place in a proper medical scientific approach to ME/CFS diagnosis and treatment.

Will you be using your grant monies to take a deeper look at this theory?

Yes, that is correct.

In one paper you suggest that phosphodiesterase inhibitors such as the ‘antidepressant’ Rolipram which has been found to have anti-inflammatory and immune modulating factors as well. Have it or any other PDE4 inhibitors been tried in ME/CFS to your knowledge?

We are not aware PDEIs have been tried in ME/CFS before. However PDEIs have been proposed by us in several publications. We urge caution, though, as these drugs are potent and have side-effects. Be clear that we are not recommending them because they may have anti-depressant effects. It just so happens these drugs may, for theoretical reasons, be useful in ME/CFS. ME/CFS is not a psychiatric disorder and no inference should be drawn from the rationale for using PDEI's.

Ottawa IACFS/ME ME/CFS Conference

PHANU has focused a great deal of attentions on natural killer and T-cells (natural killer cell receptor pictured)

The 2011 Ottawa conference was really a breakout conference for PHANU. You submitted more abstracts and presentations than any other group and some of your preliminary findings – altered immune functioning after vaccination, altered purinergic functioning, altered gene expression during pregnancy, altered miRNA levels in natural killer cells – and others were fascinating.

Thank you for the acknowledgement and it was a great regret that I could not attend, however PHANU was very well represented. Our group has worked very hard in the past three years to get to where are today. I am very proud to lead a very talented group of researchers and clinicians as well as have significant funding support from the Alison Hunter Memorial Foundation as well as the QLD Government and Mason Foundation.

Our research has been always been focused on the potential neuroimmune mechanisms and autoimmunity through assessing the cellular and molecular mechanisms in CFS/ME.

At the Ottawa conference Dr. Klimas called PHANU’s finding of reduced cytotoxic T-cell functioning a ‘gold star’ study and said it was a significant advance. If you can prove reduced perforin levels and functioning in cytotoxic T-cells as well as natural killer cells, how would that change things?

I feel very honoured that Professor Klimas stated this at the conference. My approach is to always approach research and outcomes very carefully and in terms of these results it may have indicated a further marker for CFS/ME.

Dr. Peterson and Simmaron

Dr. Peterson was a co-author of several PHANU studies at the Ottawa IACFS/ME conference. How did PHANU in Australia hook up with a Nevada physician/researcher?

I along with the CFS/ME research group that I lead have the greatest respect for Dr Peterson, He is a true gentleman and an amazing clinician. I met Dr Peterson when he came to Bond University in December 2010 when he was invited to an International Science Symposium for CFS/ME that I was leading with Dr Staines from Queensland Health.

Our meeting was organized by the Alison Hunter Memorial Foundation - a wonderful group of dedicated people. I am very proud to say that Dr Peterson is a significant collaborator on a number of large national grants for CFS/ME that I have.

Biomarker for CFS

You stated “Ultimately our aim is to develop a clear diagnostic test for CFS and establish a national testing facility here at Bond University, which we believe could happen within five years”. A biomarker, of course, kind of like the holy grail for ME/CFS; lots of people have tried (and are trying) yet we still don’t have one. Regarding PHANU’s ability to find a clear diagnostic in five years would you say you are hopeful, cautiously optimistic, quite optimistic or feel pretty sure it will happen).

Quietly confident

Could we have a biomarker right now and not know it? Something that has been identified but not fully validated?

Probably not. It will be important to truly understand the pathomechanisms of ME/CFS before anyone can be 100% confident in a biomarker.

Research

The preliminary results from PHANU's pregnancy study suggests estrogen could play a role in neuro-immune issues in chronic fatigue syndrome

Phanu also presented a fascinating study focusing on gene expression during pregnancy in chronic fatigue syndrome patients at the Ottawa Conference. The study was prompted by two observations: (1) that some women with CFS temporarily get better in the midst of their pregnancy and (2) that women with autoimmune disorders such as multiple sclerosis often experience the same pattern. Preliminary results from the study suggested that the normal gene expression patterns found in pregnancy may not occur in pregnant women with ME/CFS.

This is a fascinating much under-investigated area in ME/CFS area given the gender predominance in CFS and it goes nicely with a CDC story showing strikingly high rates of women with CFS with heavy rates of bleeding, premenstrual problems and other gynecologic abnormalities including disturbing high rates of hysterectomies. Can you tell what these studies may mean?

Yes, these studies provide significant insight into the possible neuroimmune mechanism that may possibly underlie CFS/ME. Moreover, the predominance of CFS/ME in females and the associated symptoms that have been documented may be possibly explained by oestrogen having pleotropic effects on the immune system.

It has been shown that exposure to oestrogens stimulates antibody production but decreases T-cell mediated delayed-type hypersensitivity (DTH), granulocyte-mediated inflammation and natural killer (NK)-cell mediated cytotoxicity. The heightened antibody response, while decreased immune function, suggests as we have thought for many years, the neuroimmune influences on CFS/ME.

Preliminary results from a PHANU blood and spinal fluid study suggested that neuropeptides involved with a central nervous signaling pathway called the purinergic system were abnormal in ME/CFS patients.

This system showed up in neon lights in the Light gene expression studies. The purinergic receptors they found play a role in several areas of interest in CFS including immune regulation, the smooth muscles lining the blood vessels (think blood volume), pain sensitization in the immune cells in the spinal cord/ brain, and in sympathetic nervous system functioning. Can you comment on this finding?

Further evidence on the role of the purinergic system is also required. The purinergic system has a significant influence over T cell functioning and neurotransmitter roles such as in neuropathic pain. Generally this supports the notion that neruoimmune mechanisms may underlie CFS/ME

You’ve done quite a bit of research on the effect hormones have on the immune system and on exercise. There do appear to be hormonal irregularities in ME/CFS but they appear to be mostly mild. Do you think problems with hormones such as cortisol, norepinephrine, epinephrine will play a major role in the immune dysfunctions found or in the problems with exercise?

This is a very complex question. At this stage we would simply suggest there may be disorders of neurotransmitter metabolism that we will better understand when the pathomechanisms are known. These disorders are likely to be exacerbated by exercise. We do not support exercise testing in ME/CFS patients; however, our understanding of exercise physiology and biochemistry has been a significant strength for us.

(eds. note - neurotransmitters are a big focus in chronic pain disorders such as fibromyalgia, IBS, TMD, etc.)

Your exercise study with healthy people suggested that increased stress hormone production (norepinephrine, epinephrine and cortisol) after exercise tends to reduce natural killer, cytotoxic T-cell and B-cell levels and that NK cell levels were knocked down for over 24 hours. Given the problems with NK (and now T-cell functioning) levels in ME/CFS and the exercise issue this is an intriguing finding.

Yes, it is true these studies provide a very good insight into the possible neuro-immune interactions following a stressed induced activity such as exercise. CFS/ME patients may not be ideally applied for a blanket method intervention, however, due to the number of CFS/ME sub groups.

The biphasic response of total lymphocytes numbers may be due to circulating stress hormones, including epinephrine, norepinephrine, and cortisol. It has been suggested that catecholamines induce the initial increase in lymphocyte numbers, whereas cortisol induces lymphopenia after exercise. This exercise induced immunoregulation of the endocrine system on lymphocytes is seen in lymphocytes including CD8+ T-cells and NK cells.

Further evidence on effects on catecholamine metabolism is required along with evidence of a possible disorder of the cholinergic system.

• PHANU Rising Pt I: Australian Research Group Making Waves
• Next Up: PHANU at Work - the Immune Findings

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[/quote]View the Post on the Blog

 

I would just like to suggest that referring to ME/CFS as a neuroimmune or neuroendocrineimmune disorder implies that the basic problem lies in the nervous system, the endocrine system and the immune system. I think this is misleading. It's true that many of the symptoms in ME/CFS are associated with dysfunction in these three systems. In addition, there are other symptoms that are associated with the skeletal and heart muscles and with the digestive system.

But I maintain that the basic problem is not in any of these individual systems and organs as they are usually compartmentalized for study. Rather, the dysfunctions in all these organs and systems stems from a common cause, which is more fundamental. That common cause is in the basic biochemistry, which affects all these organs and systems. It's the vicious circle that includes glutathione depletion, a functional B12 deficiency, a partial block in the methylation cycle, loss of folates from the cells, and draining of the sulfur metabolism.

This is the essence of the pathophysiology, in my view, and the dysfunctions in all the above systems and organs stem from it. It explains why this disorder is chronic. It explains the oxidative stress. It explains the mitochondrial dysfunction. It explains why certain other vital organs are not seriously impacted, including the liver, kidneys and pancreas. It explains the leading candidate for being a biomarker, i.e. the lowered activity of the NK cells, which is due to low perforin production, in turn due to glutathione depletion in the NK cells. It explains why the gene expression for perforin was observed to be higher than normal, while the amount of perforin produced was found to be lower than normal.

So far, the GD-MCB hypothesis appears to be able to explain the published research results in ME/CFS, and treatment based on it is reported by many PWMEs to be helping them.

I have shared my views with the PHANU group. I wish them success in their ongoing research effort.

Best regards,

Rich

Rich if this is the cause..how effective is the treatment and how much work needs to be done in that area?

 

Hi, Cort.

The treatment seems to be pretty effective for correcting the vicious circle mechanism, which I believe is the core of the pathophysiology. It really needs an orthodox clinical trial in order to be taken more seriously by the mainstream medical system, though. The little clinical study that Dr. Nathan and I carried out showed good results, but without placebo control, larger numbers of patients, and other improvements, most of the M.D.s will not take tje treatment very seriously, especially since no prescription drugs are involved.

Also, the treatment does not directly address the etiologies (root causes), including the infections with various pathogens and the toxins. In addition, various infections and toxins come on board after the onset of the disorder, because the immune system and the detoxication system become dysfunctional as a result of the vicious circle mechanism. So my view is that the place where work needs to be done in order to increase the number of recoveries is in ways of knocking out the infections and supporting the immune system (such as is going on with work on Ampligen, low-dose naltrexone, the various forms of MAF, antivirals, and Retuximab), and also in detoxification of toxins.

I also think more attention should be given to determining congenital immune deficiencies and congenital deficiencies in the detox system. I suspect that many PWMEs became ill because they were genetically vulnerable to infections or buildup of toxins. We need to better understand what these genetic deficiencie are and how to compensate for them.

Best regards,

Rich

 

Hi, Heaps.

I agree that treating the partial methylation cycle block is not the whole answer for most PWMEs. As I see it, this treatment addresses the core of the pathophysiology, but it does not directly address the etiologies (root causes) or the toxins and pathogens that may have accumulated during the illness. It can help with these, because it restores the function of the immune system and the detoxication system, but if the toxic load is too high, the detox system is not able to take care of it on its own, and there are many ways that various pathogens can hide from the immune system or foil it, so they may need to be dealt with directly, also. I agree that positive results seen in some cases with Ampligen, antivirals, Rituximab, LDN and the various forms of MAF are clues suggesting that the above is true. I also suspect that many PWMEs have congenital immune deficiencies that made them vulnerable to various infections. These may include IgG subclass deficiencies and mannose binding lectin deficiency, among others.

Best regards,

Rich

Hi Rich,

i think everyone has their specialties like ritux or treating the herpes viruses or yourself with methylation block. I think we are just waiting on someone to be able to bring it all together. I think many of us patients here are trying to do this is some form. As for PHANU i dont think that they are 100% into looking at a treatment, more looking into a diagnostic test for cfs/me.

cheers!!!

 

A very intriguing interview, not least the attention to changes in pregnancy. As someone who 17 years into the illness had her first of 2 pregnancies (the second swiftly following the first.. though not designed that way !!) and after severe hyperemesis had a very pronounced improvement which was maintained for almost 18 months post parturition I'm impressed that someone of SMG's calibre is at last looking at this. I suppose it's a logical step if you're going to treat ME as a possible autoimmune illness (I have had positive ANAs for many years at different points in my long ME history). What I'd hope the team might consider is the effect pregnancy might then have on women with ME in the long term. I revelled in the (almost but not quite 100%) improvement I had for those months in parts of my pregnancies and after the second, but since that time my ME has become much worse generally. I became housebound when my youngest first started school and that situation has not changed..has only become worse. Looking back I see the first 17 years as being very difficult, but 'cycling' in remissions and relapses where no remission met the quality of that attained in pregnancy but where, at times, I could pretend (almost) that I was 'functioning' as part of society, even if it was at a very low level. Since then, and my son turns 25 on Saturday, I have had a consistently downward trajectory and as I meet menopause I have also met my very worst symptom thus far: severe neuropathic pain of the skin which is horrific. It seems to me that the upheaval of pregnancy somehow creates changes which fundamentally change the terrain of the ME-ridden body, and not for the better. I do hope PHANU continue to look at this aspect in greater detail, not least as it may inform more generally.

Lilpink - your story is so similar to mine! I became ill during my 4th pregnancy. I went into a good remission for my 5th and relapsed about 3 months after she was born. I went into a short remission during my 6th pregnancy but miscarried and heamorraged (sp?) and then lost the 7th too (had a D&C to avoid another big bleed out). I went into a shorter remsission during my 8th pregnancy but relapsed with a serious chest infection at the end and she arrived earlier than the booked c-section when I had to have an emergency section. Thankfully she was fine. I lost a lot of blood during all 3 c-sections and docs got their knickers in a twist over my low platelets.
Even though I relapsed before Heleyna was born I found breast feeding helped symptoms (or at least symptoms were not as bad while I fed her) at least for the first 3 or 4 months.

I had a serious relapse just over 2 years ago, recovered a bit and am now getting progressively worse (my youngest is 5).

I really hope PHANU find some good solid answers.