Tuesday, 11 February 2014

Guest Post: Professor Michael Pender

Professor Michael Pender explains how anti-EBV cell therapy works in MS. #MSBlog #MSResearch

"At the request of one of you and following on from his recent publication on treating EBV by transfer of virus killing T cells we asked Prof. Michael Pender from Australia to give you more details on his group's work."


Professor Michael Pender graduated from The University of Queensland in 1974 with First Class Honours in Medicine and a University Medal. Over the next six years he trained as a physician and neurologist at the Royal Prince Alfred Hospital and St Vincent's Hospital, Sydney, and became a Fellow of the Royal Australasian College of Physicians in 1981. During his clinical training he developed a keen interest in multiple sclerosis which has continued since then. 

After completing clinical training in neurology, he commenced research on experimental autoimmune encephalomyelitis under the supervision of Professor Tom Sears at the Institute of Neurology, Queen Square, London. In 1983 he was awarded a PhD from the University of London and Queen Square Prize for Research. From 1984-1986 he continued this research as a Research Fellow at the John Curtin School of Medical Research, Australian National University, Canberra, in the Department of Experimental Pathology chaired by Professor Peter Doherty, Nobel laureate. In 1987 he was appointed Senior Lecturer in the Department of Medicine, The University of Queensland, at the Royal Brisbane Hospital. In 1989 he was awarded a Doctorate of Medicine from The University of Queensland for research on experimental autoimmune encephalomyelitis and was promoted to Reader in Medicine. In 1995 he was promoted to Professor of Medicine (Personal Chair), The University of Queensland. He also held the position of Director of Neurology, Royal Brisbane and Women's Hospital, from 1992-2005. He is Director of The University of Queensland Multiple Sclerosis Research Centre and an Honorary Senior Principal Research Fellow at the QIMR Berghofer Medical Research Institute, and directs the Multiple Sclerosis Clinic at the Royal Brisbane and Women's Hospital. In 2006 he was awarded the Multiple Sclerosis Australia Prize for Multiple Sclerosis Research - 'For outstanding commitment and dedication to research into the cause and cure of Multiple Sclerosis in Australia'. In 2011 he received the John H Tyrer Prize in Internal Medicine, The University of Queensland, for research in the field of Internal Medicine.

Professor Pender writes
A large body of evidence indicates that infection with Epstein-Barr virus (EBV) has a role in the development of multiple sclerosis (MS). EBV infects B cells and plasma cells, the white blood cells that make antibodies. Once a person is infected with EBV, they carry the virus in their B cells for the rest of their life. Normally the number of EBV-infected B cells is kept under tight control by the immune system especially by CD8+ T cells, which kill the infected cells. 
In 2003 I published a new theory in Trends in Immunology proposing that chronic autoimmune diseases such as MS and rheumatoid arthritis are caused by uncontrolled EBV infection leading to infection of autoreactive B cells, which accumulate in the organ affected by the autoimmune disease. I proposed that MS was caused by the accumulation in the brain of EBV-infected autoreactive B cells which produce anti-brain antibodies and also provide survival signals to autoreactive T cells that would otherwise die in the brain by apoptosis (programmed cell death). The theory made predictions which have subsequently been verified, namely: the presence of EBV-infected B cells in the brain in MS; a beneficial effect of rituximab which kills B cells, including EBV-infected B cells; decreased CD8+ T cell immunity to EBV in MS; and EBV infection of autoreactive plasma cells in the joints of people with rheumatoid arthritis. It also predicted that boosting CD8+ T cell control of EBV by vaccination or by adoptive immunotherapy would prevent and successfully treat chronic autoimmune diseases.

EBV-specific adoptive immunotherapy involves growing T cells from the blood in the laboratory with an EBV vaccine to retrain the cells to be potent killers and then returning them to the patient by intravenous infusion. This treatment was developed by Professor Rajiv Khanna of the QIMR Berghofer Medical Research Institute in Brisbane to treat patients with EBV-related malignancy and does not require the use of any drugs. Professor Khanna and his team have successfully used this therapy to treat EBV-related metastatic nasopharyngeal carcinoma. This EBV vaccine expresses parts of three EBV proteins, which are crucial in allowing EBV-infected B cells to multiply and mature into memory B cells and plasma cells capable of producing large amounts of antibody. As it happens, Francesca Aloisi’s group have shown that these same three EBV proteins are the main EBV proteins present in the brain-infiltrating EBV-infected B cells in MS.

EBV-specific adoptive immunotherapy has not previously been used to treat people with MS or any other autoimmune disease. Because we were concerned that the therapy might aggravate inflammation in the brain and actually worsen MS, we reduced the initial dose of T cells to 25% of the dose used by Professor Khanna to treat EBV-related malignancy. We then gradually increased the dose over the next three infusions, which were administered at fortnightly intervals. The first recipient was a 42 year old man with secondary progressive MS. The treatment had no adverse effects and within 2 weeks the patient began to experience clinical improvement. This was followed by further improvement, with a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T cell infusion, when neurological examination demonstrated increased movement of his legs. There was also reduced disease activity on his MRI brain scan and reduced antibodies in the cerebrospinal fluid.

We believe that the beneficial effects of the therapy are due to the killing of EBV-infected B cells in the brain by the transferred CD8+ T cells. The beneficial effect of boosting immunity to EBV by this treatment highlights the importance of impaired immunity to EBV in the development of MS. A clinical trial is now needed to determine safety and therapeutic efficacy across the clinical spectrum of MS.

CoI: None

34 comments:

  1. Prof. Pender you and Prof G seem to be convinced that EBV is the cause of MS. Why can't it simply be an association? How do you explain the results so many DMTs with their varied modes of action in terms of the EBV hypothesis? How do reconcile the fact that there EBV negative people with MS? It all seems to simple.

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    1. Thank you for these good questions. Yes, I do believe that EBV infection causes MS through the mechanism I first proposed in 2003 (Pender [2003] Trends in Immunology 24:584-588) and again in 2011 (Pender [2011] The Neuroscientist 17:351-367) (http://nro.sagepub.com/content/17/4/351.long). My hypothesis proposes that MS is truly an autoimmune disease that is dependent on the professional antigen-presenting capacity of EBV-infected autoreactive B cells in the brain to provide survival signals to autoreactive T cells that would otherwise die in the brain (as well on the production of anti-brain antibodies by the infected B cells and plasma cells). The beneficial effects of disease-modifying therapies (DMTs) in relapsing-remitting MS can be explained by inhibition of the activation and proliferation of autoreactive T cells and/or inhibition of the entry of these T cells into the brain. The efficacy of interferon beta in relapsing-remitting MS might also be due to its potent antiviral actions and ability to enhance the antiviral CD8+ T cell response. However, none of the currently available DMTs is directed against what I believe is the cause of MS, namely EBV-infected B cells in the brain. This is why these DMTs do not work in progressive MS. Indeed it is likely that the salutary actions of natalizumab, alemtuzumab, fingolimod and immunosuppressive drugs on the activation, proliferation and/or trafficking of autoreactive T cells are offset by aggravation of the already impaired CD8+ T cell control of EBV in MS.
      With regard to your comment about there being EBV-negative people with MS, this is by no means certain. Some people with MS may be negative for one type of anti-EBV antibody but positive for another type. The careful study by Pakpoor and colleagues in 2013 (Multiple Sclerosis Journal 19:162-166) concluded that, when looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. The one study on children with MS where only 86% of patients were EBV-seropositive compared to 64% of matched controls (Banwell and colleagues [2007] Lancet Neurology 6:773-781) stands in contrast to the study of Pohl and colleagues in 2006 (Neurology 67:2063-2065) who found that 99% of children with MS are EBV-seropositive compared to only 72% of healthy children.
      I agree that my hypothesis is simple but that does not mean it is less likely to be true.

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    2. where can I sign up for trials please?

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  2. Thanks for this - very interesting and great to have an explanation of how it is envisaged the action of EBV works in this context. Thanks very much

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  3. Thank you also to the patient who was brave in doing the trial.

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  4. "The beneficial effect of boosting immunity to EBV by this treatment highlights the importance of impaired immunity to EBV in the development of MS."

    I think that this is a good explanation of how EBV may play a role in MS. EBV does not directly cause the disease, but it is they way people vulnerable to MS react to EBV. This susceptibility is most likely a product of genetics. Since nearly all adult humans have EBV and nearly all adults do not have MS (relatively speaking), EBV is not the cause of MS.

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    1. "EBV is not the cause of MS."

      Prove it! Anon, you can't make such glib statements without substantiating it.

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    2. Prove that it is.

      The burden if proof is not on me or the vast majority of the scientific data or the consensus of the people working in the field. The burden of proof falls on the nutters making outrageous claims.

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    3. Which outrageous claims did you have in mind?

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    4. Also, why didn't you ask Professor Pender if he thought EBV was the direct cause of MS as I requested? I imagine you don't want any common sense interjected into the debate, but his explanation is evidence enough for us free thinkers.

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    5. Individuals are complaining that Dr. Pender does not have any proof of EBV as being the cause of MS; but, what proof is there of MS being an auto-immune illness? There isn't any! Doctors just assumed it was, even though they did not have any proof and society just went along with this unqualified assumption!!! Dr. Pender should continue his research, as I completely agree with him!!

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    6. Dr. Lender does not believe EBV is causing MS, it is the renegades on this site. Unfortunately they are using his results to prop up their flimsy notion that EBV directly causes the damage in MS.

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    7. The argument that nearly everyone has EBV and very few get MS, so MS is not caused by EBV is flawed. EBV causes lymphomas but only in a small percentage of the population. Ramsey Hunt Syndrome is caused by varicella zoster virus, most people have this virus very few get the syndrome. In these cases you have the unlucky few. Now there may be a genetic variation is how the immune system works, and vitamin d is part of the immune system that controls the bodies response to viruses. It is therefore worth checking if it is EBV that starts the chain reaction that leads to the disease. The damages may be orchestrated by the infected cells rather than by the virus directly, but kill/avoid the virus then you would avoid the disease.

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    8. I have never seen an explanation of this, may be someone can enlighten me. What is the mechanism by which autoimmune diseases go into remission? This has bothered my for years as I cannot see why they don't just keep on going.

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    9. I don't think he's saying EBV causes MS. I think he says impaired immunity to EBV is the problem. I don't think he's claiming to know how we became impaired. He's suggesting a fix that so far looks promising.

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    10. "I don't think he's saying EBV causes MS. I think he says impaired immunity to EBV is the problem. I don't think he's claiming to know how we became impaired. He's suggesting a fix that so far looks promising."

      This is exactly right. I don't blame him if he doesn't want to clarify his position. After reading this thread he has probably concluded MS also causes severe defects in cognition.

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  5. This is a interview with the guy who did the trial

    http://blogs.abc.net.au/nsw/2014/02/multiple-sclerosis-breakthrough.html

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  6. "In 2003 I published a new theory in Trends in Immunology proposing that chronic autoimmune diseases such as MS and rheumatoid arthritis are caused by uncontrolled EBV infection..."

    Prof G or MD:

    Could you explain, in Dr. Pender's theory, why the EBV-infected cells are causing myelin destruction and neuro-degeneration (or in the case of RA, destruction of the joints)? Although the link is there, I haven't seen anything that might explain how EBV is causing the disease.

    Also, what might be causing the accumulation of the infected B-cells in the affected organ?

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  7. Thanks to Dr. Pender for providing a guest post. After immunotherapy with CD8+ T-cells was there a measurable drop in the number of B-cells in the CNS? In the paper a graph shows the reduction in intrathecal IgG, is this an indirect measure of B-cell reduction? Also, would intrathecal administration of the T-cells be of benefit? I think there is a study involving intrathecal rituximab in SPMS at the NIH.

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  8. Thank you Prof. Pender for this very interesting and informative post. We appreciate all of your hard work on behalf of us MSers and hope you enjoy continued success.

    Question--Do clinical trials of this sort generally take less time than those developing new drugs, since there is no new chemicals to be tested and proven safe? If this new treatment proves successful, would it be 8-10 years like a regular drug to be approved, or would it likely be available sooner?

    Thank you!

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    1. Yeah I've been wondering about that as well Sam H

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  9. I would love to know if there is a genetic failing to cope with EBV. My relative had Multiple Sclerosis, but I do not, I have Chronic Fatigue Syndrome, and just published is "Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome" - could it be that both of us were genetically unable to cope with EBV, but leading to different autoimmune illnesses? I know CFS responds to Rituximab in latest trials.

    K

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    1. I agree with the above comment, except to say that calling it CFS is not particularly helpful. There is now good evidence to believe that people with M.E or Myalgic Encephalomyelitis (best defined by the Canadian Consensus criteria), do have a similar immune deficiency to those with M.S., which renders them unable to control EBV infection, leading to the same kinds of autoimmune problems experienced by patients with Multiple Sclerosis. As Prof Pender has pointed out in his article, this finding raises the important question: are these diseases (M.S, M.E., arthritis, etc) different manifestations of the same problem ?

      This is the paper in PlosOne, which highlights the immune deficiency in PwME : "Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome"
      http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085387

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  10. I just found this:

    http://www.msdiscovery.org/news/news_briefs/9705-exploiting-ebv-ms-link-quell-secondary-progressive-disease

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  11. An interview with Michael Pender's patient. Very interesting:

    http://patienttalk.org/killer-t-cells-a-new-way-to-fight-multiple-sclerosis-read-our-interview-with-gary-allen-one-of-the-test-subjects-for-prof-michael-pender-ms-research/

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  12. Prof Pender will you be testing this in PPMS also?

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  13. This research paper has just come to my attention: "The Epstein–Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species."
    http://www.pnas.org/content/106/7/2313.full.pdf
    I'm sure that it has relevance to many diseases, including M.S.

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  14. This is a rather interesting research article in Plos One concerning the differences in gender may affect Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapse.

    qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males.

    The question is asked what genetic differences are there between male MSers and healthy male controls while having similar genetic code with female MSers?

    Transcriptomic Profile Reveals Gender-Specific Molecular Mechanisms Driving Multiple Sclerosis Progression

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0090482;jsessionid=19263B6B9466A896D804DE48D98EC9D1

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  15. Thanks its waiting in ProfGs Box to see if he wants to interpret this.On face value unless the males and females had different disease courses it is hard to get my head round. I'll have a read.

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  16. How can I become part of the clinical trials?

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  17. I know this may not be the appropriate place to say this, I was diagnosed with Epstein Barr when I was 28, after six months of battling everything from strep throat to multiple common colds,(I did not get "mono") I finally felt myself. 2 years later began the problems with MS type symptoms (as have yet to be dx with ms as I don't have adequate healthcare). I truly believe it was the EB virus that caused this, would love to help prove it!!!1

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  18. As a prior military US Army Medical Corp Officer, I was the OIG medical consultant on our chemical weapons sites post first gulf war. Appropriate PPE was not provided and were exposed to sarin nerve agent. I lost motor use, worked up at Walter Reed where I was on staff, as a neurosurgery patient and when nothing was found, nor MRI was performed, I was sent to PMR who performed steroid trigger point injections with immediate relief. The only think that was interesting was that on the spinal tap showed that I had a positive plus 1 EBV titer. No other specifics were provided. No oliclonal bands or anything else.

    I am well trained in toxicology and neurotoxicology with my MPH from Johns Hopkins, with formal residency training through the US Army, with Board Certification in Occupational Medicine. My adviser at Hopkins was certified in toxicology and a previous director of OSHA. The point is that the article may put me in the category with a positive EBV. Many of the medications mentioned did not help me from becoming secondary progressive, and I was told directly from the Senate staff committee for the VA portion of the senate with have direct over site, that three of us, all medical corp officers, have a new environmentally related form of MS. I had a genetic work up of my DNA at Children's Hospital in St Louis MO. He never saw anything like it on any other results. I wanted my two afflicted colleagues to get their DNA analysis done to see if our genetic results were the same or similar but never came to fruition.

    So if it was me, I would spend the money and get the therapy in Sydney. I am also clinical epidemiologist and my quality of life is only by steroid infusions. The hypothesis make sense. An infectious cause then an environmental cause leading to an autoimmune disease.

    My choices are now simple. Stay on the Fumaric Acid, undergo plasmaphoresis with risk of stem cell transplant, follow a rheumatoid treatment protocol, take Remicaid and risk cardiomyopathy, or go to Sydney which is the most plausible option. This is a an autoimmune disease and I always suspected or hypothesized RA and MS have similar mechanisms of action. My maternal grandmother had RA but no other family relative have anything similar.

    I am well trained in my field of medicine, which is surprising most neurologists in the United States do not take into account learning about neurological exposures. Our program is a subspecialty of preventive medicine. Only those residency trained can sit for the Occupational portion of the boards now and we are the only program that is trained in this core area of neurotoxicology.

    An article came out of the New York Times just this week, indicating potential USA actions in coordination other European powers to help develop and manufacture these WMD for Iraq to use in their war with the Iranians. This information published from the New York Times explains the potential culpability why data cannot be found and or disappeared. People have died already, or still waiting for their VA benefits from the first gulf war.

    Hypothesis: Industrial nations using organophosphate pesticides in the food supply help facilitate to create a higher rate of MS, associated with a genetic predilection, with positive EB or regardless of what infectious trigger.

    I am trying to get my VA neurologist to see the best people in Washington DC to look at my case. Look up Mitch Wallin MD, Neurologist and epidemiologist on his research in this area. I vote for seeing Dr Pender for undergoing his treatment protocol regardless of debate now.

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  19. I care for my wife who is permanently bed and wheelchair ridden due to MS. I cook, clean, wash her bum and brush her teeth. Personally I couldn't give the flying proverbial as to whether EBV is the cause or not of MS. If there is a clinical trial of Prof. Pender's theory, my wife is up for it.
    Anon

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  20. Prof. Pender, Thank you for your excellent hypothesis. , I think CD8+ T cell exhaustion is important step in development of MS and/or autoimmunity. Could you explain about it?

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