IRN АР13067593 “Study of MDSC role in the regulation of the immune response to the vaccine during aging and the development of pharmacological approaches to improve the effectiveness of vaccination”

Relevance

Numerous studies have found that vaccination of older people over 65 years of age is largely ineffective, the reason for which is believed to be an age-related decrease in the functionality of the immune system, called immunoaging. It is assumed that one of the possible causes of the onset and maintenance of immunoaging in the body are (Myeloid-Derived Suppressor Cells, MDSC), which are a heterogeneous population of pathologically activated monocytes and granulocytes with a unique metabolic and genetic profile, which attract special attention due to their ability to induce systemic and local immunosuppression and promote the accumulation of other immunosuppressive cells such as regulatory T cells. The negative role of MDSC in the inhibition of specific T-cell antitumor immunity has been convincingly proven in the oncological process, both in the experiment and in the clinic. The number of works proving the participation of these cells in the development of chronic inflammation, both infectious and non-infectious, is rapidly growing. The possible negative impact of MDSC on the development of anti-infective adaptive immunity is evidenced by a number of experimental studies. The present study is devoted to the study of the negative role of MDSC in the regulation of the adaptive immune response to anti-infective vaccines in an experiment on old animals and the development of approaches to increase the effectiveness of vaccination by pharmacological suppression of the immunosuppressive activity of these cells. 

Project target:

Evaluate the role of MDSC in the suppression of the immune response to vaccines during aging in the experiment and to develop pharmacological methods to increase the effectiveness of vaccination.

Expected and achieved results:

It is expected that during the implementation of the project work it will be proved that: 1) the principal regulators of the immune response induced by the vaccine are MDSC, the level of which increases significantly with the aging of the organism. 2) suppression of MDSC activity by pharmaceuticals will lead to an improvement in the immune response to vaccines.

An inbred mouse line BALB/c will be used as a study model. It is planned to use preparations of inactivated whole-virion SARS-CoV-2 as a test vaccine, this choice is primarily due to the ongoing COVID-19 pandemic and the need to develop new approaches aimed at improving the effectiveness of vaccination in the elderly and other risk groups from COVID -19.

The research group members:

The research team includes highly qualified specialists in the field of molecular and cellular immunology and immunobiotechnology:

Research group publications: 

1. Perfilyeva Y.V., Abdolla N., Ostapchuk Y.O., Tleulieva R., Krasnoshtanov V.K., Perfilyeva A.V., Belyaev N.N. Chronic inflammation contributes to tumor growth: Possible role of L-selectin-expressing myeloid-derived suppressor cells (MDSCs)//Inflammation. – 2018. – V.42(1). – P.276-289. https://doi.org/10.1007/s10753-018-0892-6.
2. Perfilyeva Y.V., Ostapchuk Y.O., Abdolla N., Tleulieva R., Krasnoshtanov V.K., Belyaev N.N. Exogenous melatonin up-regulates expression of CD62L by lymphocytes in aged mice under inflammatory and non-inflammatory conditions//Immunological investigations. – 2019.- V.48(6). – P.623-643. https://doi.org/10.1080/08820139.2019.1586918.
3. Abdolla N., Perfilyeva Yu.V., Tleuliyeva R., Ostapchuk E.O., Krasnoshtanov V.K., Tuleukhanov S.T., Belyaev N.N. Myeloid-derived suppressor cells (MDSCs) activated by chronic inflammation stimulate tumor growth//Vestnik KazNMU.- 2018. — No. 2. — P. 233-236.
4. Perfilyeva Y.V., Kustova E.А., Urazalieva N.Т., Baisheva S.А., Aubakirova А.Т., Tleulieva R.T., Belyaev N.N., Zakiryanova G.К. Effects of L-Selectin stimulation on the expression of chemokine receptor CXCR4 on NK Cells of healthy donors and tumor patients//Bull. Exp. Biol. Med.–2012.-V.153.-N1.-P. 86-88. https://doi.org/10.1007/s10517-012-1650-7.
5. Perfilyeva Y., Ostapchuk Y., Aktas Cetin E., Yilmaz A., Deniz G., Talaeva S., Omarbaeva N, Oskolchenko I., Belyaev N. Hyaluronan-binding T regulatory cells in peripheral blood of breast cancer patients//J. Clin. & Cell Immunol. – 2014. – V.6(1). – e286. https://doi.org/10.4172/2155-9899.1000286.
6. Ostapchuk Y.O., Actas Cetin E., Perfilyeva Y.V.,Yilmaz A., Skiba Y.A., Chirkin A.P., Omarbaeva N.A., Talaeva Sh.G., Belyaev N.N., Deniz G. Peripheral blood NK cells expressing HLA-G, IL-10 and TGF-b in healthy donors and breast cancer patients//Cell. Immunol.-2015.-V.298.-P.37-46. https://doi.org/10.1016/j.cellimm.2015.09.002.
7. Ostapchuk E.O., Perfil’eva Yu.V., Talaeva Sh.Zh. , Omarbaeva N.A., Belyaev N.N. Content of HLA-G+ T cells in the peripheral blood from healthy women and breast cancer patients//Bull. Experim. Biol. Med.- 2015.-V.159.-N5.-Р.649-651. https://doi.org/10.1007/s10517-015-3038-y.
8. Perfilyeva Y., Abdolla N., Ostapchuk Y.O., Tleulieva R., Krasnoshtanov V.C., Belyaev N.N. Expansion of CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption//Inflamm. Res. — 2017. – N66. — P. 711-724. https://doi.org/10.1007/s00011-017-1052-4.
9. Belyaev N.N., Abdolla N., Perfilyeva Y.V., Ostapchuk Y.O., Krasnoshtanov V.K., Kali A., Tleulieva R. Daunorubicin conjugated with alpha-fetoprotein selectively eliminates myeloid-derived suppressor cells (MDSCs) and inhibits experimental tumor growth//Cancer Immunology, Immunotherapy. – 2018. — V.67. – P.101-111. https://doi.org/10.1007/s00262-017-2067-y.
10. Balabekova M.K., Ostapchuk Y.O., Perfilyeva Y.V., Tokusheva A.N., Nurmuhambetov A., Tuhvatshin R.R., Trubachev V.V., Akhmetov Z.B., Abdolla N., Kairanbayeva G.K., Sulev K., Belyaev N.N. Oral administration of ammonium metavanadate and potassium dichromate distorts the inflammatory reaction induced by turpentine oil injection in male rats//Drug and chemical toxicology, 2019. https://doi.org/10.1080/01480545.2019.1585446.
11. Zakiryanova G., Perfilyeva Y., Abdolla N., Kustova E., Urazalieva N., Ostapchuk E., Tleulieva R., Belyaev N. Human CD117-positive and CD117-negative NK cell subsets// Immunology, Special Issue: Abstracts of the Annual Congress of the British Society for Immunology, Liverpool, UK, 5–8 December, 2011.- Immunology. – 2011. — V.135. – Р.90.
12. Ostapchuk E.O., Perfilyeva Y.V., Kustova E.A., Urazalieva N.T., Omarbaeva N.A., Talaeva S.G., Belyaev N.N. Functional heterogenity of circulating T regulatory cell subsets in breast cancer patients//Breast cancer. – 2018. — V.25(6). – P.687-697. https://doi.org/10.1007/s12282-018-0874-4., 4 citation.
13. Belyaev N. N., Ostapchuk Y.O., Perfilyeva Y.V. Regulatory NK cells: A potentially negative role in cancer//Chapter in the book Horizons in cancer research. Vol.69. Editor Watanabe H.S., New York, by Nova Science Publishers, Inc., 2018. — P.1-57.

Information for potential users

As life expectancy increases, the world population and the number of people aged 65 and over are expected to double by 2050, reaching 1.5 billion people. Worldwide, the share of the population aged 65 and over has increased from 6 percent in 1990 to 9 percent in 2019. It is predicted that this share will grow and reach 16 percent by 2050, thus, every sixth person in the world will be at the age of 65 or older. A similar situation is observed in Kazakhstan. The severity of many infections is higher in older people than in younger adults, and infectious diseases are often associated with complications resulting in disability and independence. This poses a major challenge to public health systems and therefore infectious disease prevention is an important intervention to ensure healthy aging and improve quality of life.

The immediate socio-economic effect from the implementation of this project is of a remote nature, as well as from any fundamental research. Nevertheless, the implementation of this project will provide primary data on possible ways to increase the immunogenicity of vaccination in the elderly, which, ultimately, can lead to a decrease in the mortality of the elderly and other risk groups with chronic inflammation of people from infectious diseases, an improvement in the quality of life of these population groups, raising the border of socially active, working age and, ultimately, to increase the economic potential of the country and lower costs in health care.