Activity of Negative Regulation of the PD-1/PD-L1/PD-L2 T-Cell Response System in Patients with Pneumonia and Influenza A (H1N1)

Systemic inflammation is an integral pathophysiological component of many critical illnesses. The systemic inflammatory response is based on a cascade of interactions leading to hypercytokinemia and, as a consequence, multiple organ failure, which is one of the main causes of mortality in intensive care units.

Aim of the study. To evaluate the activity of the negative regulation system of T-cell response by determining the plasma levels of PD-1, PD-L1 and PD-L2 molecules in pneumonia patients with influenza A (H1N1).

Materials and methods. 85 patients with pneumonia and underlying influenza A (H1N1) were examined. Among them there were 30 patients with severe pneumonia, and 55 patients with non-severe pneumonia. Plasma levels of PD-1, PD-L1, PD-L2 molecules was determined by flow cytofluorometry method.

Results. In patients with severe pneumonia and underlying influenza A (H1N1), the plasma level of PD-1 receptor increased 4.6-fold, while the concentration of its ligands PD-L1 and PD-L2 increased 10.6 and 2.2-fold, respectively.

Conclusion. Significant increase in levels of PD-1 and its ligands PD-L1 and PD-L2 in patients with pneumonia and underlying influenza A (H1N1) indicates the involvement of negative regulation system of T-cell response in the cascade of immunological reactions and is associated with the severe disease. Possible correction of immune reactions realized through PD-1/PD-L1/PD-L2 complex in critically ill patients is a promising research avenue.

1. Gusev E. Yu., Chereshnev V.A. Immunological and pathophysiological mechanisms of systemic inflammation. Meditsinskaya Immunologiya = Medical Immunology (Russia). 2012; 1–2 [In Russ.]. URL: https://cyberleninka.ru/article/n/immunologicheskie-i-patofiziologicheskie-mehanizmy-sistemnogo-vospaleniya (date of access: 04/02/2021)

2. Gusev E.Yu., Zotova N.V., Lazareva M.A. Cytokine response and other distinctive features of critical phases of systemic inflammation in sepsis. Meditsinskaya Immunologiya = Medical Immunology (Russia). 2014; 2 [In Russ.]. URL: https://cyberleninka.ru/article/n/tsitokinovyy-otvet-i-drugie-otlichitelnye-osobennosti-kriticheskih-faz-sistemnogo-vospaleniya-pri-sepsise (date of access: 04/02/2021)

3. Khanova M.Yu., Grigoryev E.V. Roles of PD-1 and PD-L1 receptors in the development of systemic inflammatory response and immunoadjuvant therapy. Patologiya krovoobrashcheniya i kardiokhirurgiya = Circulation Pathology and Cardiac Surgery. 2019; 23 (3): 76–83. [In Russ.] DOI: 10.21688/1681-3472-2019-3-76-83

4. Huang X., Venet F., Wang Y.L., Lepape A., Yuan Z., Chen Y., Swan R., Kherouf H., Monneret G., Chung C.S., Ayala A. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA. 2009; 106 (15): 6303–8. PMID: 19332785. DOI: 10.1073/pnas.0809422106

5. Qin W., Hu L., Zhang X., Jiang S., Li J., Zhang Z., Wang X. The Diverse Function of PD-1/PD-L Pathway Beyond Cancer. Front Immunol. 2019; 10: 2298. DOI: 10.3389/fimmu.2019.02298. PMID: 31636634; PMCID: PMC6787287

6. Jubel J.M., Barbati Z.R., Burger C., Wirtz D.C., Schildberg F.A. The Role of PD-1 in Acute and Chronic Infection. Front Immunol. 2020; 11: 487. DOI: 10.3389/fimmu.2020.00487. PMID: 32265932; PMCID: PMC7105608

7. Sayapina M.S. Immunoregulatory functions of PD-1/PD-L1 inhibitors and development of resistance to them. Malignant tumours. 2017; (2): 94–99. [In Russ.] DOI: 10.18027/2224-5057-2017-2-94-99

8. Zitvogel L., Kroemer G. Targeting PD-1 / PD-L1 interactions for cancer immunotherapy. OncoImmunology. 2012; 1 (8): 1223–1225. PMID: 23243584 PMCID: PMC3518493 DOI: 10.4161/onci.21335

9. Klyuchagina Yu.I., Sokolova Z.A., Baryshnikova M.A. Role of PD1 Receptor and its Ligands PD-L1 and PD-L2 in Cancer Immunotherapy. Oncopediatria. 2017; 4 (1): 49–55. [In Russ.]. DOI: 10.15690/onco.v4i1.1684

10. Wilson J.K., Zhao Y., Singer M., Spencer J., Shankar-Hari M. Lymphocyte subset expression and serum concentrations of PD-1/ PD-L1 in sepsis pilot study. Crit Care. 2018; 22 (1): 95. DOI: 10.1186/s13054-018-2020-2

11. Yu X., Pan Y., Fei Q., Lin X., Chen Z., Huang H. Serum soluble PD-1 plays a role in predicting infection complications in patients with acute pancreatitis. Immun Inflamm Dis. 2021; 9 (1): 310-318. Epub 2021 Jan 8. DOI: 10.1002/iid3.394. PMID: 33417300; PMCID: PMC7860599

12. Zhao Y., Jia Y., Li C., Shao R., Fang Y. Predictive Value of Soluble Programmed Death-1 for Severe Sepsis and Septic Shock During the First Week in an Intensive Care Unit. Shock. 2019; 51 (3): 289-297. DOI: 10.1097/SHK.0000000000001171. PMID: 29702526

13. Terekhov I.V., Khadartsev A.A., Bondar S.S., Voevodin A.A. Expression The Toll- And Nod-Like Receptors, The Levels In Mononuclear Cells Whole Blood, Regulatory Factors Of Antiviral Defense And Interferon Production Product Under The Influence Of Low-Intensity Microwave Radiation With A Frequency Of 1 Ghz. Journal of New Medical Technologies, eEdition. 2016. No. 3. Publication 2-22. [In Russ.] URL: http://www.medtsu.tula.ru/VNMT/Bulletin/E2016-3/2-22.pdf (date accessed: 17.09.2016). DOI: 12737/21557

14. Wang H., Wei Y., Zeng Y., Qin Y., Xiong B., Qin G., Li J., Hu D., Qiu X., Sooranna S.R., Pinhu L. The association of polymorphisms of TLR4 and CD14 genes with susceptibility to sepsis in a Chinese population. BMC Medical Genetics. 2014; 15: 123. PMID: 25394369 PMCID: PMC4411696 DOI: 10.1186/s12881-014-0123-4

15. Matveev V.B., Kirichek A.A., Safronova V.M., Kokosadze N.V., Khalmurzaev O.A., Kamolov B.Sh., Lyubchenko L.N. Prognostic value of PD-L1 tumor status in patients with metastatic prostate cancer. Onkourologiya=Cancer Urology. 2019; 15 (1): 57–65. [In Russ.]. DOI: 10.17650/1726-9776-2019-15-1-57-65

16. Boomer J.S., To K., Chang K.C., Takasu O., Osborne D.F., Walton A.H., Bricker T.L., Jarman S.D. 2nd, Kreisel D., Krupnick A.S., Srivastava A., Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011; 350: 17–37. DOI: 10.1007/82_2010_116. PMID: 21061197

17. Chen J., Chen R., Huang S., Zu B., Zhang S. Atezolizumab alleviates the immunosuppression induced by PD-L1-positive neutrophils and improves the survival of mice during sepsis. Mol Med Rep. 2021; 23 (2): 1. DOI: 10.3892/mmr.2020.11783. Epub 2020 Dec 15. PMID: 33655320; PMCID: PMC7751480

18. Li J., Tang Z., Xie M., Hang C., Yu Y., Li C. Association between elevation of plasma biomarkers and monocyte dysfunction and their combination in predicting sepsis: An observational single-centre cohort study. Innate Immun. 2020; 26 (6): 514–527. DOI: 10.1177/1753425920926602. Epub 2020 May 26. PMID: 32456597; PMCID: PMC7491234

19. Shao R., Fang Y., Yu H., Zhao L., Jiang Z., Li C.S. Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study. Crit Care. 2016; 20 (1): 124. PMID: 27156867. DOI: 10.1186/s13054-016-1301-x

20. Tomino A., Tsuda M., Aoki R., Kajita Y., Hashiba M., Terajima T., Kano H., Takeyama N. Increased PD-1 expression and altered T cell repertoire diversity predict mortality in patients with septic shock: a preliminary study. PLoS One. 2017; 12 (1): e0169653. PMID: 28072859. DOI: 10.1371/journal.pone.0169653

21. Swanson P.E., Green J.M., Hotchkiss R.S. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011; 306 (23): 2594–2605. PMID: 22187279. DOI: 10.1001/jama.2011.1829

22. Chang K., Svabek C., Vazquez-Guillamet C., Sato B., Rasche D., Wilson S., Robbins P., Ulbrandt N., Suzich J.A., Green J., Patera A.C., Blair W., Krishnan S.,. Hotchkiss R. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014; 18 (1): R3. PMID: 24387680. DOI: 10.1186/cc13176

23. Huang X., Chen Y., Chung C.S., Yuan Z., Monaghan S.F., Wang F., Ayala A. Identification of B7-H1 as a novel mediator of the innate immune/proinflammatory response as well as a possible myeloid cell prognostic biomarker in sepsis. J Immunol. 2014; 192 (3): 1091–1099. PMID: 24379123. DOI: 10.4049/jimmunol.1302252

24. Interim guidelines of the Ministry of Health of Russia «Prevention, diagnosis and treatment of new coronavirus infection (COVID-19).» [In Russ.] Https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/054/669/original/%D0%98%D0%BD%D1%84%D0%BE%D0%B3%D1%80%D0%B0%D1%84%D0%B8%D0%BA%D0%B0_COVID-19_v10.pdf

25. Smirnov V.S., Totolyan A.A. Some possibilities of immunotherapy for coronavirus infection. Infektsiya i immunitet= Russian Journal of Infection and Immunity. 2020; 10 (3): 446–458. [In Russ.]. DOI: 10.15789/2220-7619-SPO-1470

26. Nasonov E.L. Coronavirus Disease 2019 (COVID-19): The Importance of IL-6 Inhibitors. Pul’monologiya. 2020; 30 (5): 629–644 [In Russ.]. DOI: 10.18093/0869-0189-2020-30-5-629-644

27. Stashkiv V.I., Zamyatina K.A., Shantarevich M.Yu., Nikitina I.V., Kаrmаzаnovsky G.G., Revishvili A.S. CT findings in patients with COVID-19 pneumonia after treatment with tocilizumab: foreign literature review. Meditsinskaya vizualizatsiya=Medical Visualization. 2020; 24 (2): 96–97. [In Russ.]. DOI: 10.24835/1607-0763-2020-2-96-97

28. Safety of Remdesivir and Tocilizumab in COVID-19 Treatment. Bezopasnost’ i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2020; 8 (3): 160–162. [In Russ.]. DOI: 10.30895/2312-7821-2020-8-3-160-162

29. Andrusova N.N., Kolganova M.A., Aleshina A.V., Shohin I.E. PD-L1 as a Potential Target in Cancer Therapy (Review). Drug development & registration. 2021; 10 (1): 31–36. [In Russ.] DOI: 10.33380/2305-2066-2021-10-1-31-36