Laboratory of clinical immunopathology

Abramova Tatyana Y. - Senior Research Fellow, MD, PhD

Academician of RAMS Vadim Petrovich Losovoy who had founded the Laboratory and the Institute formulated the doctrine of the antigenic-structural homeostasis, within the bounds of which the studies of immune system structural elements (molecules and cells), temporal organization (ontogenesis and seasonal, daily and hourly rhythms), interactions with the endocrine and nervous systems (inter-system interactions) had been developing. Much attention was paid to the processes of regulation and autoregulation and detection of their defects which may underly the pathogenesis of disease-dependent immune system dysfunctions. These studies led to the development of the concept of a pathogenetic heterogeneity of immunopathological diseases which implies theexistence of several variants of the disease development (pathogenesis) within the nosological form, that leads to the formation of special clinical and immunological subtypes of the disease. As a result a new direction of clinical trials originated that aimed studying the disease variants in order to develop effective methods of immunodiagnostics and targeted immune correction as the basic method of pathogenic therapy. High efficiency of the results led to their widespread application in the leading hospitals in Novosibirsk and other RF cities, as well as in specific new establishments created: city Center of Allergology, city Center of Rheumatology, city Center of Clinical Immunology, etc. In addition, in 1996 year the new ivision of the Institute had been inaugurated - the Clinic of the Immunopathology, in which the main areas of research were consistent with the known types of immunopathological processes studied in the laboratory: allergy, immunodeficiency, autoimmunity and lymphoproliferation. The studies of the immunodeficiency conditions developing after operations and trauma (thermal, mechanical) are of great theoretical importance. Considering the injury as a "model" of the induced secondary immune deficiency, the dynamic study revealed the relationship of origins and mechanisms of immune deficiency with the emergence of pathologic processes depending on the infection and reparation defects. Studies carried out in terms of pathogenetic heterogeneity of immunopathological processes allowed to characterize the three types of posttraumatic immunodeficiency states, each of which is the basis of certain clinical course (with or without complications) of traumatic or burn patients. These and other studies have confirmed the efficiency of studying the human diseases from the standpoint of a pathogenetic heterogeneity of immunopathological diseases, and formed the main direction of scientific activities of the laboratory, current at the present time as well. The present-day scientific direction of laboratory is formulated as the study of pathogenetic heterogeneity of immunopathological processes: identification of the main components of pathogenesis manifested by characteristic changes in the genetic, phenotypic and functional parameters of the of immune cells and the development of new methods of immunodiagnostics and immune correction. In the last decade, the focus of this research direction was given to the mechanisms of T-cell homeostasis maintaining. The traditional set of the quantitative and functional parameters of immune cells evaluation methods (CD-labeling, evaluation of the intracellular molecules of cytokines, the identification of cells in different phases of the cell cycle, phagocytosis, serum concentrations of immunoglobulins, etc.) has been extended with the new molecular biology methods. This is possible thanks to international cooperation and collaboration with institutions of the Siberian Branch of RAS. Together with the Pro-neuron.inc company (USA) the method was developed for the determination of the relative telomere length of immune cells using the fluorescence in situ hybridization and subsequent flow cytometry analysis of the cell suspension labeled with antibodies to surface antigens (Flow FISH). This method was then modified for the determination of the catalytic subunit of telomerase (hTERT) mRNA. Together with the Institute of Cytology and Genetics SB RAS the studies were conducted that allowed to use Flow FISH for the determination of the absolute length of telomeres (the number of base pairs), and with the help of the Institute of Chemical Biology and Fundamental Medicine of SB RAS the primers have been selected and synthesized for the RT PCR determination of DNA ring structures generating during the maturation of thymocytes (TREC) for the purpose of thymopoesis assessment. This gave the opportunity to explore the relationship of epigenetic, structural and functional characteristics of immune cells and their role in the pathogenesis of the disease, as well as to create the new effective methods of diagnostics and treatment of immunopathologic processes. One of the conceptual aspects based on the results of the research has been the possibility of the use of the vaccination with polyclonally activated T cells for the treatment of immunopathological diseases. Rheumatoid arthritis (RA) and atopic dermatitis (AD) being etiologically different states are identical in the fact that effectors of the pathological process (at least in part) are immune cells that accumulate in the body due to proliferation (homeostatic expansion in RA and antigen-reactive cells expansion in AD). In both cases the launch of proliferation is accompanied by the expression of activation markers (ergotopes), and therefore the induction of the antiergotypic response by immunization of polyclonally activated T cells (irrespectively of their antigen specificity) should lead to a restriction of accumulation of these cells. The clinical trials demonstrated safety and efficacy of this approach, and the patent "Method for the treatment of rheumatoid arthritis" was included in the roster of "Top 100 Inventions of Russia" in 2008 and had awarded a Diploma of Rospatent (Rospatent Order from 25.06.2009 № 98 "On awarding with the diplomas of the Federal Service for Intellectual Property, Patent and Trademarks of the Office patent holders in the category of "Top 100 Inventions of Russia.") This confirms once again the effectiveness of the approach in terms of pathogenetic heterogeneity of immunopathological processes formulated by the founder of Laboratory of Clinical Immunopathology and Clinical Immunology, Academician of RAMS V.P. Losovoy, and determines the prospects of further investigation of molecular genetic and epigenetic mechanisms of the regulation of immune cells functions.

 

1. Losovoy VP, Shergin SM Structural and functional organization of the immune system .- Novosibirsk: Nauka, 1981. – 226p;
2. Kozhevnikov VS, Nabiullin RR, Lozowoy VP Causes and the role of immunodeficiency in trauma. Bulletin of Medical Sciences USSR.-1991 .- № 12.-P.3-7;
3. Aghajanian VV, Kozhevnikov VS Immunology and surgery in the treatment of purulent arthritis.-Novosibirsk-1996.-Nauka. -366p;
4. Kisselev S., Kozhevnikov V. Expression of the Protein with Molecular Weight 104-110 kDa by Normal and Malignant Human B lymphoid Cells. Russian Journal of Immunol., 2001, Vol. 6, No. 2, pp.158-166;
5. Kozhevnikov VS, Konenkova LP, Sizikov AE, Zonova EV, Korolev, MA, Pronkina NV, Evsukova EV, Menyaeva EV, Frolov NI, Kozlov VA. Assessment of immune-modulating effect of therapy with erythropoietin in patients with rheumatoid arthritis / / Med. immunologiya.-2004.-Vol.6, № 6.-P.557-562;
6. Pronkina NV, Kozhevnikov VS, Lisukov IA, Kulagin AD, Sizikova SA, Kryuchkova IV, Gilevich AV. Changes in cell cycle progression of T lymphocytes in patients with hematological malignancies after autologous transplantation of peripheral stem cells / / Siberian Journal of Oncology. - 2005 .- № 1 (13) .- P.36-39;
7. Pronkina NV, Kozhevnikov VS, Lisukov IA. Kozlov VA, Gelfgat EL, Sizikova SA, Kulagin AD, Kryuchkova IV, Gilevich AV. Method of prediction of the early recurrence of primary disease after autologous transplantation of peripheral stem cells in patients with hematological malignancies. RF patent № 2337712, publ. 10.11.2008, Bull. Number 31;
8. Borisov VI, Kozhevnikov VS, Senyukov VV, Sizikov AE, Konenkova LP, Gertsog OA, Kozlov VA. Telomere length shortening in monocytes in rheumatoid arthritis / / Medical Immunology .- 2006.-Vol.1.-P.87-90;
9. Borisov VI, Demakov SA, Nepomnyashchikh VM, Leonova MI, Demina DV, Barovskaya NA, Kozhevnikov VS. Patterns of the average telomere length changes in lymphocytes from patients with bronchial asthma / / Medical Immunology. - 2009, vol.11, № 6, P.523-530;
10. Kozhevnikov VS, Korolkova OY, Borisov VI. Method of determining mRNA levels of telomerase catalytic subunit (hTERT). RF patent № 2346279, publ. 10.02.2009, Bull. Number 4. Kozhevnikov VS. Antiergotypic response: theoretical aspects and clinical implications / / Proc. scientific. pr.: Cellular technologies: Theoretical and applied aspects / ed. Kozlov VA, Sennikov SV, Chernykh ER, Ostanin AA. - Novosibirsk: Nauka, 2009. - P. 75-86;
11. Barovskaya NA, Korolkova OY, Leonova MI, Demina DV, Nepomnyashchikh VM, Kozhevnikov VS. The effectiveness of immunotherapy with autologous activated T lymphocytes in patients with atopic dermatitis and psoriasis. / / Omsk Scientific Bulletin. - 2007. - № 3. – Appendix 2. - P.345-348;
12. Kozhevnikov VS, Barovskaya NA, Korolkova OY, Nepomnyashchikh VM, Leonova MI, Demina DV. Method for atopic dermatitis treatment. RF patent № 2340348, publ. 10.12.2008, Bull. Number 34;
13. Kozhevnikov VS, Korolkova OY, Ilyina NA, Sizikov AE, Konenkov VI, Konenkova LP. Method for treaing rheumatoid arthritis treatment. RF patent № 2339385, publ. 27.11.2008, Bull. Number 33; Korolkova OY, Senyukov VV, Kozhevnikov VS. Expression of ergotop-associated markers by activated T lymphocytes / / Medical Immunology. - 2009. - Vol. 11, № 2-3. - P. 255-260.
14. Shestakova NA, Borisov VI, Pronkina NV, Trufakina EV, Shishkova IV, Demina DV, Leonova MI, Nepomnyashchikh VM, Kozhevnikov VS. Immunologic features of allergic and non-allergic forms of atopic dermatitis / / Medical Immunology, 2009, Vol. 11, № 6, P. 531-540;
15. Korolkova OY, Abramova TY, Kulagin AD, Nepomnyashchikh VM, Sizikov AE, Kozhevnikov VS, Kozlov VA. Telomerase expression in intact and stimulated human lymphocytes in normal and immunopathologic states / / Russian journal of immunology.-2010.-Vol.4 (13). № 2 .- P.145-154;
16. Zinnatova EV, Borisov VI, Kozhevnikov VS, Kozlov VA. Changes of telomere length in lymphocytes of patients with bronchial asthma of different genesis // Russian Journal of allergology 2011, № 4, Issue 1, P. 133-134;
17. Zinnatova EV, Borisov VI, Kozhevnikov VS, Sizikov AE, Kozlov VA. Telomere profile of B-lymphocytes in patients with rheumatoid arthritis / / Medical Immunology, 2011, Vol. 13, № 2-3, P. 151-157.
18. Ilyina NA, Goyman EV, Kudayeva OT, Kolesnikova OP, Kozhevnikov VS Antiergotypic response: influence on the immune response and the development of autoimmune pathology in the experiment. / / Medical Immunology. - 2011. - № 1. - P.29-34.
19. Bezuglova, A.M., Dmitrenok P.S., Konenkova L.P., Buneva, V.N., Nevinsky G.A. Multiple sites of the cleavage of 17- and 19-mer encephalytogenicoligopeptides corresponding to human myelin basic protein (MBP) by specific anti-MBP antibodies from patients with systemic lupus erythematosus // PEPTIDES. – 2012. – Vol. 37, Issue: 1.- P. 69-78.
20.  Borisov V., Korolkova O., Blinova E., Baev D., Kozhevnikov V. and Kozlov V. Measuring telomere length in proliferating cells by Flow-FISH method // Journal of Life Sciences. – 2012. – V. 6 (8). – P. 945-951.

 

Address of laboratory:

630090, Novosibirsk, Yadrintsevskaya street 14, rooms 409

Laboratory phone number: 8 (383)227-01-35