Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Eliseev AV, Fedorova AD, Lebedin MY, Chudakov DM, Shugay M

In-depth study of mechanisms of immune response to the human immunodeficiency virus (HIV) is critical for better understanding of how immunodeficiency develops in patients with HIV, as well as for designing effective immunotherapy strategies and vaccines against the virus. In this work we analyze sequencing profiles of T-cell receptor repertoires previously obtained from healthy donors (601 Americans and 65 Russians) to estimate the population frequency of HIV-specific naive T-cells. We demonstrate that frequencies of T-cells recognizing different HIV epitopes vary considerably across the population (F-statistic = 2007, p < 10<sup>–100</sup>, ANOVA). Although the frequency of T-lymphocytes recognizing a particular epitope does not change significantly between the individuals, it still largely depends on the presence of certain HLA alleles (p < 0.01, post-hoc Tukey’s test), cytomegalovirus infection (F = 61, p = 7 × 10–15, ANOVA), and age (Pearson correlation coefficient ranging from –0.53 to –0.14 in different groups).

Received: 2017-10-23

Published online: 2018-01-14

DOI: 10.24075/brsmu.2017-05-08

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VIEWS 3557

Merzlyak EM, Kasatskaya SA, Sosnovskaya AV, Israelson MA, Staroverov DB, Nakonechnaya TO, Novikov PI, Chudakov DM, Britanova OV

Although mechanisms underlying development of autoimmune vasculitis and polyangiitis remain understudied, these pathologies are already known to be largely mediated by T-lymphocytes. Cyclophosphamide (CF) is widely used to treat autoimmune diseases. Lymphoid cells in general (T, B, and NK cells) and naive T-lymphocytes in particular are highly sensitive to CF. In this work we analyzed the repertoires of T-cell receptors (TCRs) in the peripheral blood of young (aged 24 to 35 years, n = 4) and elderly (aged 52 to 68 years, n = 5) patients with ANCA-associated vasculitis (Wegener granulomatosis and Churg–Strauss syndrome) treated with high doses of CF > 3 years before the study. The control group included 7 young and 14 elderly healthy individuals. We revealed no TCR variants previously reported as typically found in patients with ANCA-associated vasculitis. Relative frequency of “public" (often found in a population, largely formed during an embryonic period) TCR variants in the repertories of young patients was significantly lower than in the repertories of healthy donors of the same age, and was similar to the elderly healthy donors. We hypothesize that CF-treatment eliminates substantial proportion of naïve T-cells in the young donors, that contains "public" TCR variants of fetal origin. Long-term consequences of such changes in the structure of T-cell immunity require further investigations.

Received: 2017-10-04

Published online: 2018-01-14

DOI: 10.24075/brsmu.2017-05-07

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VIEWS 3678

Zlatnik EYu, Nerodo GA, Ardzha AYu, Seliutina ON, Bondarenko ES

Understanding the role of immunological memory mediated by T-lymphocytes in patients with malignant tumors is a pressing issue. This study aimed to assess the contribution of memory T-cells to antitumor immunity in patients with ovarian cancer undergoing neoadjuvant chemoimmunotherapy with recombinant interferon-gamma (rIFNγ). Quantification of central (Tсm) and effector (Tеm) memory T-cells (Тm), as well as naive T-lymphocytes (Th0), was done using flow cytometry. Compared to healthy females, untreated cancer patients were found to have more Tm and less Th0 cells in their blood CD4<sup>+</sup> and CD8<sup>+</sup> T-cell subpopulations. In cancer patients, Tm cells accumulated in the ascitic fluid, exceeding 7.7 times the number of CD4<sup>+</sup> Th0 cells and 6.5 times the number of CD8<sup>+</sup> Th0 cells, with Tem prevailing over Tcm. After chemotherapy with rIFNγ, blood Th0 decreased in cancer patients, while Tcm dominated the CD8+ Tm subpopulation both in the blood and ascitic fluid. Tem cells were a prevalent cell type in patients who received chemotherapy without interferon-gamma. Decreased Th0 and Tcm prevalence were a positive sign accompanied by a good response to treatment, including lower relapse rates (46.7 % vs. 80 % in controls) and a longer relapse-free period (17.5 ± 1.6 vs. 11.3 ± 1.5 months in controls). Therefore, we conclude that chemoimmunotherapy alters proportions of T-cell subpopulations in the blood and ascitic fluid of patients with ovarian cancer, with Tcm cells prevailing over Tem, which may be one of the mechanisms of rIFNγ (Ingaron) action.

Received: 2017-09-22

Published online: 2018-01-14

DOI: 10.24075/brsmu.2017-05-06

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VIEWS 3704

Nozdracheva AV, Gritsik AA, Kuzin SN, Semenenko TA

As the modern society becomes more vaccine-dependent, the need arises for population immunity studies aimed to estimate the prevalence of antibodies against a particular infection in the donors from different populations, including sentinel groups. This work reveals the actual susceptibility of the Russian population to a number of vaccine preventable infections, including measles, rubella, and mumps. The study was conducted using blood serum samples provided by the Blood serum bank of Gamaleya Federal Research Center for Epidemiology and Microbiology (Moscow). Of 866 samples used in the study, 293 and 117 samples had been collected from healthcare workers in 2011 and 2017, respectively; 220 samples had been obtained from military servants in 2016–2017, and 236 samples had been collected from healthy donors in 2016. All samples were studied by solid phase enzyme immunoassay using diagnostic kits by Vector-Best (Russia). We discovered that 19.4 % and 28.8 % of individuals were susceptible to measles and mumps, respectively, which is insufficient for ensuring epidemiological safety (the herd immunity thresholds for these diseases are 7 % and 15 %, respectively) and puts the population at risk of infection spread, should the pathogens enter the country. The proportion of individuals susceptible to rubella was 6.5 %, which is below the herd immunity threshold (7 %).

Received: 2017-09-22

Published online: 2018-01-14

DOI: 10.24075/brsmu.2017-05-05

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VIEWS 3738

Mazunina EP, Kleymenov DA, Manuilov VA, Gushchin VA, Tkachuk AP

Multiplex screening assays for measuring antibodies to vaccine-preventable infections are routinely used in large-scale seroepidemiological studies, but not commercially available, because such studies are too specific and normally employ a particular type of the assay only once. This prompts researchers to develop their own solutions for exploring herd immunity. In this work we discuss theoretical principles and practical approaches to developing multiplex screening assays and give examples of protocols and recommendations based on our own experience in the field.

Received: 2017-09-26

Published online: 2018-01-13

DOI: 10.24075/brsmu.2017-05-04

Comments 0

VIEWS 4425

Cell-mediated immunity and the cytokine interferon gamma (IFNγ) have an important role in promoting host resistance against tuberculosis-causing mycobacteria (TBM), but the exact mechanism of developing immunity against tuberculosis (TB) is unknown. In this work we evaluate the immune response in TB and the association between IFNG gene polymorphism rs2069705 (T-1488C) and the intensity of specific immune reactions in children. The study was conducted in 310 children below 18 years distributed into 3 groups: the TB group included 110 children with TB confirmed by medical evaluation; the LTB group consisted of 156 children with latent infection; and the NTB group was represented by 44 non-infected children. A few immunoassays and molecular-genetic tests were performed; specifically, we evaluated the immune status of patients and the distribution of genotypic frequencies of the studied polymorphism, in the context of previous vaccination against TB. The cell-mediated immune response was mild in children with LTB, while in children with TB inflammation showed signs of chronicity due to the lack of functional activity of immune cells (p < 0.05). We also measured IFN-γ synthesis induced by specific mitogens (PPD-L, CFP32B, Rv2660c, ESAT6, 85a and ESAT6-CFP10), only to detect attenuation of the immune response in patients with TB, which was associated with the heterozygous rs2069705 variant (p < 0.05). Children with homozygous TT and CC genotypes demonstrated a more pronounced immune response. Low effectiveness of the TB vaccine was shown to be associated with the heterozygous genotype (50 %), while its high effectiveness was associated with the homozygous T genotype (40 %), possibly indicating the protective role of the latter. Our findings suggest that the studied polymorphism (specifically, its heterozygous variant) can be a predictive marker of TB in children.

Received: 2017-09-24

Published online: 2018-01-13

DOI: 10.24075/brsmu.2017-05-03

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VIEWS 3649

Kleymenov DA, Mazunina EP, Lunin VG, Koptev EYu, Manuilov VA, Gushchin VA, Tkachuk AP

So far BCG, a live attenuated Mycobacterium bovis strain remains the only available vaccine for tuberculosis prevention and control. Although BCG is effective against miliary tuberculosis and tuberculous meningitis in children, it barely protects adults and adolescents from the pulmonary form of the disease or reactivation of the latent infection. Still, its effectiveness can be increased by using recombinant booster vaccines containing both M. bovis and M. tuberculosis antigens. This article reports preliminary data on the safety and immunogenicity of a recombinant vaccine candidate, GamTBvac, developed for tuberculosis prevention. Its immunogenicity was studied in 12 volunteers. Over the course of 20 weeks following GamTBvac administration, we measured cell-mediated and humoral immune responses using interferon-gamma release assays and multiplex xMAP- based immunoassays. On day 140 after the first administration of the vaccine, 10 participants of the study (83 %) still showed a positive cellular response to all antigens contained in the vaccine. Both sense antigens CFP10 and ESAT6 induced production of IgG antibodies between days 98 and 140 of the observation. The Ag85 antigen induced a relatively weak humoral response. On the whole, the recombinant GamTBvac is safe and activates cell-mediated and humoral components of the adaptive immunity, forming immunological memory.

Received: 2017-09-20

Published online: 2018-01-13

DOI: 10.24075/brsmu.2017-05-02

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VIEWS 3830

Gushchin VA, Manuilov VA, Mazunina EP, Kleymenov DA, Semenenko TA, Gintsburg AL, Tkachuk AP

Immunological memory is one of the key features of the adaptive immunity. It confers the ability to resist infection and prevents development of cancer or autoimmune diseases. Most importantly, immunological memory mediated by preexisting antigen- specific clones of T- and B-cells ensures a rapid and effective response to an invasion by a previously encountered pathogen. Since vaccination induces a specific long-lived response to infectious agents, it becomes a basis for preventive medicine. In a human population, immunological memory of individuals shapes the so-called herd or community immunity crucial for national health. The present review touches upon significant population-wide research studies of immunological memory with regard to immunization. We discuss the principles of serological testing and the outcomes of serological monitoring conducted in different countries, and talk about standard and innovative analytical approaches to studying immunological memory. We also pinpoint the drawbacks of methods used for herd immunity assessment in Russia and propose a comprehensive system for seroepidemiological surveillance.

Received: 2017-09-24

Published online: 2017-12-11

DOI: 10.24075/brsmu.2017-05-01

Comments 0

VIEWS 4325