31 October 2017

Surrender or die

Russian scientists have found two ways to combat multiple sclerosis

RIA News

Russian scientists from Institute of Bioorganic Chemistry named after Academicians M.M. Shemyakin and Yu.A. Ovchinnikov (IBH) The Russian Academy of Sciences has found two ways to combat multiple sclerosis: targeted killing of "rebels" (immune cells) and "forcing them to peace." This was reported by scientists at the II interdisciplinary conference "Autoimmune and immunodeficiency diseases". The research was supported by an RNF grant.

Multiple sclerosis begins in people aged 20-40 years and occurs quite often: 30-70 cases per 100,000 people. It has nothing to do with either absent–mindedness or "senile sclerosis" - the name means that the sclerotic lesion (scars and plaques of connective tissue) is scattered (spread) through the nervous system. This disease belongs to autoimmune, because its cause is the rebellion of some immune cells against the native organism. However, usually, fighting multiple sclerosis, we can also kill normal immune cells that are not to blame for anything.

Alexey Belogurov, © RNF.

"Neurons do not exist in a vacuum, they all have long processes, axons that are covered with a myelin sheath," says study co–author Alexey Belogurov from the biocatalysis laboratory of the IBH RAS. "This myelin layer is formed by oligodendrocyte cells, which provide insulation for conducting a nerve impulse, nutrition, protection, and so on. Unfortunately, the main protein of myelin is a target for the immune system. She recognizes him as an alien and starts hunting for him."

Having established that not only autoreactive T cells (as previously thought), but also B cells play an important role in the development of multiple sclerosis, scientists realized that B cells can become a target for drugs. They recognize a piece of foreign or harmful protein on the cell surface, if the cell has put it "for testing", and either remember it as a sign of an "enemy", or produce antibodies – protein compounds to fight infections. Also, B cells secrete other substances to raise the alarm in the body, and this is how inflammation begins.

The problem is that there are a huge number of B-cells, and we do not want to kill them all, because the vast majority of such cells protect us from bacteria, viruses and other parasites. "There are ten to the tenth degree B cells in the body,– explains Alexey Belogurov. – If you build everything one to one, they will take up the length of more than ten football fields, the variety is huge. Each clonotype is unique, they carry their own receptors that determine specificity."

At the same time, the share of "wrong" among them may be much less than a percent. This is enough for the disease, but, according to biologists, attempts to fight all B-cells at once (including popular therapy with monoclonal antibodies) resemble carpet bombing (this is continuous, intense, sequential bombing over large areas), after which the immune system comes to a very deplorable state.

To avoid this, scientists decided to look for and use unique receptors on the surface of B cells, which make them pathogenic. The choice fell on those that recognize fragments of normal myelin as foreign. According to such receptors, a special molecule must search for pathogenic B cells in order to attach a deadly toxin to them without affecting normal B cells.

The next direction is to turn rebellious B cells into peaceful ones, reducing the destructive disease to a small allergy. This can be done if we strengthen the formation of other immune cells, T-regulatory cells, which, as overseers, will be engaged in suppressing the immune response. To do this, fragments of myelin antigen were injected through the nasal mucosa to animals with a disease model resembling multiple sclerosis. It has been shown that some of them work.

The scientists selected three fragments that were inserted into liposomes – ultra-small particles from lipids that make up the cell membrane. 1% of lipids were combined with the carbohydrate mannose. It helps liposomes a lot to get into specialized cells that professionally show proteins on their surface. These cells have a mannose receptor designated CD206. Mannose binds to it, which greatly helps liposomes get inside.


Liposome consisting of lipids (yellow), filled with fragments of MBP (myelin basic protein, myelin basic protein) (blue), enlarged a million times. Small tails on the yellow surface are remnants of mannose. © A.Belogurov.

"These are real nanotechnologies: if you increase a person to the size of the Earth, then our liposomes will be the size of a basketball," says Alexey Belogurov. "Trillions of these liposomes are injected subcutaneously into the body." Tests showed that the severity of the model disease in animals decreased by 40%. The studies have moved into the first phase of clinical trials on 20 patients. Their condition has stabilized, and, most importantly, the number of plaques in the brain has stopped growing in 15 of them. It was possible to find out the mechanism of action of the drug. It turned out that the injected molecules caused the release of the intercellular signaling substance interleukin-10, which reduced the severity of the disease. Then there was a "reboot" of the immune system, thanks to which T-regulatory cells were formed – the very "overseers" suppressing the autoimmune response.

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