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

Posted by Cort Johnson

Griffiths University home o2
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.


Sonya Marshall Gradisnuk PH1
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 PDEIs.

Ottawa IACFS/ME ME/CFS Conference

natural killer cell recepto
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.


Estrogen receptor
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.


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