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.