Posts Tagged ‘multiple sclerosis’
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.
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.
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 email@example.com.
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.”
Control of pathological immunity in multiple sclerosis may be accomplished (at least in part) by antigen-specific vaccination, by administration of immune modulators such as Interferon Beta, or by depletion of activated effector T cells using antibodies.
Immune modulation by hormones offers a new method of addressing multiple sclerosis. For example, it is known that mesenchymal stem cells have therapeutic effects in animal models of multiple sclerosis, and that these effects seem to be mediated both by immune modulaton but also by stimulation of regeneration. Interestingly, hormones such as progesterone have been demonstrated to stimulate immune modulatory activities of mesenchymal stem cells.
A recent paper (Theil et al. Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin. J Immunol 2009 Jul 20) described the ability of the “hunger hormone” ghrelin to inhibit the mouse model of multiple sclerosis, experimental allergic encephalomyelitis (EAE).
Ghrelin is a hormone made by the pancreas and stomach cells that stimulates the feeling of hunger. It is also known to stimulate growth hormone release. Some have compared ghrelin as the opposite of leptin, a hormone known to inhibit hunger. Interestingly leptin has been associated with induction of inflammation of autoimmunity. For example, administration of leptin has been demonstrated to augment mouse multiple sclerosis (Matarese et al. Leptin potentiates experimental autoimmune encephalomyelitis in SJL female mice and confers susceptibility to males. Eur J Immunol. 2001 May;31(5):1324-32).
In the paper we are discussing, EAE was induced in B6 mice by administration of MOG peptide (myelin oligodendrocyte glycoprotein 35-55) and treated groups were administered ghrelin after immunization with the autoantigen. As compared to vehicle-controls, the treated groups had a profound inhibition of EAE induction as assessed by the disease severity index. Additionally, suppression of the inflammatory triad of TNF, IL-1, and IL-6 was observed at the mRNA level in cells that have infiltrated the spinal cord, as well as resident microglial cells. In vitro treatment of microglial cells by ghrelin resulted in suppressed ability to produce inflammatory trial cytokines after stimulation with lps.
These data suggest that ghrelin itself may be useful for the treatment of multiple sclerosis, as well as the possibility of using it in combination with other agents that block microglial activation. For example, the endocannabinoid anandamide has previously been demonstrated to inhibit microglial inflammatory activity.
Suppression of microglial-based inflammation is important because the microglia are activated by cytokine producing T cells and are critical components of multiple sclerosis neurodegeneration, not only by inflammatory mediators, but also by glutamate excitotoxicity.
Conceptually the best way to treat multiple sclerosis is to specifically inhibit the immune response against the myelin sheath, while leaving the immune response against other proteins intact. Additionally, the best way to treat it, is also to induce regeneration of neurons and central nervous system components that have already been damaged, perhaps through the use of stem cells.
Successful use of stem cell therapy in multiple sclerosis is believed to occur because the fat contains numerous cell populations that inhibit pathological immune responses, such as T regulatory cells (whose function is suppressed in multiple sclerosis), while at the same time containing stem cells, especially mesenchymal stem cells, which can repair damaged tissue.
The reprogramming of the immune system to selectively stop attacking one protein, or a series of specific proteins is called “immunological tolerance”. Originally the concept of tolerance came from experiments by the scientists Billingham-Brent-Medawar decades ago who demonstrated that if two genetically distinct animals had shared circulation during embryonic development, when the animals reached adulthood they would readily accept tissue grafts from each other but reject grafts from others. In other words the animals were made “tolerant” to each other.
This concept of selectively “teaching” the immune system that it should not attack a specific antigen is how approaches such as the myelin basic protein DNA vaccine developed by Bayhill Therapeutics seems to work. This vaccine, called BHT-3009, was demonstrated to induce antigen-specific immune modulation in multiple sclerosis patients in a Phase I/II study, and was subsequently demonstrated to be capable of causing a 50-61% reduction in new lesion formation as detected by MRI and profound reduction of anti-myelin antibodies in a subsequent Phase II study in multiple sclerosis patients. DNA vaccines seem to work in part through inducing interferon beta, which seems to be involved in shifting of the T cell cytokine production profile away from Th1 and Th17, although this is controversial.
Another way to “trick” the immune system into selectively not attacking an antigen is to provide the antigen orally. A published study fed multiple sclerosis patients cow myelin (which contains both myelin basic protein and proteolipid protein) and examined whether this affected immune response to myelin (Hafler, DA et al. Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann NY Acad Sci 1997 Dec 19;835:120-31).
The investigators took blood from 34 patients with relapse remitting multiple sclerosis that were either fed cow myelin (17 patients) or not fed it (17 control patients) and generated T cell lines that recognized either myelin basic protein (MBP), proteolipid protein (PLP), or tetanus toxin (TT).
A profound increase in the number of cells secreting the antiinflammatory cytokine TGF-b on stimulation with MBP or PLP was seen in patients who ate the cow myelin as opposed to controls. Interestingly, there was no increase in production of the inflammatory cytokine interferon gamma, nor were there alterations in response to tetanus toxin.
These data suggest that at least at an immunological level administration of oral cow myelin is helpful in patients with multiple sclerosis. The question now because, can one increase therapeutic effects by combining the cow myelin with something like lithium, or with fat stem cells? Furthermore, clinically used drugs such as metformin, which may conceptually increase Treg generation by suppressing IL-17 may be useful to expand the overall tolerogenic profile of oral tolerance induction.
A recent study (Rossi et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol Dis 2009 Jul 7) seems to suggest that exercise may be beneficial in slowing progression of multiple sclerosis.
The investigators induced a multiple sclerosis-like disease in mice by administration of peptides derived from the myelin protein called myelin oligodendrocyte glycoprotein (MOG) and induced the mice to undergo voluntary running in a wheel.
Voluntary exercise decreased progression of disease, and overall severity, as compared to control animals. Furthermore, the inflammation-associated suppression of GABA synapse stimulation by cannabinoid CB1 receptors, that is associated with the animal model of multiple sclerosis was inhibited as a result of exercise. Additionally, exercise effectively reduced dendritic spine loss induced by by the multiple sclerosis-like disease in striatal neurons.
Exercise has been demonstrated to induce insulin like growth factor (IGF)-1 expression in certain cell types in response to mechanical motion, as well as growth hormone administration. It is interesting to note that IGF-1 stimulates production of new myelin, as well protects the animal model of multiple sclerosis from disease (Yao et al. Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. Life Sci 1996;58(16):1301-6). So it would be interesting to see if exercise, along with vitamins and stem cells may be syngergistic in treatment of multiple sclerosis.
Stem cell therapy of multiple sclerosis is associated with immune modulation, as well as the possibility of inducing regeneration of damaged neural tissue. In the quest to figure out novel agents that may be useful in combination with stem cell therapy, scientists assess various drugs. One class of interesting drugs to evaluate are drugs that are already on the market for different diseases. For example, erythropoietin was previously demonstrated to inhibit multiple sclerosis in animal models. Erythropoietin is a hormone made by the kidneys that normally stimulates red blood cell production from the bone marrow hematpoietic stem cell. Erythropoietin is administered as a drug in patients with anemia to increase red blood cells. Interestingly, erythropoietin is also associated with suppression of inflammatory Th1 and Th17 responses, upregulation of antiinflammatory Th2 responses, and stimulation of endogenous stem cells, including stem cells in the brain.
The video above describes the effects of lithium on the animal model of multiple sclerosis called experimental allergic encephalomyelitis (EAE). It demonstrates that administration of lithium suppresses autoreactive T cells but not overall T cell responses. Furthermore, the paper demonstrated that lithium administration not only suppressed disease onset, but also reversed established disease.
It appears that lithium mediates its effects through the suppression of the GSK-3 enzyme, which is involved not only in inflammation but also self-renewal of stem cells.
The above video is provided for educational purposes only and is not suggesting the use of lithium in treatment of multiple sclerosis patients, it is only providing some scientific information that may be useful in future clinical trials and scientific experiments.