Nobel prizes for investigations in immunology (1901‑2018)
1901. Nobel prize for implementation of immune sera for treatment of diphtheria and other infectious diseases
1905. Nobel prize for investigations in relation to tuberculosis
1913. Nobel prize for investigations of anaphylaxis
1919. Nobel prize for investigations in immunity (awarded in 1920 )
1930. Nobel prize for discovery of human blood groups
1951. Nobel prize for his discoveries concerning yellow fever and how to combat it
1957. Nobel prize for investigations of structure and function of antihistaminic drugs and other synthetic antagonists
1972. Nobel prize for investigations of the chemical structure of antibodies
1977. Nobel prize for the development of radio-immunoassays of peptide hormones
1984. Nobel prize for theories concerning the specificity in development and control of the immune system
1984. Nobel prize for the discovery of the principle for production of monoclonal antibodies with hybridomas
1987. Nobel prize for discovery of the genetic principle for generation of antibody diversity
1990. Nobel prize for discoveries concerning organ and cell transplantation
1996. Nobel prize for discoveries concerning the specificity of the cell mediated immune defence
1997. Nobel prize for the discovery of Prions - a new biological principle of infection
2008. Nobel prize for discovery of human immunodeficiency virus (HIV)
2011. Nobel prize for investigations of the activation of innate immunity
2011. Nobel prize for discovery of the dendritic cell and its role in adaptive immunity
2018. Nobel prize for discovery of cancer therapy by inhibition of negative immune regulation
2018. Nobel prize for the phage display of peptides and antibodies

Иммунология № 1, 2024

Immunologiya

The journal covers major theoretical and practical issues in general and applied immunology and allergology. It disseminates the results of original research in the fields of immunogenetics, molecular and cellular immunology, immunochemistry, immunomorphology, clinical immunology, and immunopathology.


Current issue
1 . 2024
Editorial

Academician of RAS Alexander Viktorovich Karaulov awarded with the Order of Pirogov

Abstract
Molecular immunology

Synthetic small interfering RNAs targeted to conservative region of the rhinovirus genome suppress the infection in vitro

Abstract

Introduction. Human rhinoviruses (HRVs) belong to the genus Enterovirus of the Picornaviridae family. HRV upper respiratory tract infection can be associated with various complications and exacerbation of chronic respiratory diseases such as bronchial asthma. Due to the large number of virus serotypes, vaccination against HRV isn’t possible. Despite advances in antiviral research no specific antiviral drug has been approved for the treatment of the disease caused by HRV. Antiviral agents based on the RNA-interference mechanism are developing fast. Such drugs block virus replication specifically in an infected cell.

Aim of this study – to develop siRNA molecules specifically inhibiting rhinovirus replication in human cells.

Material and methods. Bioinformatic analysis of rhinovirus genomes was carried out using the Vector NTI program. The design of siRNA molecules was carried out using the OligoWalk program. Antiviral activity experiments of the siRNAs were carried out in vitro in HeLa Ohio cells. The tested siRNAs were delivered into cells using commercial transfection reagent Lipofectamine 3000 or peptide-carrier KK-46. The antiviral activity was assessed by the ability to reduce the virus titer in cell supernatants and the number of viral RNA copies in cell lysates.

Results. The most conservative regions in the rhinovirus genome were identified and 125 siRNA complementary to them were designed. Based on bioinformatic analysis 7 variants were selected to study the antiviral activity in vitro. It was found that two variants siRV-5UTR-4-3 and siRV-5UTR-5-3 have the most evident antiviral effect. They both can significantly suppress HRV replication in mammalian cells. Based on these siRNA variants complexes with the peptide-carrier KK-46 were created. Other in vitro experiments have proven the antiviral activity of the siRV-5UTR-4-3/KK-46 and siRV-5UTR-5-3/KK-46 complexes against rhinovirus.

Conclusion. In this study siRNA molecules were designed against conservative regions of the rhinovirus genome and their antiviral effect was proved in vitro. The created siRNA molecules can be components of antiviral drugs.

Innate immunity

Intracellular signaling pathway inhibitors suppress inflammatory response induced by synergistically acting bacterial substances

Abstract

Introduction. Combined activation of NOD-like and Toll-like receptors of innate immune cells is a potent pro-inflammatory stimulus that may underlie the systemic inflammatory response in bacterial sepsis.

Aim – to evaluate the possibility to suppress pro-inflammatory cytokine production by macrophages activated with NOD1 and TLR4 agonist combination using inhibitors of NF-κB-dependent and mitogen-activated protein kinase (MAPK)-dependent signaling pathways.

Material and methods. Macrophages generated from healthy donor monocytes were stimulated with NOD1 and TLR4 agonists separately or simultaneously. The activity of NF-κB-dependent and MAPK-dependent signaling pathways was suppressed using low-molecular-weight kinase inhibitors that were added before or after commencement of cell activation. As read-outs, we measured mRNA expression of pro-inflammatory cytokines TNF, IL6, IL12B and IL23A using RT-PCR as well as secretion of TNF, IL-6 and IL-23 using ELISA.

Results. Inhibition of NF-κB-dependent and MAPK-dependent signaling pathways allowed to prevent or interrupt expression and production of TNF, IL-6 and IL-23 by macrophages activated by a potent pro-inflammatory stimulus, a NOD1 + TLR4 agonist combination. Most effective was simultaneous inhibition of both signaling pathways. We also show contribution of NF-κB-dependent and MAPK-dependent signaling pathways to synergistic enhancement of IL12B gene expression.

Conclusions. These results obtained can be utilized when developing novel approaches to anti-inflammatory therapy of severe bacterial infections.

Cellular immunology

Исследование антигенной специфичности Т-клеточных иммунных реакций в ответ на иммунизацию лабораторных мышей рекомбинантным аденовирусным вектором, кодирующим Spike-белок SARS-CoV-2

Abstract

Введение. Рекомбинантные аденовирусные векторы являются одной из ведущих технологических платформ при разработке и производстве современных вакцин. В России и в других странах мира на базе рекомбинантных аденовирусов созданы и зарегистрированы вакцинные препараты против вируса лихорадки Эбола и коронавирусной инфекции SARS-CoV-2. Проводятся клинические испытания вакцин против гриппа, вируса Марбург, вирусов папилломы человека.

Закодированный в ДНК аденовирусного вектора целевой антиген экспрессируется в организме вакцинированного и против этого целевого белка-антигена развиваются адаптивные иммунные реакции. Векторная частица является вирусной и содержит в себе десятки вирусных антигенов. Следовательно, наряду с иммунными реакциями на целевой антиген в организме вакцинированного могут развиваться иммунные реакции на антигены самого вектора.

Цель данной работы – исследовать, как соотносятся между собой по интенсивности и качеству две разнонаправленные по антигенной специфичности иммунные реакции: против целевого антигена коронавируса и антигенов аденовирусного вектора.

Материал и методы. У мышей C57BL/6 исследовали интенсивность иммунных реакций CD4- и CD8-Т-клеток в ответ на иммунизацию рекомбинантным аденовирусным вектором, кодирующим S-белок SARS-CoV-2 (Ad5-S). Через 2 и 3 мес после иммунизации в селезенке мышей определяли количество и антигенную специфичность CD4- и CD8-T-клеток памяти. Реакцию Т-клеток индуцировали in vitro в совместной культуре с антиген-презентирующими дендритными клетками. Очищенные популяции CD4- и CD8-T-клеток получали сортировкой на лазерном проточном сортировщике BD FACS Aria II. Антиген-презентирующие клетки трансдуцировали аденовирусным вектором Ad5-S, кодирующим S-белок коронавируса, или контрольным рекомбинантным аденовирусным вектором без целевой вставки (Ad5-0). Ответ Т-клеток определяли методом ELISPOT по числу клеток, секретирующих ИФН-γ. В отдельных экспериментах для реактивации CD4-Т-клеток антиген-презентирующие дендритные клетки нагружали рекомбинантным RBD-фрагментом S-белка SARS-CoV-2. Для усиления ответа Т-клеток антиген-презентирующие дендритные клетки стимулировали агонистом TLR4.

Результаты. Установлено, что однократная интраназальная иммунизация вектором Ad5-S в дозе 108 БОЕ индуцирует сильные системные Т-клеточные иммунные реакции у мышей C57BL/6. Через 2 мес после иммунизации в селезенке мышей обнаруживается около 100–200 тыс. антиген-реактивных Т-клеток памяти, секретирующих ИФН-γ при реактивации in vitro дендритными клетками, презентирующими целевой S-антиген SARS-CoV-2. Большинство антиген-реактивных CD8-T-клеток памяти специфично к S-антигену SARS-CoV-2. Содержание таких клеток после иммунизации вектором Ad5-S превышает 1 % от всех CD8-T-клеток. Количество антиген-реактивных CD8-T-клеток памяти, специфичных к аденовирусным антигенам вектора, было приблизительно в 3 раза ниже, чем количество антиген-реактивных CD8-T-клеток памяти, специфичных к целевому S-антигену. Интенсивность иммунной реакции CD4-T-клеток на иммунизацию вектором Ad5-S была сравнима с интенсивностью иммунной реакции CD8-T-клеток. Подавляющее большинство антиген-реактивных CD4-T-клеток памяти было специфично к антигенам аденовирусного вектора. Эти CD4-Т-клетки секретировали ИФН-γ в ответ на рестимуляцию in vitro дендритными клетками, трансдуцированными рекомбинантным аденовирусным вектором Ad5-0 без целевой вставки. Число CD4-T-клеток, реагирующих на рестимуляцию дендритными клетками, нагруженными рекомбинантным RBD, было исчезающе малым.

Показана возможность повышения интенсивности ответа CD8-T-клеток, специфичных к целевому S-антигену, путем увеличения дозы вектора Ad5-S при трансдукции антиген-презентирующих дендритных клеток, а также путем использования TLR4-агониста для стимуляции антиген-презентирующих дендритных клеток.

Предложены возможные механизмы кооперативного взаимодействия CD8-T-клеток, специфичных к целевому S-антигену SARS-CoV-2, и CD4-T-клеток, специфичных к антигенам аденовирусного вектора. Рассматриваются возможные пути усиления ответа CD4-T-клеток на целевой S-антиген.

Заключение. Иммунизация рекомбинантным аденовирусным вектором, кодирующим S-антиген SARS-CoV-2, индуцирует сильные CD8- и CD4-T-клеточные иммунные реакции с формированием массивного пула антиген-реактивных Т-клеток памяти. CD8- и CD4-T-клетки, реагирующие на иммунизацию вектором Ad5-S, различаются своей специфичностью к антигенам. CD8-T-клетки памяти в основном специфичны к целевому S-антигену SARS-CoV-2, CD4-T-клетки памяти специфичны к антигенам аденовирусного вектора.

Сytokines

Effect of leu-enkephalin analogue on the content of pro- and anti-inflammatory cytokines in the colonic wall in experimental ulcerative colitis

Abstract

Introduction. The development of ulcerative colitis is associated with impaired immune homeostasis in the colonic wall, activation of CD8+IL-17+-cells, increased production of pro-inflammatory and impaired secretion of anti-inflammatory cytokines. The formation of immune inflammation leads to the development of infiltrates and ulcers, as well as crypts destruction. Considering the low efficiency of existing methods for the treatment of ulcerative colitis, the search for new treatments for inflammatory colonic diseases is an urgent task. Investigated leu-enkephalin analogue has a unique combination of pharmacological effects, including immunomodulatory effect.

The aim of study – investigation of leu-enkephalin analogue (Tyr-D-Ala-Gly-Phe-Leu-Arg) effect on the content of pro- and anti-inflammatory cytokines in the colonic wall in mice with experimental ulcerative colitis.

Material and methods. Ulcerative colitis in Balb/c mice was simulated by replacing drinking water with a 5 % solution of dextran sodium sulfate in boiled water for 5 days. On the 5th, 7th and 28th days of the experiment, the content of IL-1β, IL-4, IL-6, IL-10 and IL-17 was measured in the homogenate of the medial section of the colon. The leu-enkephalin analogue was administered subcutaneously at a dose of 100 mcg/kg for 7 days.

Results. An increase in the content of IL-1β, IL-6, IL-10 and IL-17, as well as a decrease in the concentration of IL-4 in the colonic wall of mice of the control group with ulcerative colitis on the 5th and 7th days of the experiment was established. In chronic ulcerative colitis, only the concentration of IL-6 was significantly higher by 2.5 times than in naïve mice. The administration of leu-enkephalin analogue had an immunomodulatory effect: the content of proinflammatory cytokines decreased, while the content of Th2-cytokines increased during the acute period of the disease. In chronic ulcerative colitis, the administration of investigated peptide caused a decrease in the concentration of IL-6 and an increase in the content of IL-10 in the colonic wall.

Conclusion. The mechanism of leu-enkephalin analogue action on the content of inflammatory cytokines is apparently associated with the activation of opioid μ-receptors, which are widely present on the mononuclear cells of the colon wall, and whose expression increases in colonic inflammation development.

Clinical immunology

Predictor role of IL-6 and IL-1β in the formation of cellular bronchial inflammation in patients with bronchial asthma in response to inhalation exposure to cold air

Abstract

Introduction. Interleukins (IL) can play a significant role in the development of neutrophil inflammation of the bronchi under the influence of cold in patients with asthma.

Aim – to study the predictive role of IL-6 and IL-1β in the formation of cellular bronchial inflammation in asthma patients in response to inhalation exposure to cold air.

Material and methods. The observational study included 78 asthma patients of both sexes aged 39.0 ± 0.8 years. We studied the cellular composition of induced and spontaneously produced sputum, IL in exhaled breath condensate (EBC) before and after a bronchoprovocation test with 3-minute isocapnic hyperventilation with cold (-20 °C) air (IHCA) and an assessment of the airway response according to forced expiratory spirometry (ΔFEV1).

Results. Group 1 included 32 patients with cold airways hyperresponsiveness (CAHR), group 2 included 46 patients without CAHR (ΔFEV1 -16 [-22; -10.6] and -4 [-6; -0.4] %, respectively, p < 0.00001). Patients had no intergroup differences in the level of asthma control (ACT 18.3 ± 0.9 and 18.4 ± 0.7 points) and FEV1 (93.8 ± 2.8 and 96.0 ± 3.1 %; р > 0.05). In individuals with CAHR, after the IHCA test, a significant increase in the contents of neutrophils in sputum was recorded from 40.8 ± 2.0 to 47.8 ± 2.5 % (p = 0.037), in contrast to patients without CAHR. In addition, after the IHCA test, the concentration of IL-6 in the EBC significantly decreased in them (p = 0.018) and the concentration of IL-1β increased two-fold in relation to the initial value, as well as compared with the same indicator in asthma patients without CAHR. The initial values of IL-1β and IL-6 were closely correlated with each other (Rs = -0.84; p = 0.0003).

Conclusion. Bronchial asthma with cold airway hyperresponsiveness probably belong to the Th17 endotype associated with activation of IL-6 and IL-1β and Th1/Th17 immune response. The profile of the functional activity of IL-6 and IL-1β for the entire set of signs can be a predictor of the formation of a mixed/neutrophilic pattern of bronchial inflammation in this category of asthma patients.

Oncoimmunology

Effect of detoxified Shigella sonnei lipopolysaccharide on the expression of tumor-associated antigen gp100 and MHC I antigens by B16 melanoma cells

Abstract

Introduction. In recent decades, active researches have been conducted on the suitability immunotherapeutic agents based on drugs that stimulate the innate immune response, in particular TLRs ligands (agonists) (Toll-like receptors, TLRs), in complex therapy for malignant melanoma. TLR agonists are considered as promising drugs due to their ability to stimulate the antitumor immune response. It has been established that TLRs are present both on cells of the immune system and on malignant melanocytes, therefore the effect of drugs based on TLRs agonists on the progression of malignant melanoma will depend on both the effect on tumor cells and on cells of the immune system.

Aims of the study – to investigate the effect of detoxified lipopolysaccharide (Ac3-S-LPS) of Shigella sonnei, phase I, on the expression of tumor-associated gp100 antigen and MHC I antigens by B16 melanoma cells in vitro and on the infiltration of primary tumor nodes by CD8+-T lymphocytes after administration of Ac3-S-LPS in vivo.

Material and methods. To study the effect of Ac3-S-LPS on B16 melanoma cells, we used two experimental models: B16 melanoma cell culture (provided by the Cellular Immunity Laboratory, Research Institute of Experimental Diagnostics and Tumor Therapy, N.N. Blokhin NMRCO, MOH of Russia) and primary tumor nodes (PTN), obtained after inoculation of melanoma cells into experimental animals. When assessing the effect of Ac3-S-LPS on melanoma cells in culture, melanocytes were cultured with the drug for 48 hours. To study the effect of Ac3-S-LPS on subpopulations of cells in the PTN, the drug was injected into the area of the formed nodes.

The expression of TLR4 and gp100 antigens (AGs) was determined using fluorochrome-labeled polyclonal antibody (Abs) to melanoma cells grown on coverslips, followed by analysis of the preparations with a fluorescence microscope.

The expression of the AGs CD8a, CD45, MHC I, CD F4/80 was determined using monoclonal Abs labeled with fluorochromes in cell suspensions obtained after culturing cells in vitro and in cell suspensions of PTN, and subsequent analysis of the resulting suspensions with a flow cytometer.

To assess the effect of Ac3-S-LPS on the proliferation of tumor cells in culture, a test with the VPD450 dye was used.

Results. B16 melanoma cells have been shown to express TLR4. The presence of this receptor on the surface of malignant melanocytes suggests that the effects that were noted when culturing cells with Ac3-S-LPS are due to its interaction with this receptor, since it has been established that lipopolysaccharides of gram-negative microorganisms (including Shigella sonnei cells) are ligands of this receptor. Cultivation of melanoma cells with Ac3-S-LPS leads to a change in the pattern of expression of surface AGs – gp100 and MHC I. The level of gp100 expression decreases, while the number of cells bearing MHC I increases. The proliferative activity of tumor cells decreases. When Ac3-S-LPS is administered directly into the area of PTN, in the tumor node the relative amount of tumor cells expressing MHC I and T lymphocytes carrying the CD8a antigen increases.

Conclusion. The effect of detoxified lipopolysaccharide (Ac3-S-LPS) of Shigella sonnei, phase I on B16 malignant melanoma cells was studied using experimental models in vitro and in vivo. It was found that the use of Ac3-S-LPS reduces the expression of melanoma-associated antigen gp100 on tumor cells and increases the expression of MHC I antigens, which is accompanied by increase the amount of T lymphocytes expressing the antigen CD8a in PTN.

For help to practical physician

Allergen immunotherapy: on the path to achieving immune tolerance

Abstract

Allergen immunotherapy (AIT) is one of the main methods for the pathogenetic treatment of IgE-mediated allergic diseases. The AIT degrades the sensitivity to a significant allergen and the clinical symptoms severity, reduces the risk of medications use, prevents the asthma and new sensitization. AIT-induced tolerance is an active highly-regulated state of immunity resistance to the allergen and is mediated by a complex interaction between various cells of the innate and adaptive immune system. Numerous cellular and molecular studies have brought us closer to understanding the processes that characterize allergic inflammation and AIT-induced immune tolerance. However, the AIT mechanism remains unclear. An understanding of the immune response modification during AIT is necessary for the physicians to predict the therapeutic effects and the timing of their achievement, assess the possibility of combining AIT with other methods of therapy, and minimize the risks of adverse events. This review describes modern conception of the IgE-mediated allergic reactions mechanisms and the AIT points of action.

Reviews

Studies on the immunogenicity of therapeutic proteins: methodological aspects of identifying and studying of the anti-drug antibodies

Abstract

Biotechnological medicines (such as therapeutical proteins) are widely used in medical practice due to their high specificity to factors associated with the pathogenesis of diseases of various origins. However, the development of immune response to therapeutical proteins is big issue because it affects pharmacokinetic and pharmacodynamic profile, safety and efficacy of the drug. The clinical significance of therapeutic proteins immunogenicity mainly depends on its’ mechanisms of development and robustness, as well as specificity and affinity of the anti-drug antibodies (ADA). Identification, quantification and determination of anti-drug antibodies functional activity is the most important objective in drug development process as a key drug safety characteristic. This paper reviews different approaches of the therapeutic proteins immunogenicity assessment, choice of analytical methods for analysis and characterization of ADA during the clinical development process.

The role of IL-37 in neutrophil-mediated inflammatory diseases

Abstract

Neutrophils are a key element of the innate immune system which protect the body against pathogens. Generated in the bone marrow, they play a crucial role in the acute phase of inflammation. However, these cells can also cause unwanted tissue and organ damage due to excess inflammation.

IL-37 plays a role as a negative regulator of innate immunity. This cytokine has the potential to suppress neutrophil activity in various pathologies, including autoimmune diseases, psoriasis and cancer.

The review provides information on IL-37 as a potential therapeutic agent and diagnostic biomarker in pathologies associated with excessive neutrophilic inflammation.

Chronicle

International Congress on molecular immunology and allergology (IMAC 2023) (November 23–24, Moscow)

Abstract
Memorial dates

Immunologist of the epoch. To 80th anniversary of academician R.M. Khaitov

Abstract

Memories about R.M. Khaitov

Abstract
Obituary

Irina Solomonovna Freydlin (07.03.1936–23.01.2024)

Abstract

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

EDITOR-IN-CHIEF
EDITOR-IN-CHIEF
Musa R. Khaitov

Corresponding member of Russian Academy of Sciences, MD, Professor, Director of the NRC Institute of Immunology FMBA of Russia


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