October 12th, 2009
October 12th, 2009
September 28th, 2009
August 23rd, 2009
This video discusses how the hormone leptin inhibits expansion of T regulatory cells. Theoretically blocking of leptin may be one method of repairing the immune defects in multiple sclerosis and in other types of autoimmune conditions.
August 10th, 2009
We have previously discussed the importance of T cells in the initiation and maintenance of multiple sclerosis. For example, it is known that CD4 T cells infiltrate the central nervous system of patients with multiple sclerosis and that through secretion of cytokines they induce microglial activation (associated with glutamate toxicity), as well as directly contribute to demyelination.
An interesting component of the immune system that is only recently beginning to attract significant attention is the complement cascade. This series of proteins is activated either by antibodies, or by proteins that secrete a “danger” signal to the body. The activation of the complement cascade results in the formation of an “arrow-like” protein structure that inserts itself into the cellular membrane and results in the killing of the target cell. This protein structure is called the “membrane attack complex”.
Usually immunologists think of complement as a means of the immune system clearing bacteria and other pathogens, however a recent study (Li et al. Augmenting DAF levels in vivo ameliorates experimental autoimmune encephalomyelitis. Mol Immunol 2009 Aug 4) demonstrated that complement may actually play a role in multiple sclerosis, or at least in the animal model of multiple sclerosis.
The investigators began by reporting data that in the experimental allergic encephalomyelities (EAE) model, when the mice are knocked out for the complement inhibitor decay accelerating factor (DAF), then the extent of autoimmune-mediated damage to the central nervous system is greatly amplified as compared to wild-type animals.
If lack of the complement inhibitor exacerbates disease, it would seem logical that higher concentrations of the inhibitor may suppress disease.
The investigators generated DAF-transgenic mice, that is, mice that express high levels of the complement inhibitor DAF all throughout their bodies. They observed that dendritic cells from DAF transgenic mice were poor stimulators of T cells. This is an interesting observation because to my knowledge this is the first I see about complement affecting T cell proliferation.
The authors demonstrated that in contrast to wild-type (normal) mice, mice that were transgenic for DAF had reduction in inflammation and multiple sclerosis-like symptoms after induction of EAE with the administration of myelin oligodendrocyte glycoprotein antigen.
In conclusion this current study seems to suggest that augmenting levels of complement inhibitors may be a useful method of approaching multiple sclerosis. Conversely, these data may stimulate research into small molecule inhibitors of complement activitors. This reminds me…one of the well known complement inhibitors is cobra venom factor ! In fact, Tereny et al actually have a paper (Transient decomplementation of mice delays onset of experimental autoimmune encephalomyelitis and impairs MOG-specific T cell response and autoantibody production. Mol Immunol. 2009 Feb 6) demonstrating that cobra venom factor has some positive effects on the relapse remitting SJL model of multiple sclerosis.
July 28th, 2009
Breakthroughs on the Brink: Turning the Tide on MS
By Patrick Perry
Richard Burt, M.D., chief of immunotherapy for autoimmune diseases at Northwestern University’s Feinberg School of Medicine, and his research team appear to have reversed the neurological dysfunction of early-stage multiple sclerosis patients by using the patients’ own adult stem cells, thereby “resetting” their immune systems.
In May one of the study participants, Edwin McClure, walked across the stage to receive his degree after completing a rigorous graduate program at Virginia Commonwealth University. The young man appeared strong, healthy, and confident.
The scene was in stark contrast to four years earlier when the high school star football player was battling a severe cold, fatigue, and inexplicable visual changes.
“It was like someone turned down a dimmer switch,” he recalls. “My mom thought the problems were due to sinus pressure and would eventually go away, but when I got over the cold and still had difficulty seeing, she took me to an optometrist.”
When nothing surfaced during visits to an optometrist and an ophthalmologist, McClure was referred to a neurologist for follow-up.
After a series of tests and an MRI scan, the doctor delivered the diagnosis - multiple sclerosis (MS). The visual changes the young man was experiencing were due to optic neuritis, an inflammation of the optic nerve that occurs in approximately 50 percent of patients with the disease.
McClure was placed on steroids and interferon injections?-?a regimen that successfully controlled symptoms for two years. But when the MS started to break through, his physician switched to another medication.
“Over the course of four months, I started to develop an allergic reaction to the drug,” McClure says. “Meanwhile, my disease was still progressing.”
McClure was at a crossroads: begin medications with significantly greater risk of side effects or, as his neurologist suggested, investigate a promising clinical trial underway at Northwestern University in Chicago.
He chose the latter, qualified, and enrolled in Dr. Burt’s study. McClure was one of the 21 patients in the trial, ages 20 to 53, who had relapsing-remitting MS for an average of five years and had not responded to at least six months of treatment with interferon beta. After an average follow-up of three years posttreatment, 17 patients (81 percent) improved and none got worse, according to Dr. Burt, whose findings were published in the March issue of The Lancet Neurology.
Resetting the Immune System
Dr. Richard Burt, M.D.
Courtesy Dr. Richard Burt, M.D.
“The concept is that your immune stem cells - your blood stem cells - could be used to regenerate a new immune system in virtually any autoimmune disease,” Dr. Burt tells the Post. “If we treated patients in the early relapsing-remitting phase of MS who were experiencing frequent acute attacks despite the use of interferon, patients got better. Six months after the procedure, they were even better. By two years, they seemed to have reached their peak improvement in neurological function. Most people tend to be early- to mid-range in their disability, and that’s when this therapy is really effective. But if you treat MS in a later stage, called secondary progressive MS, it doesn’t really help. In this stage, patients experience a steady worsening of irreversible neurological damage.”
In the procedure, Dr. Burt and colleagues first push immune stem cells from the bone marrow into the blood by using a growth factor and a drug called Cytoxan (cyclophosphamide). Ten days later, they harvest cells from the blood via catheter. The cells are then separated, frozen, and cultured to ensure that none are contaminated with bacteria during the process. Next, the patients are treated with drugs to inhibit the old immune system, and then the frozen stem cells are thawed and infused back into the patients to make a new immune system.
Reversing the Tide
Courtesy Edwin McClure
“I started to feel improvement while I was in the hospital,” McClure says. “I realized that I didn’t need my glasses to see. At home my parents noticed that my balance was improving and that I didn’t seem as fatigued as before. Honestly, these changes started within the first month after coming home. My life continued to improve. By the third month, I was actually going to the YMCA to exercise.”
Three years after treatment, McClure remains off medication and now experiences no symptoms of MS.
Like McClure, the majority of trial participants experienced benefits.
“We’ve seen patients who have had marked improvement in symptoms,” notes Dr. Burt, principal investigator of the clinical trial. “Your nervous system controls everything, so the part of the brain attacked by MS determines where you have a problem. Some patients had trouble walking - falling down and having to hold on to things - but after the procedure, they had marked improvement. Others had issues with incontinence, and that’s gone away. If you’re worried about incontinence, that’s quite remarkable. Numbness, tingling, inability to feel things, visual problems - blurred and double vision - can all reverse. Basically, any type of deficit can reverse.
In some patients, we actually had complete reversal - everything went away, and they were completely normal in all functional exams. In others, symptoms never completely reversed, but improved dramatically.”
The study participants are also off all conventional disease-modifying medications now used to slow the rate of disease progression.
While the small trial is only a first step, the results offer a completely new way to treat MS. “This is the first time in the history of any therapy used to treat MS where it actually reverses neurological deficit,” stresses Dr. Burt.
“All other therapies were studied or approved for their ability to slow the rate of progression - in terms of clinical deficits or MRI load of lesion burden - but nothing has, up to this time, reversed deficit. That’s what’s exciting. However, I want to stress that we cannot say it is a cure and current results with three years of follow-up are encouraging.”
Dr. Burt and colleagues are enrolling patients in a larger trial to test the procedure in a randomized setting. “If the results of the trial hold up, I believe it will help open the door for it to be accepted as standard therapy,” adds Dr. Burt.
At present, clinical trials are underway at the University of Calgary in Canada, the University of Sao Paulo in Brazil, and at Northwestern University. If interested in learning more about the trial, e-mail firstname.lastname@example.org.
A Different Approach
Courtesy Sergeant Preston Walker
After undergoing conventional therapy for MS for several years, Fort Worth police sergeant Preston Walker learned about a new treatment for autoimmune disorders. Researchers were utilizing adult stem cells derived from cord blood at The Institute of Cellular Medicine in Costa Rica. Walker inquired about the potential of the treatment for multiple sclerosis.
“We knew that if the treatment worked, the potential benefits for multiple sclerosis patients could be limitless,” says Walker.
Dr. Neil Riordan, CEO of the Institute, suggested a therapy under consideration - using stem cells derived from a patient’s fat tissue. In May 2008, Walker flew to the clinic where doctors removed samples of his abdominal fat through a mini-liposuction, drawing out stem cells, which were later re-injected. According to Dr. Riordan, Walker and a colleague were the first to undergo this treatment protocol. “My quality of life has improved significantly,” Walker told the Post. “The problems with depression, fatigue, and balance have been corrected. I feel really good.”
In June 2009, Walker, who continues to take Avonex as a maintenance drug, plans a return trip to Costa Rica for a “tune-up,” as he puts it. “I’m curious to see if they can further improve my cognitive abilities.”