Relationship between NKT cell phenotype and liver fibrosis degree in patients with chronic hepatitis C before and after treatment

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Objective. Determination of the features of the NKT cell phenotype in patients with chronic hepatitis C (CHC) with varying fibrosis degrees before and after treatment with direct-acting antiviral drugs (DAAs).

Materials and methods. A total of 112 patients with CHC aged 44.2 ± 7.4 years were examined. The diagnosis was confirmed by PCR-RNA of the hepatitis C virus (HCV). To diagnose liver fibrosis, the shear wave transient elastometry method was used. Patients with CHC were treated with DAAs, Sofosbuvir 400 mg/day and Velpatasvir 100 mg/day, for 12 weeks. Depending on the liver fibrosis degree before the start of DAA treatment, patients with CHC were divided into 3 groups: with fibrosis F0-F1, with fibrosis F2 and with fibrosis F3–F4. All patients were examined before and after DAA treatment. As a control, 23 healthy people of the same age range were examined. The study of the phenotypic composition of NKT cells was performed by flow cytometry.

Results. The features of the NKT cell phenotype which characterize the functional activity of this fraction of lymphocytes were established. Changes in the NKT cell phenotype in patients with CHC depended on the examination period (before or after DAA treatment). Before treatment, against the background of a high viral load and ALT activity in the blood, the NKT cell phenotype slightly depended on the fibrosis degree and was characterized by a high level of expression of the CD57 receptor on the membranes of total NKT cells, as well as lymphocytes of this fraction expressing CD8, CD62L and CD94 markers. After treatment, patients achieved complete HCV clearance. Against this background, the features of the NKT cell phenotype began to depend more significantly on the fibrosis degree, while characterizing the preservation of inflammatory imprinting in the immune system. The most significant changes in the NKT cell phenotype were found in patients with fibrosis F3–F4, which were expressed in a reduced number of CD62L+NKT cells, the maximum level of CD73+NKT cells, and the preservation of a high level of CD57 expression on the surface of CD8+ and CD94+NKT cells.

Conclusion. It is necessary to develop a differentiated approach to the treatment of liver fibrosis and methods for predicting the development of hepatocellular carcinoma in patients with a high degree of fibrosis after successful antiviral therapy.

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Sobre autores

Andrey Savchenko

Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences

Autor responsável pela correspondência
Email: aasavchenko@yandex.ru
ORCID ID: 0000-0001-5829-672X

Research Institute of Medical Problems of the North, Professor, MD, Head, Laboratory of Cellular and Molecular Physiology and Pathology

Rússia, Krasnoyarsk

Elena Tikhonova

Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University

Email: tihonovaep@mail.ru
ORCID ID: 0000-0001-6466-9609

MD, Head, Department of Infectious Diseases and Epidemiology with the Course of Postgraduate Education, Professor

Rússia, Krasnoyarsk

Anna Anisimova

N.S. Karpovich Krasnoyarsk Interdistrict Clinical Hospital of Emergency Medicine

Email: tada1@mail.ru

Physician, Infectious Diseases Department

Rússia, Krasnoyarsk

Igor Kudryavtsev

Research Institute of Experimental Medicine; Pavlov First Saint Petersburg State Medical University

Email: igorek1981@yandex.ru
ORCID ID: 0000-0001-5637-2143

Cand. Biol. Sci., Head, Cellular Immunology Laboratory, Immunology Department, Associate Professor, Immunology Department

Rússia, Saint Petersburg; Saint Petersburg

Elena Anisimova

Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences

Email: foi-543@mail.ru
ORCID ID: 0000-0002-6120-159X

Research Institute of Medical Problems of the North, Cand. Med. Sci., Senior Researcher, Cellular and Molecular Physiology and Pathology Laboratory

Rússia, Krasnoyarsk

Aleksandr Borisov

Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences

Email: 2410454@mail.ru
ORCID ID: 0000-0002-9026-2615

Research Institute of Medical Problems of the North, Cand. Med. Sci., Leading Researcher, Laboratory of Cellular and Molecular Physiology and Pathology

Rússia, Krasnoyarsk

Bibliografia

  1. Ивашкин В.Т., Чуланов В.П., Мамонова Н.А., Маевская М.В., Жаркова М.С., Тихонов И.Н. и др. Клинические рекомендации Российского общества по изучению печени, Российской гастроэнтерологической ассоциации, Национального научного общества инфекционистов по диагностике и лечению хронического вирусного гепатита С. Российский журнал гастроэнтерологии, гепатологии, колопроктологии 2023; 33 (1): 84–124. DOI: 10.22416/ 1382-4376-2023-33-1-84-124 / Ivashkin V.T., Chulanov V.P., Mamonova N.A., Maevskaya M.V., Zharkova M.S., Tikhonov I.N. et al. Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C. Russian Journal of Gastroenterology, Hepatology, Coloproctology, 2023; 33(1): 84 –124. (In Russ.). DOI: 10.22416/ 1382-4376-2023-33-1-84-124
  2. Gavril O.I., Gavril R.S., Mitu F., Gavrilescu O., Popa I.V., Tatarciuc D. et al. The Influence of Metabolic Factors in Patients with Chronic Viral Hepatitis C Who Received Oral Antiviral Treatment. Metabolites 2023; 13(4): 571. doi: 10.3390/metabo13040571
  3. Vujovic A., Isakovic A.M., Misirlic-Dencic S., Juloski J., Mirkovic M., Cirkovic A. et al. IL-23/IL-17 Axis in Chronic Hepatitis C and Non-Alcoholic Steatohepatitis-New Insight into Immunohepatotoxicity of Different Chronic Liver Diseases. Int. J. Mol. Sci. 2023; 24(15): 12483. doi: 10.3390/ijms241512483
  4. Борисов А.Г., Савченко А.А., Тихонова Е.П. Современные методы лечения вирусного гепатита С. Красноярск: Версона, 2017; 74 с. / Borisov A.G., Savchenko A.A., Tikhonova E.P. [Modern methods of treatment of viral hepatitis C.] Krasnoyarsk: Versona, 2017; 74 p. (In Russ.).
  5. Alghamdi A.S., Alghamdi H., Alserehi H.A., Babatin M.A., Alswat K.A., Alghamdi M. et al. SASLT guidelines: Update in treatment of hepatitis C virus infection, 2024. Saudi J. Gastroenterol. 2024; 30(1): 1–42. doi: 10.4103/sjg.sjg_333_23
  6. Li W., Liang J., An J., Liu L., Hou Y., Li L. et al. Geographic Distribution of HCV Genotypes and Efficacy of Direct-Acting Antivirals in Chronic HCV-Infected Patients in North and Northeast China: A Real-World Multicenter Study. Can. J. Gastroenterol. Hepatol. 2022; 2022: 7395506. doi: 10.1155/2022/7395506
  7. Ng M., Carrieri P.M., Awendila L., Socнas M.E., Knight R., Ti L. Hepatitis C Virus Infection and Hospital-Related Outcomes: A Systematic Review. Can. J. Gastroenterol. Hepatol. 2024; 2024: 3325609. doi: 10.1155/2024/3325609
  8. Li W., Liang L., Liao Q., Li Y., Zhou Y. CD38: An important regulator of T cell function. Biomed. Pharmacother 2022; 153: 113395. doi: 10.1016/j.biopha.2022.113395
  9. Chen C., Cai H., Shen J., Zhang X., Peng W., Li C. et al. Exploration of a hypoxia-immune-related microenvironment gene signature and prediction model for hepatitis C-induced early-stage fibrosis. J. Transl. Med. 2024; 22(1): 116. doi: 10.1186/s12967-024-04912-6
  10. Ferrasi A.C., Lima S.V.G., Galvani A.F., Delafiori J., Dias-Audibert F.L., Catharino R.R. et al. Metabolomics in chronic hepatitis C: Decoding fibrosis grading and underlying pathways. World J. Hepatol. 2023; 15(11): 1237–1249. doi: 10.4254/wjh.v15.i11.1237
  11. Hensel N., Gu Z., Sagar, Wieland D., Jechow K., Kemming J. et al. Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection. Nat. Immunol 2021; 22(2): 229–239. doi: 10.1038/s41590-020-00817-w
  12. Tonnerre P., Wolski D., Subudhi S., Aljabban J, Hoogeveen R.C., Damasio M. et al. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat. Immunol. 2021; 22(8): 1030–1041. doi: 10.1038/s41590-021-00982-6
  13. Tsukanov V.V., Savchenko A.A., Cherepnin M.A., Kasparov E.V., Tikhonova E.P., Vasyutin A.V. et al. Association of blood NK cell phenotype with the severity of liver fibrosis in patients with chronic viral hepatitis c with genotype 1 or 3. Diagnostics 2024; 14(5): 472. doi: 10.3390/diagnostics14050472
  14. Kleczka A., Mazur B., Tomaszek K., Gabriel A., Dzik R., Kabała-Dzik A. Association of NK Cells with the Severity of Fibrosis in Patients with Chronic Hepatitis C. Diagnostics (Basel) 2023; 13(13): 2187. DOI: 10.3390/ diagnostics13132187
  15. Poddighe D., Maulenkul T., Zhubanova G., Akhmaldtinova L., Dossybayeva K. Natural Killer T (NKT) Cells in Autoimmune Hepatitis: Current Evidence from Basic and Clinical Research. Cells 2023; 12(24): 2854. doi: 10.3390/cells12242854
  16. Satoh M., Iwabuchi K. Contribution of NKT cells and CD1d-expressing cells in obesity-associated adipose tissue inflammation. Front. Immunol. 2024; 15: 1365843. doi: 10.3389/fimmu.2024.1365843
  17. Козлов В.А., Тихонова Е.П., Савченко А.А., Кудрявцев И.В., Андронова Н.В., Анисимова Е.Н. и др. Клиническая иммунология. Практическое пособие для инфекционистов Красноярск: Поликор; 2021. 563 с. / Kozlov V.A., Tikhonova E.P., Savchenko A.A., Kudryavtsev I.V., Andronova N.V., Anisimova E.N. et al. Clinical immunology. A practical guide for infectious disease specialists. Krasnoyarsk: Polikor 2021, 563 p. (In Russ.).
  18. Cairo C., Webb T.J. Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut. J. Immunol. 2022; 208(2): 235–246. doi: 10.4049/jimmunol.2100799
  19. Yi Q., Yang J., Wu Y., Wang Y., Cao Q., Wen W. Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells. Front. Immunol. 2023; 14; 1204524. doi: 10.3389/fimmu.2023.1204524
  20. Zhao W., Li M., Song S., Zhi Y., Huan C., Lv G. The role of natural killer T cells in liver transplantation. Front. Cell. Dev. Biol. 2024; 11: 1274361. doi: 10.3389/fcell.2023.127436
  21. Ma C., Han M., Heinrich B., Fu Q., Zhang Q., Sandhu M. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018; 360( 6391): 5931. doi: 10.1126/science.aan5931
  22. Gao M., Li X., He L., Yang J., Ye X., Xiao F. et al. Diammonium Glycyrrhizinate Mitigates Liver Injury Via Inhibiting Proliferation Of NKT Cells And Promoting Proliferation Of Tregs. Drug Des. Devel. Ther. 2019; 13: 3579–3589. doi: 10.2147/DDDT.S220030
  23. Wolf M.J., Adili A., Piotrowitz K., Abdullah Z., Boege Y., Stemmer K. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014; 26(4): 549–564. doi: 10.1016/j.ccell.2014.09.003
  24. Meng Y., Zhao T., Zhang Z., Zhang D. The role of hepatic microenvironment in hepatic fibrosis development. Ann. Med. 2022; 54(1): 2830–2844. doi: 10.1080/07853890. 2022.2132418
  25. Nilsson J., Hцrnberg M., Schmidt-Christensen A., Linde K., Nilsson M., Carlus M. et al. NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis. Sci. Rep. 2020; 10(1): 21778. doi: 10.1038/s41598-020-78688-2
  26. Senff T., Menne C., Cosmovici C., Lewis-Ximenez L.L., Aneja J., Broering R. et al. Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C. JCI Insight 2022; 7(2): 155432. doi: 10.1172/jci.insight.155432
  27. Савченко А.А., Борисов А.Г., Кудрявцев И.В., Беленюк В.Д. Особенности фенотипа NKT-клеток в зависимости от исхода распространенного гнойного перитонита. Инфекция и иммунитет 2022; 12(6): 1040–1050. doi: 10.15789/2220-7619-DPP-2004 / Savchenko A.A., Borisov A.G., Kudryavtsev I.V., Belenjuk V.D. Disseminated purulent peritonitis outcome affects NKT cell phenotype. Russian Journal of Infection and Immunity 2022; 12 ( 6): 1040–1050. (In Russ.). doi: 10.15789/2220-7619-DPP-2004
  28. Elias Junior E., Gubert V.T., Bonin-Jacob C.M., Puga M.A.M., Gouveia C.G., Sichinel A.H. et al. CD57 T cells associated with immunosenescence in adults living with HIV or AIDS. Immunology 2024; 171(1): 146–153. doi: 10.1111/imm.13707
  29. Swieboda D., Rice T.F., Guo Y., Nadel S., Thwaites R.S., Openshaw P.J.M. et al. Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth. Clin. Exp. Immunol. 2024; 215(1): 1–14. doi: 10.1093/cei/uxad094
  30. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J. Hepatol. 2018; 69(2): 461–511. doi: 10.1016/j.jhep.2018.03.026
  31. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL Recommendations on Treatment of Hepatitis C 2016. J. Hepatol. 2017; 66(1): 153–194. doi: 10.1016/j.jhep.2016.09.001
  32. Poynard T., Bedossa P., Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349(9055): 825–832. doi: 10.1016/s0140-6736(96)07642-8
  33. Ben A.J., Neumann C.R., Mengue S.S. The Brief Medication Questionnaire and Morisky-Green test to evaluate medication adherence. Rev. Saude Publica 2012; 46(2): 279–289. doi: 10.1590/s0034-89102012005000013
  34. Кудрявцев И.В., Субботовская А.И. Опыт измерения параметров иммунного статуса с использованием шести-цветного цитофлуоримерического анализа. Медицинская иммунология 2015;17(1): 19-26. doi: 10.15789/1563-0625-2015-1-19-26 / Kudryavtsev I.V., Subbotovskaya A.I. Application of six-color flow cytometric analysis for immune profile monitoring. Medical Immunology 2015; 17(1):19-26. (In Russ.). doi: 10.15789/1563-0625-2015-1-19-26
  35. Segura J., He B., Ireland J., Zou Z., Shen T., Roth G. et al. The Role of L-Selectin in HIV Infection. Front. Microbiol. 2021; 12: 725741. doi: 10.3389/fmicb.2021.725741
  36. Almeida J.S., Casanova J.M., Santos-Rosa M., Tarazona R., Solana R., Rodrigues-Santos P. Natural Killer T-like Cells: Immunobiology and Role in Disease. Int. J. Mol. Sci. 2023; 24(3): 2743. doi: 10.3390/ijms24032743
  37. Zhang C., Wang X.M., Li S.R., Twelkmeyer T., Wang W.H., Zhang S.Y. et al. NKG2A is a NK cell exhaustion checkpoint for HCV persistence. Nat. Commun. 2019; 10(1): 1507. doi: 10.1038/s41467-019-09212-y
  38. Wang X., Xiong H., Ning Z. Implications of NKG2A in immunity and immune-mediated diseases. Front. Immunol. 2022; 13: 960852. doi: 10.3389/fimmu.2022.960852
  39. Mani H., Yen J.H., Hsu H.J., Chang C.C., Liou J.W. Hepatitis C virus core protein: Not just a nucleocapsid building block, but an immunity and inflammation modulator. Tzu. Chi. Med. J. 2021; 34(2): 139–147. doi: 10.4103/tcmj.tcmj_97_21
  40. Rezayat F., Esmaeil N., Rezaei A., Sherkat R. Contradictory Effect of Lymphocyte Therapy and Prednisolone Therapy on CD3+CD8+CD56+ Natural Killer T Population in Women with Recurrent Spontaneous Abortion. J. Hum. Reprod. Sci. 2023; 16(3): 246–256. doi: 10.4103/jhrs.jhrs_8_23
  41. Wang C., Liu X., Li Z., Chai Y., Jiang Y., Wang Q. et al. CD8(+)NKT-like cells regulate the immune response by killing antigen-bearing DCs. Sci. Rep. 2015; 5: 14124. doi: 10.1038/srep14124
  42. Dong M., Wang S., Pei Z. Mechanism of CD38 via NAD+ in the Development of Non-alcoholic Fatty Liver Disease. Int. J. Med. Sci. 2023; 20(2): 262–266. doi: 10.7150/ijms.81381
  43. Takasawa S. CD38-Cyclic ADP-Ribose Signal System in Physiology, Biochemistry, and Pathophysiology. Int. J. Mol. Sci. 2022; 23(8): 4306. doi: 10.3390/ijms23084306
  44. Baghbani E., Noorolyai S., Shanehbandi D., Mokhtarzadeh A., Aghebati-Maleki L., Shahgoli V.K. et al. Regulation of immune responses through CD39 and CD73 in cancer: Novel checkpoints. Life Sci. 2021; 282: 119826. doi: 10.1016/j.lfs.2021.119826
  45. Zhao S., Si M., Deng X., Wang D., Kong L., Zhang Q. HCV inhibits M2a, M2b and M2c macrophage polarization via HCV core protein engagement with Toll-like receptor 2. Exp. Ther. Med. 2022; 24(2): 522. doi: 10.3892/etm.2022.11448
  46. Devi P., Ota S., Punga T., Bergqvist A. Hepatitis C Virus Core Protein Down-Regulates Expression of Src-Homology 2 Domain Containing Protein Tyrosine Phosphatase by Modulating Promoter DNA Methylation. Viruses 2021; 13(12): 2514. doi: 10.3390/v13122514
  47. Жданов В.В., Чайковский А.В., Пан Э.С. Роль звездчатых клеток в формировании ниши прогениторных клеток печени. Бюллетень сибирской медицины 2024; 23(1): 126–133. DOI: 10.20538/ 1682-0363-2024-1-126-133 / Zhdanov V.V., Chaikovskii A.V., Pan E.S. Hepatic stellate cells and their role in the formation of the progenitor cell niche. Bulletin of Siberian Medicine 2024; 23(1): 126–133. (In Russ.). doi: 10.20538/1682-0363-2024-1-126-133
  48. Carter J.K., Friedman S.L. Hepatic Stellate Cell-Immune Interactions in NASH. Front. Endocrinol. (Lausanne) 2022; 13: 867940. doi: 10.3389/fendo.2022.867940

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