In this video we discuss the paper Bai et al. in which the immunological and regenerative activities of human bone marrow derived mesenchymal stem cells were assessed in two different animal models of multiple sclerosis.

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.

Bristol, UK -

An interesting study was published by Gordon et al (Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration, Neurosci Lett 2008 Dec 19;448(1):71-3) describing the use of human bone marrow derived mesenchymal stem cells in the treatment of EAE, a mouse model of multiple sclerosis.

Previously people have demonstrated that administration of mouse mesenchymal stem cells into mice with EAE results in remission of disease.  In this current paper an interesting, and very relevant variation of the previous study was made….human stem cells were used.  This is important since human mesenchymal and mesenchymal-like stem cells are being developed by companies such as Osiris and Medistem as “universal donor” cells.  This means that theoretically these cells are not rejected by the immune system.  So the authors of this paper wondered whether the human cells would survive in the mouse, and whether they would actually mediate a therapeutic effect.

The investigators induced EAE through administration of the peptide MOG 35-55 together with an adjuvant in order to elicit immune responses against myelin.  They injected 1 million mesenchymal stem cells intraperitoneally and found a statistically significant reduction in disease score.  Disease score is measured on a scale of 0-5 (0 – Normal; 1 – Tail flaccidity or hind limb weakness; 2 – Partial hind limb paralysis; 3 – Complete hind limb paralysis, spastic paresis, impaired righting reflex; 4 – Complete hind and fore limb paralysis; 5 – Dead).

On day 50 the disease score seemed to have went in remission (about 0.5) in the mice receiving mesenchymal stem cells but was still active (2) in the control mice.  Interestingly tracking of the cells showed that few mesenchymal stem cells were found in the brain on day 50.

This paper was really nicely written and provides some good background references for people interested in this area.  It is available for free online at this link.