Immune System Destruction and Recreation Can Cure Multiple Sclerosis

The latest update for ongoing efforts to test destruction and recreation of the immune system in patients suffering from the autoimmune disease multiple sclerosis demonstrates that this approach is effectively a cure if the initial destruction of immune cells is comprehensive enough. Researchers have been able to suppress or kill much of the immune system and then repopulate it with new cells for about as long as the modern stem cell therapy industry has been underway, something like fifteen years or so. Methodologies have improved, but the destructive side of this process remains unpleasant and risky, something you wouldn't want to try if there was any good alternative. Yet if not for the scientific and commercial success of immunosuppressant biologics such as adalimumab, clearance and recreation of immune cell populations may well have become the major thrust of research for other prevalent autoimmune conditions such as rheumatoid arthritis. Destroying these immune cell populations requires chemotherapy, however, and with avoiding chemotherapy as an incentive for patients, and the ability to sell people drugs for life as an incentive for the medical industry, biologics won. For conditions like rheumatoid arthritis, the aim became control and minimization of symptoms rather than the search for a cure. Only in much more damaging, harmful autoimmune conditions like multiple sclerosis has this research into wiping and rebuilding the immune system continued in any significant way.

Beyond being able to pinpoint which tissues are suffering damage due to inappropriately targeted immune cells, the underlying mechanisms of most autoimmune conditions are very poorly understood. Multiple sclerosis, for example, results from immune cells attacking the myelin sheathing essential for proper nerve function. Collectively, the cells of the immune system maintain a memory of what they intend to target, that much is evident, but the structure and nature of that memory is both very complex and yet to be fully mapped to the level of detail that would allow the many types of autoimmunity to be clearly understood. That these autoimmune conditions are all very different is evidenced from the unpredictable effectiveness of today's immunosuppressant treatments - they work for some people, not so well for others. Many autoimmune diseases may well turn out to be categories of several similar conditions with different roots in different portions of the immune system.

Destruction of the immune system offers a way around present ignorance: it is an engineering approach to medicine. If immune cell populations can be removed sufficiently comprehensively, then it doesn't really matter how they are storing the bad data that produces autoimmunity. That data is gone, and won't return when immune cells are restored through cell therapies. The cost of that process today is chemotherapy, which is not to be taken lightly, as the results presented here make clear. A mortality rate of one in twenty is enough to give pause, even if you have multiple sclerosis. In the future, however, much more selective cell destruction mechanisms will be developed, such as some of those emerging from the cancer research community, approaches that will make an immune reboot something that could be undertaken in a clinic with no side-effects rather than in a hospital with all the associated damage of chemotherapy. Autoimmune diseases are far from the only reason we'd want to reboot our immune systems: as we age, the accumulated impact of infections weighs heavily upon the immune system, and its limited capacity fills with uselessly specialized cells rather than those capable of destroying new threats. Failure of the immune response is a large part of age-related frailty, leading to both chronic inflammation and vulnerability to infection, and it is something that could be addressed in large part by an evolution of this approach to autoimmune disease.

New stem cell transplantation method may halt multiple sclerosis symptoms long-term, but therapy comes with high risk

A new use of chemotherapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has fully halted clinical relapses and development of new brain lesions in 23 of 24 patients with multiple sclerosis (MS) for a prolonged period without the need for ongoing medication, according to a new phase 2 clinical trial. This is the first treatment to produce this level of disease control or neurological recovery from MS, but treatment related risks limit its widespread use. Some specialist centres offer aHSCT for MS, which involves harvesting bone marrow stem cells from the patient, using chemotherapy to suppress the patient's immune system, and reintroducing the stem cells into the blood stream to "reset" the immune system to stop it attacking the body. However, many patients relapse after these treatments, so more reliable and effective methods are needed.

Researchers tested whether complete destruction, rather than suppression, of the immune system during aHSCT would reduce the relapse rate in patients and increase long-term disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals who had all previously undergone standard immunosuppressive therapy which did not control the MS. All patients had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100m. The researchers used a similar method of aHSCT as is currently used, but instead of only suppressing the immune system before transplantation, they destroyed it completely using a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. This treatment is "similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system."

The primary outcome of the study was multiple sclerosis activity-free survival at 3 years (as measured by relapses of MS symptoms, new brain lesions, and sustained progression of Expanded Disability Status Scale (EDSS) scores) which occurred in 69.6% of patients after transplantation. Out of the 24 patients, one (4%) died from hepatic necrosis and sepsis caused by the chemotherapy. Prior to the treatment, patients experienced 1.2 relapses per year on average. After treatment, no relapses occurred during the follow up period (between 4 and 13 years) in the surviving 23 patients. These clinical outcomes were mirrored by freedom from detectable new disease activity on MRI images taken after the treatment. The initial 24 MRI scans revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion. Furthermore, progressive brain deterioration typical of MS slowed to a rate associated with normal aging in 9 patients with the longest follow-up.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT.

Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6%. With up to 13 years of follow-up after aHSCT, no relapses occurred and no lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. In summary, we describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Comments

Here is an article from The Scientist saying that MS could be cured with 'reverse vaccines' if the offending autoantigens could be identified:

http://www.the-scientist.com/?articles.view/articleNo/46152/title/Toward-Targeted-Therapies-for-Autoimmune-Disorders/

"There have been a few trials of antigen-specific therapy in multiple sclerosis (MS). Specifically, my group and others have designed therapies to tolerize MS patients to various proteins of the myelin sheath that surrounds nerve axons in the brain and spinal cord and is attacked by the immune system. However, we simply do not know which of the dozen myelin proteins and several dozen lipids are the targets of the autoimmune affront."

Posted by: Jim at June 9th, 2016 11:47 PM

Makes one wonder if this would also work perhaps for RA and type 1 diabetes?

Posted by: bmack500 at June 10th, 2016 12:26 AM

@bmack500 - If you read through that (long) article that I linked to you can read about Tolerion's success in type 1 diabetes in a stage 1 clinical trial:

"With these preclinical results in hand, we founded a biotechnology company, Tolerion, to sponsor an 80-patient, placebo-controlled clinical trial in the U.S., Australia, and New Zealand in which participants received 12 weekly injections of either the tolerizing plasmid encoding proinsulin or a placebo. The primary endpoint of the trial, which was completed in 2012, was to measure C-peptide, a 31-amino-acid-long section of the proinsulin molecule that is cleaved before secretion from the pancreas as insulin. The level of C-peptide serves as a measure of how well the pancreas is functioning, and C-peptide levels typically decline over time in patients with type 1 diabetes. At the end of the injection period, we observed an increase in the production of C-peptide in the treated individuals, and a drop in C-peptide in the placebo group, compared with C-peptide levels at the start of the trial."

Posted by: Jim at June 10th, 2016 1:41 AM

@bmack500: As I recall, it was tried on just a few RA patients quite some years ago, with mixed success. Then that approach was abandoned in favor of biologics.

Posted by: Reason at June 10th, 2016 7:38 AM

Fasting-like diet reduces multiple sclerosis symptoms
https://www.sciencedaily.com/releases/2016/05/160526151941.htm

"During the fasting-mimicking diet, cortisone is produced and that initiates a killing of autoimmune cells," said Valter Longo, the study's lead author and professor who directs the USC Longevity Institute at the Davis School of Gerontology. "This process also leads to the production of new healthy cells."

Cell Reports: http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30576-9

Posted by: Annonymous at June 10th, 2016 10:32 AM

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