Boosting Immune Cells

Anne Kingston, reporter and senior writer at Maclean's Magazine, has just published a fantastic interview with pioneering neuroimmunologist Michal Schwartz.   I've recommended Dr. Schwartz's new book, Neuroimmunity: A New Science That Will Revolutionize How We Keep our Brains Healthy and Young, on this blog.  I'm thrilled that Anne not only read the book,  but got in touch with Dr. Schwartz and interviewed her, to learn even more.
http://www.macleans.ca/society/health/a-healthy-immune-system-is-the-key-to-a-healthy-mind/

I found this particular question especially insightful.

Anne Kingston: Your research indicates the immune system needs to be boosted, not suppressed. Doesn’t that run contrary to the immunosuppressant therapies routinely prescribed for many autoimmune diseases?

Dr. Schwartz: I’ve told everyone for a while to be careful when prescribing any anti-inflammatory drug for any neurodegenerative disease. They understand, but don’t have an alternative.

In other words, since there's nothing better, neurologists haven't changed their treatment target.  They understand that immune suppressing drugs (also known as anti-inflammatory) are keeping helpful immune cells away from the brain, but they don't have anything else they can prescribe which is FDA approved.  Here's more on the FDA pay to play system, which is maintaining the current $20 billion a year MS treatment industry.
http://ccsviinms.blogspot.com/2013/10/the-fda-and-multiple-sclerosis.html 

The last several years of research have directly questioned the current MS treatments.   Recent discoveries of the brain's lymphatic vessels and connection to the immune system and the neuroprotective role of immune cells.  The fact that the brain is not immune privileged and needs immune cells to repair the blood brain barrier.  The glaring fact that this immune cell and lymphatic cleansing system is relient on functioning venous drainage system  ---- in light of all of this research, the continued silence of the MS community is deafening.  They carry on as if nothing has changed, still prescribing immune cell sequestering and ablating medications, without a second thought.  They ignore vascular issues and the compounding evidence that cardiovascular lifestyle intervention can modify disease progression.   

Why?  They understand the science, but they don't have an FDA-approved alternative to sell MS patients.

Readers of this blog know that the current mouse model for MS, called experimental autoimmune encephalomyelitis (EAE) is not an appropriate model for MS.  EAE it is initiated by injecting the mice with lots of stuff we certainly don't find in the CNS of humans with MS, in order to create an inflammatory reaction.

Did you know that the MS drug Copaxone was originally created in an attempt to CAUSE the animal model of MS?   It was formulated to give mice EAE?  That's right.
http://www.ncbi.nlm.nih.gov/pubmed/20106343 

Glatiramer acetate (GA) was created in a lab over 40 years ago to cause EAE.   It consists of four synthetic protein compounds combined together to replicate myelin basic protein (MBP.)  Myelin basic protein is what the immune system damages in MS.  So, the idea was, inject the animals with this myelin-like formulation, and the immune system would go to town and attack ---creating an MS-like disease process, and disabling the mice.

What actually happened, however,  was the exact opposite. The animals injected with GA could not develop EAE.  What happened was that this formulation did indeed activate t-cells and boosted an immune reaction,  but these t-cells were not damaging, they were protective.
http://www.jimmunol.org/content/186/4/1887.full.pdf

This is how Copaxone was developed to treat humans--what MS researchers like to call serendipity, I think is essential to understand.  Copaxone is not an immune ablating or suppressing drug, it is an immune boosting drug.

Glatiramer acetate, now called Copaxone, was created in a lab at the Weizmann Institute in Israel. Not coincidently, this is the same institute where Dr. Schwartz has been conducting her research.  It would be the discovery of how GA increased the body's t cells and protected axons which would coincide and overlap with her studies.

Boosting immune cells, instead of suppressing them, protects the central nervous system. 

Granted, we now know Copaxone is most certainly not a cure for MS.  Although it blocked EAE in mice, its longterm efficacy in humans with MS is more of a mixed bag.  But what the creation of Copaxone should have instigated, at least in mind, were questions regarding the long-term safety of serious immune ablating treatments for MS and the development of immune boosting and modulating treatments.

"They understand, but they do not have an alternative."

Let's continue to put pressure on MS researchers for alternatives.  For immune modulating treatments, for venous treatments, for cardiovascular therapies, for immune boosting treatments. It's vitally important to study the endothelium, the connection between the vascular and immune systems.

Until we understand more, please be careful with serious immune cell sequestering MS drugs (like Tysabri, Gilenya, Tecfidera) or immune ablating chemotherapies (like Campath and Lemtrada.)   Do everthing you can do to live your best vascularly, endothelially, heart-healthy life.

The research keeps coming in.  And we do not know what we do not know.

be well,
Joan

The brain needs immune cells

In 2010, Dr. Alasdair Coles, an academic neurologist at Cambridge University, said to the press:

'We know MS is an auto-immune disease because if you block the immune response with drugs, people get better.'
This now infamous quote from Dr. Coles came when he was asked to comment on Jeff's treatment for CCSVI, as reported in the UK's Daily Mail.

http://www.dailymail.co.uk/health/article-1242441/Could-multiple-sclerosis-caused-blocked-veins.html

In my mind, linking the cause of MS to how the drugs work (for some) is akin to saying, 

"We know the earth is flat because we don't fall off!"
The relationship between the brain and immune system is much more complex than ever imagined.

Labeling MS a classic autoimmune disease is a serious misnomer--since we see the same immune cell reaction to myelin after hypoxic injury and stroke.

Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx

http://www.ncbi.nlm.nih.gov/pubmed/26527183
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162361/

There are no antigen specific antibodies in MS. There is no specific immune target in Multiple Sclerosis.  

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1168912/ 
http://www.ncbi.nlm.nih.gov/pubmed/26265268?dopt=Abstract

And, thanks to new research, we now know that immune cells are vital to a functioning brain.  

1.They provide healing after a break of the blood brain barrier, as we see in MS.
http://www.pnas.org/content/113/4/1074.abstract
2.They aid healing of axons after injury to the central nervous system, via glial scar formation
http://www.ncbi.nlm.nih.gov/pubmed/24756949
3.The "autoimmune" t cells often ablated in MS treatment are also responsible for neuroprotection.
http://www.ncbi.nlm.nih.gov/pubmed/12374425

At the time of his quote, Dr. Coles was bringing his life's work to market--the chemotherapy drug Alemtuzumab, repackaged for MS as Lemtrada.  Cole's overarching premise in his research is that the immune cells in multiple sclerosis are completely damaging to the brain, and need to be entirely removed.

And his theory then that "people get better" when the immune system is ablated is actually not true.  Yes, inflammation is tamped down in those with RRMS.  But, just like swatting a pesky fly with a sledgehammer, there is a lot of residual damage.   Immune ablation with chemotherapy has a host of horrific side effects, including fatal cancers, fatal viral and bacterial infections, worse autoimmune reactions in other parts of the body including kidney failure, lung tissue swelling, and hypothyroidism.  Not necessarily "all better!"  Which is why this medication has a black box warning, 

http://www.fda.gov/downloads/Drugs/DrugSafety/UCM426512.pdf

Meanwhile, Dr. Coles is busy trying to create an antidote to stop the new autoimmune diseases his drug has caused.  That's right...Lemtrada actually causes autoimmune disease!
The principal adverse effect of alemtuzumab (Lemtrada) is autoimmunity, which arises when reconstitution of the immune repertoire after alemtuzumab occurs by homeostatic expansion of residual lymphocytes. Therefore we are now testing the ability of keratinocyte growth factor to promote thymic lymphopoiesis and so prevent autoimmunity after alemtuzumab, in a MRC-funded clinical trial.
http://www.neuroscience.cam.ac.uk/directory/profile.php?Alcool

Even worse,  the MS disease process does not stop with Dr. Cole's Lemtrada.  Cerebral atrophy and disability continue, even without any new lesions.

Unfortunately, this did not lead to a clinical improvement in the disability in these patients. In fact, their disability worsened with time at a rate of 0.02 EDSS points for each patient each year. Evidence for continued neurodegeneration in these patients was shown by progressive cerebral atrophy on follow-up MRI scanning. 
http://europepmc.org/articles/PMC3629751


In the past decade, a narrative developed in the MS drug industry by MS researchers like Dr. Coles:  the idea that the immune system is at fault, and needs to be halted.   This has led to the creation of a class of drugs which create "lymphocyte sequestration" and "lymphocyte depletion"---meaning they keep the white blood cells walled off in the lymph tissue or deplete them, keeping them out of the body's circulation.  Instead of allowing immune cells protective entry into the body and around the brain, they are held back.  This new class of more powerful disease modifying drugs include Tysabri, Gilenya and Tecfidera.  

Not surprisingly, there is a price to pay when you hold back immune cells, deplete them, and don't let them do their job.  And one of those side effects is the reactivation of latent viruses and bacterial infections, including the John Cunningham virus (JCV).  This virus causes the deadly brain infection, progressive multifocal leukoencephalopathy (PML).  

Neurologists have comforted their patients regarding their PML risk and Tysabri use, telling them that if they were tested as JC virus negative, they would remain that way and not to worry.   But this was simply not true.  

The JC virus is very common in the general population, infecting almost 90% of us in childhood.  It stays under control and latent because our immune system keeps it in check.  This means we have a JC negative status.  The virus is able to cross the blood brain barrier where it attacks myelin and destroys brain tissue.  

New research shows that the risk of JCV reactivation due to Tysabri use is ten times higher than previously estimated.  That not 1%, but 10% of all patients on Tysabri were seen to go from JCV negative status to JCV positive status while taking Tysabri.  The drug is apparently what turns people from JC virus negative to positive.  This makes sense, if you understand that what Tysabri is doing is holding back immune cells, and rendering them unable to stop a virus from reactivating.

http://nn.neurology.org/content/3/1/e195.full

It also makes sense as to why Tecfidera and Gilenya have now been linked to PML...and I fear it's only a matter of time until real world reporting comes in showing JCV reactivation on these drugs.
                                                              +++++++++++++  

Dr. Michal Schwartz has been publishing on the importance of immune cells for brain health for decades.  Both she and Dr. Nedergaard are two of my research heros.  They are brilliant, determined women who have challenged the neurological status quo and are actively publishing their findings.

Dr. Schwartz explains her decades long search in understanding the importance of the immune system for the brain in her new book,  Neuroimmunity: A New Science That Will Revolutionize How We Keep Our Bodies Healthy and Young.
http://www.weizmann-usa.org/media/2015/09/22/prof.-michal-schwartz-will-change-your-mind

This book is simply wonderful!  It is written clearly and simply, so that lay people might understand her research.  But it is also in-depth enough to appeal to researchers.  All of her publications are cited.

Scientists long believed that there was no communication between the brain and the immune system; in fact, it was thought that any infiltration of immune cells into the brain was a major threat to our health. Based on this assumption, the standard treatment for inflammation associated with neurodegenerative diseases, such as Alzheimer’s, was to totally suppress the body’s immune system.

Prof. Schwartz turned this theory on its head by proving that the immune system and the brain do “speak” to each other – and that, in fact, neurodegenerative diseases are the result of a communication breakdown between the brain and the immune system. Instead of suppressing the immune system, she argues that the most effective way to treat Alzheimer’s and other chronic neurodegenerative diseases is to do the opposite: boosting targeted immune cells in the brain. 

The brain needs immune cells.

Please, if you have MS--- until we understand more about the immune system and brain health, make sure to discuss this new research with your neurologist, especially if they are putting pressure on you to try these new immune ablating and lymphocyte depleting drugs for MS.  New research is coming in every single day, showing that this method might not be the best approach for long-term brain health.

Be well, be curious.
The earth is not flat.
Joan

Independent review of new MS Drugs--Must Read

Prescrire ("to prescribe" in French) is a French medical journal, which uses evidence based science to make recommendations on drugs.  It is written by health care professionals for health care professionals,  but it is unique in that it does not accept any pharmaceutical monies for advertising or for payment to reviewers.  This journal makes money by having 33,500 subscribers---medical professionals who turn to this journal for unbiased information. This is a completely independent journal---they have signed a "Non, Merci" (no, thank you) charter to maintain no conflicts of interest.  
http://english.prescrire.org/en/82/173/0/0/About.aspx

Prescrire’s subject matter mainly consists of critical reviews of medicines and other treatment options. Prescrire’s editorial staff is made up of healthcare professionals, most of whom are in active practice. Editors are specially trained and are free from any ties to pharmaceutical or other companies doing business in the healthcare arena. Prescrire’s reviews therefore help healthcare professionals to prescribe for their patients in an informed and fully independent manner.

Prescrire is also completely independent of all national and supernational institutions that determine or implement healthcare policy. Prescrire is therefore free to make recommendations in matters of ethics, public health and national and international healthcare policy.
Prescrire is written and edited by and for healthcare professionals. You could say that it’s just what the doctor ordered.
http://english.prescrire.org/en/82/169/0/322/About.aspx


And Prescrire's March issue has some startling information on MS drugs.  The reviewers names are not published (to keep them safe?) but they stand behind their recommendations.  Each article submitted has been reviewed by 20-40 other peer-reviewers.   And what they say is that when looking at all of the data we now have, these new drugs are too dangerous, with too many side effects and known and unknown risks.  That people with MS are much better off using the first line meds (interferon and copaxone), because these new, more powerful drugs have had biased trials, and have not proven any long term benefit.


1.  Tysabri and MS.  With longer follow-up:  even more toxic than suspected.
http://www.ncbi.nlm.nih.gov/pubmed/25897454
Post-marketing data confirm the adverse effects identified in clinical trials, including serious and life-threatening opportunistic infections, particularly progressive multifocal leukoencephalopathy in about two per thousand treated patients (an incidence twice as high as initially estimated), and potentially severe hypersensitivity reactions. An increased risk of cancer in the long term cannot be ruled out. Post-marketing data also show that natalizumab can cause severe liver damage. In addition, natalizumab withdrawal because of progressive multifocal leukoencephalopathy almost always triggers an immune reconsti- tution syndrome that can lead to neurological complications or even death. In practice, regardless of the severity of multiple sclerosis, it does not seem reasonable to expose patients to the many serious adverse effects of natalizumab for such an uncertain benefit.

2. Lemtrada and MS.  Biased evaluations, evidence of serious risks

http://www.ncbi.nlm.nih.gov/pubmed/25897458

Clinical evaluation in multiple sclerosis is based on three unblinded trials comparing alemtuzumab with interferon beta-1a. These trials were all biased in favour of alemtuzumab and thus fail to establish the potential value of this immunosuppressant. Overall, adverse effects, including the most severe, were more frequent with alemtuzumab than with interferon beta-1a. The adverse effects of alemtuzumab reported in these trials had already been observed in cancer patients. They included potentially severe reactions to the infusion, as well as a risk of infections and cancer due to profound and prolonged immunosuppression. At the dosage authorised in multiple sclerosis, autoimmune disorders such as thyroid disorders and immune thrombocytopenic purpura are particularly frequent and serious. In practice, patients with multiple sclerosis already have difficulty coping with the troublesome consequences of their underlying disease. They should not be subjected to the serious adverse effects of alemtuzumab, especially given the absence of any proven benefit.

3. Aubagio and MS.  just a metabolite of leflunomide.

http://www.ncbi.nlm.nih.gov/pubmed/25897452

Clinical evaluation of teriflunomide is based on a comparative trial versus interferon beta-1a in 324 patients and on two placebo-controlled trials in a total of about 2300 patients lasting 1 to 2 years. In these trials, oral teriflunomide at a dose of 14 mg per day led to a statistically significant decrease in the average annual number of relapses compared to placebo, but teriflunomide may be less effective than interferon beta. No impact on the progression of disability has been shown during less than 2 years of follow-up. The burdensome adverse effect profile of teriflunomide is similar to that of leflunomide and includes hepatotoxicity, infections, leukopenia, arterial hypertension, peripheral neuropathy and alopecia. The long half-life of teriflunomide (about 19 days) complicates the management of its adverse effects and multiple drug interactions, and has important implications for patients wishing to have children. Teriflunomide is teratogenic in animals and should not be used by pregnant women. Fetal toxicity via semen cannot be ruled out. In practice, the adverse effects of teriflunomide in multiple sclerosis are disproportionate to its efficacy. It is better to choose interferon beta, despite its limitations.

Their April issue includes a paper called "Tecfidera and MS: Too many Long-term Unknowns

http://english.prescrire.org/en/SummaryDetail.aspx?Issueid=159

I'm thankful that the researchers of Prescrire are speaking out and publishing their findings.   But I wonder how many neurologists will heed their warnings and inform their patients?  While the MS drug machine continues to crank along, now making 20 billion dollars a year in profits, people with MS are rarely given the facts.  These new drugs are exceedingly dangerous, and they do not prevent disease progression. 

Please spread the word in your own community and help others understand the risks of these drugs are known, while the benefits remain unproven. 

Take care of yourselves and be well,

Joan

Chemotherapy causes brain atrophy, demyelination and MS disease progression

While many MS specialists continue to explore chemotherapies and immunoablation for people with MS, the side effects of these drugs on the brain are rarely mentioned.

As we learn more about the long term effects of chemotherapy of the central nervous system, it is vitally important that people with MS are given the facts.

If you are being recommended to try any of these therapies, please discuss the side effects with your doctor.

Recent studies have now started to unravel the cell‑biological basis for commonly seen neurotoxic syndromes in chemotherapy associated central nervous system damage and have provided compelling explanations for delayed neurological complications, such as cognitive decline, progressive myelin disruption and brain atrophy.
http://www.ncbi.nlm.nih.gov/pubmed/20738009

1. Chemotherapy kills myelin and OPC cells--  Chemotherapies are known to affect healthy brain cells, causing them to die off long after treatment ends.   Studies have shown that months after exposure to common chemotherapies, oligodendrocytes and precursor cells continue to die, and the brain is unable to remyelinate.

This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function,” said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. “Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients.”
http://www.urmc.rochester.edu/news/story/index.cfm?id=1963

2. Chemotherapy changes the brain's metabolism--  Doctors have long-described "chemo brain"--a common and debilitating side effect of chemotherapy, causing cognitive fog and a loss of coping skills.  In fact, the brain's metabolism is altered.

Chemo brain phenomenon is more than a feeling. It is not depression. It is a change in brain function observable on PET/CT brain imaging."
With the help of special software, they were able to pinpoint differences in brain metabolism before and after chemo. They then correlated these with patient history and data from neurologic exams and chemo treatments.  The analysis reveals a statistically significant link between reductions in regional brain metabolism and symptoms of chemo brain.  Lagos says their findings show "there are specific areas of the brain that use less energy following chemotherapy".

"These brain areas are the ones known to be responsible for planning and prioritizing," she adds.
http://www.medicalnewstoday.com/articles/253277.php

3. Chemotherapy used in bone marrow transplant doubles brain atrophy in those with progressive MS.    Because of this, one neurologist is now cautioning his progressive MS patients.  The chemotherapy used in bone marrow transplant is likely to accelerate the disease progression in those with progressive MS.

The following study I was involved shows that when SPMSers are given chemotherapy they undergo increased neuronal loss, which is associated with faster progression on the EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS progressions and you can see that the MSers who had high serum levels of the neuronal toxicity marker neurofilament were much more likely to progress than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in SPMSers were in the order of 2.1% per year in those who had a BMT compared to only 1.2% per year in SPMSers who did not have a BMT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS BMT is likely to accelerate your disease progression.
http://multiple-sclerosis-research.blogspot.com/2014/02/more-on-bmt-neurotoxicity-and-brain.html

4. Current information on Lemtrada (Campath/Alemtuzumab)
New claims are that treatment reduced cerebral atrophy in RRMS patients who were followed for two years---but earlier studies showed that this was not true in secondary progressive MS.  Treated patients were followed for 14 years past infusions---and cerebral atrophy and disease progression continued.  The FDA was right to deny Lemtrada in the US---sadly, the MS patients that are asking for this treatment to be approved have been given an incomplete scenario.

Unfortunately, this did not lead to a clinical improvement in the disability in these patients. In fact, their disability worsened with time at a rate of 0.02 EDSS points for each patient each year. Evidence for continued neurodegeneration in these patients was shown by progressive cerebral atrophy on follow-up MRI scanning. This particular group of patients who showed continuing disease progression had the highest inflammatory load prior to commencing alemtuzumab therapy. This group of patients were followed up with MRI scanning many years later (14 years post treatment) and did not demonstrate any increase in lesion load but did demonstrate further cerebral atrophy [Coles et al. 2006]. This was reflected in their EDSS score, the median being 7.5 (range 4.5–9) at latest follow up [Hill-Cawthorne et al. 2012].
http://europepmc.org/articles/PMC3629751

Campath 1H treatment was associated with a sustained and marked reduction in the volume of Gd enhancement, indicating suppression of active inflammation. Nevertheless, many patients developed increasing brain and spinal cord atrophy, T1 hypointensity, and disability. 
http://www.ncbi.nlm.nih.gov/pubmed/10489036



In fact, neurologists have known about chemotherapy causing brain atrophy for many years.  Here is a study from 2006--where neurologists followed brain atrophy after chemotherapy in preparation for a bone marrow transplant.  And they included a man without MS, being treated for cancer, to see how his brain did.  His brain atrophy doubled....just like the people with MS.

The man with non-Hodgkin lymphoma provided a clue. Because he didn't have MS, he should not have had any cerebral inflammation or edema. Yet, in the three months after he received the same treatment as the MS patients, his brain shrank at the rate of about 6 percent per year, a rate of atrophy similar to the MS patients.
http://journals.lww.com/neurotodayonline/Fulltext/2006/07040/Brain_Atrophy_in_Ms_May_Result_From_Immunoablation.11.aspx

We still do not fully understand the disease mechanism of MS.  While MS specialists continue to operate under the assumption that a faulty immune system must be annihilated ----we are learning that the true progression of MS can be linked to neuronal loss, or brain atrophy.  There is a terrible and tragic irony in the fact that chemotherapies, which are known to double brain atrophy rates, are being recommended to people with MS.

Please, share this information in the MS community.  For those who have already been treated with chemotherapies, there is hope of healing through diets high in antioxidants and phytonutrients and omega 3 oil supplementation. In fact, simple lifestyle factors like diet, exercise, UV rays and vitamin D are increasing blood flow to the brain are helping reverse brain atrophy in all of those with MS.

Know the facts, and be well,
Joan