Effects of Immunosuppressive Oligonucleotides A151, ODN4084-F, and μ-ODN4084-F on Mitigation of Acute Graft-Versus-Host Disease in Experimental Model

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Abstract

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.

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About the authors

Elena D. Gavrilova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Research Institute of Fundamental and Clinical Immunology

Author for correspondence.
Email: edav.gavr@mail.ru
ORCID iD: 0000-0002-2014-3397
SPIN-code: 7062-5818

Cand. Sci. (Biology)

Russian Federation, Novosibirsk; Novosibirsk

Elena V. Goiman

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Research Institute of Fundamental and Clinical Immunology

Email: l.goiman@mail.ru
ORCID iD: 0000-0002-6443-6917
SPIN-code: 6886-9372

MD, Dr. Sci. (Medicine)

Russian Federation, Novosibirsk; Novosibirsk

Alina Sh. Derzhalova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: a.derzhalova@g.nsu.ru
ORCID iD: 0009-0005-1383-2126
SPIN-code: 2993-4230
Russian Federation, Novosibirsk

Dmitry A. Stetsenko

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: stetsenkoda@bionet.nsc.ru
ORCID iD: 0000-0002-5215-5704
SPIN-code: 2080-3218

Cand. Sci. (Chemistry)

Russian Federation, Novosibirsk; Novosibirsk

Ekaterina A. Burakova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University

Email: ekaanabur@yandex.ru
ORCID iD: 0000-0001-6644-5959
SPIN-code: 5303-6652

Cand. Sci. (Chemistry)

Russian Federation, Novosibirsk; Novosibirsk

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2. Fig. 1. Survival of mice in an experimental model of acute graft-versus-host disease (aGVHD).

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3. Fig. 2. Thymus weight and cellularity in an experimental model of acute graft-versus-host disease (aGVHD). * statistically significant difference compared with the intact control (p < 0.05); # statistically significant difference between experimental groups: aGVHD + μ-ODN4084-F vs aGVHD (p < 0.05).

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4. Fig. 3. Spleen weight and cellularity in an experimental model of acute graft-versus-host disease (aGVHD). * statistically significant difference compared with the intact control (p < 0.05); # statistically significant difference between experimental groups: aGVHD + μ-ODN4084-F vs each experimental group on day 12 (p < 0.05).

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Copyright (c) 2024 Gavrilova E.D., Goiman E.V., Derzhalova A.S., Stetsenko D.A., Burakova E.A.

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