Cytokines and inflammation

Innate immunity plays a key role in the processes of conception and the maintenance of physiological pregnancy. Changes in immune system functioning can lead to pregnancy disorders and loss. In recent years, the function of NOD-like receptors (NLRs) of the innate immune system in pregnancy pathologies has been actively studied. NLRs are intracellular receptors that recognize a wide range of ligands and are involved in various processes, including the assembly of the inflammasome. The inflammasome is a cytoplasmic, high molecular weight protein complex that initiates an inflammatory response to infection or endogenous signals of cellular stress and tissue damage. Gene expression, as well as protein products of NLRP3 inflammasome activation, have been detected at various levels of the female reproductive tract, including the placenta and fetal membranes. An increasing body of evidence supports the role of the NLRP3 inflammasome in the development of reproductive pathologies, including infertility and pregnancy loss. Inflammasome activity is influenced by numerous endogenous factors, and disruptions in any of these can lead to the development of aseptic inflammation. The outcome of such inflammation often includes spontaneous miscarriage or preterm birth. Triggers for NLRP3 inflammasome activation may involve conditions in which the concentration of molecules stimulating the NLRP3 receptor increases at the systemic or local level. Studying established noninfectious factors of excessive NLRP3 activation and integrating their diagnosis into clinical practice may allow for the timely identification and reduction of pregnancy loss risks.

BACKGROUND: Allogeneic bone marrow transplantation has significant therapeutic potential for a wide range of diseases. However, the development of severe and potentially fatal forms of graft-versus-host disease (GVHD) substantially limits its applicability. The search for effective GVHD therapies aimed at modulating immune responses is ongoing. One such approach may involve the use of inhibitory oligodeoxynucleotides due to their potential therapeutic application in immune-mediated inflammatory and autoimmune diseases, as well as ongoing research into their structural variants and modifications aimed at regulating activity.

AIM: The study aimed to evaluate the effects of two immunosuppressive oligonucleotides with phosphorothioate internucleotide linkages (A151 and ODN4084-F) and one oligonucleotide modified with mesyl groups (μ-ODN4084-F) on the Th1/Th2-lymphocyte balance in an experimental model of acute GVHD.

MATERIALS AND METHODS: In experiments conducted during the progression of acute GVHD induced in the standard semi-allogeneic model C57Bl/6 → (C57Bl/6 × DBA/2)F1, the degree of thymic destruction and the severity of splenomegaly were assessed as indicators of the intensity of Th1-dependent and Th2-dependent immune responses, respectively. Serum levels of interferon gamma (IFN-γ) and interleukin 4 (IL-4) in mice were measured using enzyme-linked immunosorbent assay kits (Mouse IFN-γ ELISA Kit and Mouse IL-4 ELISA Kit, ABclonal, China). Cytokine concentrations were determined with a multimode microplate reader (LB 941 TriStar; Berthold Technologies, Germany). Mortality rates were also evaluated in both control and experimental groups.

RESULTS: It was demonstrated that the administration of inhibitory ODNs contributed to a reduction in thymic destruction during the development of acute GVHD (on days 12–20, the thymus was better preserved in mice treated with ODNs compared with the control group), which correlated well with the improved survival of the animals. The greatest efficacy was observed with μ-ODN4084-F, which incorporates thiophosphate/mesylphosphoramide modifications; by day 50, survival was 44.6% higher compared with the untreated GVHD group. This effect was accompanied by a marked reduction in serum IFN-γ levels, as well as the maintenance or, in some cases, increase in IL-4 concentrations.

CONCLUSION: The analysis of the obtained results allows to conclude that systemic inflammation is suppressed and a shift in the Th1/Th2-balance toward greater Th2-lymphocyte activity under the influence of the studied oligonucleotides, suggesting their efficacy in acute GVHD.

BACKGROUND: The severity of respiratory distress syndrome is associated with the development of systemic multifactorial inflammatory processes leading to hyperinflammation. Proinflammatory cytokines, primarily interleukin-1 (IL-1), and reactive oxygen species substantially contribute to these pathological processes. The use of an interleukin-1 receptor antagonist (IL-1Ra) as an IL-1 blocker is a key first-line therapy for patients experiencing cytokine storm syndrome. The novelty of the approach under investigation lies in studying the effectiveness of inhaled administration of IL-1Ra, including its combined use with a reactive oxygen species inhibitor — superoxide dismutase (SOD).

AIM: To assess the efficacy of IL-1Ra administered parenterally and by inhalation, both as a standalone agent and in combination with SOD, in a bleomycin-induced acute respiratory distress syndrome model.

MATERIALS AND METHODS: Male BALB/c mice were used in the study. Respiratory distress syndrome was modeled by intraperitoneal administration of bleomycin at a dose of 2 mg/mouse on days 1, 8, and 15 of the experiment. The investigational drugs—a 10.0-mg/mL IL-1Ra solution and a 10.0-mg/mL IL-1Ra solution containing 0.4 mg/mL SOD—were administered to the experimental groups either subcutaneously or by inhalation at a dose of 2 mg/mouse daily for 15 days starting from day 1 of the experiment. Body weight, spirometry, histological studies, and animal survival were assessed.

RESULTS: Subcutaneous and inhalation administration of IL-1Ra + SOD, as well as subcutaneous administration of IL-1Ra, positively affected animal survival. Subcutaneous administration of IL-1Ra and IL-1Ra + SOD led to statistically significant improvements in indicators of external respiration in mice with bleomycin-induced intoxication. A reduction in destructive lung changes caused by intraperitoneal administration of bleomycin was observed in the experimental groups receiving inhaledIL-1Ra orIL-1Ra + SOD and in the group receiving subcutaneous IL-1Ra.

CONCLUSION: Both investigational products — IL-1Ra and IL-1Ra + SOD — administered by injection or inhalation demonstrated a positive effect in the treatment of respiratory distress syndrome induced by bleomycin in the mouse model.

Nivolumab, like other immune checkpoint inhibitors, is effective in the treatment of malignant neoplasms. However, there is a growing number of reports describing the development of immune-related adverse events associated with cytokine imbalance, including myocarditis, pericarditis, pneumonitis, myositis, joint involvement, intestinal lesions, and thyroiditis, characterized by spontaneity and a reactive course. It has been hypothesized that such events are related to the disinhibition of the immune system and the development of inflammation via an autoimmune mechanism, involving the patient’s own healthy tissues and organs due to cross-reactivity in the setting of cytokine imbalance.

We observed a 65-year-old woman over a 4-year period, beginning in 2019, when she first presented with complaints of a bleeding pigmented lesion on the right lower leg, later classified as cutaneous pigmented melanoma (nodular type, with ulceration and mitotic activity). She remained under observation for 2 years, and in 2021, following disease progression, she underwent 7 cycles of nivolumab therapy. Shortly thereafter, the patient reported a deterioration in her condition. From August 2021 to early 2022, she developed acute myocarditis and pericarditis, pneumonitis, myositis, a hematologic syndrome, skin induration of the extremities, and polyneuropathy. The patient was hospitalized in the rheumatology department.

Researchers from the scientific department conducted a plasma cytokine study to determine the levels of several cytokines previously found to be elevated in patients with autoimmune diseases. Plasma analysis revealed increased levels of interleukin-1β, MIG, PDGF-AB/BB, RANTES, and TGF-α. These findings indicated an intermediate type of inflammatory response: less controlled than in patients without adverse effects but not reaching the level of autoimmune inflammation observed in rheumatoid arthritis.

A hypothesis was proposed regarding the development of a hybrid inflammatory process, combining a systemic component of the oncologic disease and hyperactivation of the Th17 response, with a predominance of proinflammatory mediators’ characteristic of autoimmune pathologies. Nivolumab was discontinued, and comprehensive therapy was initiated to manage the cardiologic, neurologic, and rheumatic complications. Remission of the primary disease (melanoma) was achieved.

On November 24, 2024, Professor Boris Alexandrovich Frolov, a distinguished scientist and educator, Honored Worker of Higher Education of the Russian Federation, celebrated his 80th birthday. Graduated from the Orenburg Medical Institute (1967), he has dedicated his life to science and education. Beginning his career as a postgraduate student in the Department of Microbiology, by 1981 he had become head of a problem laboratory focused on stress and adaptation, collaborating with leading scientific centers across the USSR. His doctoral dissertation (1988), which addressed stress-induced immune disorders, laid the foundation for pioneering work in immunophysiology. From 1988 to 2009, Frolov served as Vice-Rector for Research, and since 1991 he has chaired the Department of Pathophysiology, where he has advanced the field of immunoprotection under extreme conditions. B.A. Frolov has presented his research at conferences in the United States, Germany, and Austria, and has delivered lectures at the University of Rochester (USA). He is the author of 250 scientific publications, 5 monographs, and 14 patents, including an invention recognized among the top 100 in Russia in 2015. He participated in the creation of the Manual on Immunophysiology and to the development of new medical technologies. Under his supervision, 12 doctoral dissertations have been defended.

This article outlines the scientific and professional achievements of Professor Frolov and highlights his contributions to experimental studies on the mechanisms of immunoprotection in secondary immunodeficiencies caused by extreme exposures.