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Invited researcher Sergey Arturovich Nedospasov
Contract number
14.Z50.31.0008
Time span of the project
2014-2016

As of 30.01.2020

9
Number of staff members
22
scientific publications
1
Objects of intellectual property
General information

Name of the project: New drugs and principles of anti-TNF therapy of autoimmune diseases

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions: Creation of new drugs and principles of anti-TNF therapy of autoimmune diseases

Project objective: To prove the hypothesis that in the arthritis myeloid cells are the main source of the «pathogenic» tumor necrosis factor (TNF), while cytokines expressed by other immunity cells has a defensive function; to provide a new concept of anti-cytokine therapy; to create a new type of anti-TNF blockers who are able to selectively neutralize TNF of myeloid cells without affecting its production by other cells


The practical value of the study

  • We have obtained new data that allowed us to propose a hypothesis on the role of skin microbiota in development of congenital immunity. The data was collected by bioimaging of mice in which the tumor necrosis factor (TNF) is expressed together with the far-red protein Katushka.
  • On the basis of the variable domain of single-domain Camelidae antibodies we have produced biospecific blockers of the mice macrophage-derived TNF. Their qualities have been assessed in vitro and in vivo, they have shown high efficiency compared to similar system blockers of TNF. We have assessed different options of domain orientations of biospecific antibodies and selected the most optimal one.
  • The Laboratory has produced selective and system blockers and sensors of TNF merged with the Katushka fluorescent protein. Using a fluorescent sensor of TNF we have proven that the main impact in development of the LPS/D-Gal model is made by macrophage-derived TNF. Approbation of selective fluorescent blockers of TNF has shown the problem of selection the optimal structure of domains of polyspecific antibodies including sequences of domains and length of linkers connecting them.
  • We have conducted phenotype screening of a pool of mice after ENU-mutagenesis using the model of LPS/D-Gal-induced of septic lethal shock that allows to select mice characterized by survival capability in this test.

Implemented results of research: We have obtained the patent for invention No. 201615045/10(080923) Mokhonov V.V., Vasilenko Ye.A., Gorshkova Ye.N., Drutskaya M.S., Astrakhantseva I.V., Nedospasov S,A< «A recombinant antibody specific to tumor necrosis factor and marker of cells of the myeloid series».

Education and career development:

  • 1 candidate dissertation, 4 masters dissertations and 8 bachelors dissertations have been defended.
  • 5 young researchers have completed career enhancement in «Methods of determining gene expression, production, cleaning and assessing activity of recombinant proteins».
  • We have developed and implemented lecture courses: a program for masters students and career enhancement «Experimental immunology», programs for postgraduates «Signaling paths of the immune system cells», «Translational immunology», «Epigenetics in immunology and biomedicine», «Problems of biomedical immunology» and «Immunogenetics».

Organizational and structural changes: On the basis of the Center for Molecular Biology and Biomedicine of the Institute of Biology and Biomedicine the Laboratory of Experimental Immunology has been created. The Laboratory has been equipped for working with with eukaryotic cells including conducting analysis using flow cytometry and fluorescent microscopy.

Collaborations:

Research Institute for Biomedical Technologies of the Privolzhsky Research Medical University (Russia), Laboratory of Molecular Mechanism of Immunity of the Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences: joint scientific research

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Mokhonov V.V., Vasilenko E.A., Gorshkova E.N., Astrakhantseva I.V., Novikov D.V., Novikov V.V
SlyD-deficient Escherichia coli strains: A highway to contaminant-free protein extraction. Biochemical and Biophysical Research Communications, 23 May, 499(4): 967-972 (2018).
Drutskaya M.S., Efimov G.A., Astrakhantseva I.V., Kruglov A.A., Nedospasov S.A.
Making anti-cytokine therapy more selective: Studies in mice. Cytokine 101: 33-38 (2018).
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