Туберкулез (ТБ), вызываемый облигатным внутриклеточным микроорганизмом Mycobacterium tuberculosis, – одно из древнейших известных инфекционных заболеваний человека. Современное лечение ТБ, состоящее из нескольких антибактериальных препаратов, является длительным, токсичным и требует от пациента высокой комплаентности, поэтому разработка новых терапевтических стратегий, которые позволили бы минимизировать сроки лечения и предотвратить образование лекарственно-устойчивых форм микобактерий, представляется актуальной и важной. Клеточная терапия открывает перспективу потенциальных дополнительных терапевтических возможностей для лечения лекарственно-устойчивого ТБ. В последние годы широко изучаются возможности использования мезенхимных стволовых клеток в терапии ТБ различной локализации. Применение таких клеток совместно со стандартной противотуберкулезной терапией может оказаться весьма перспективным в плане сокращения продолжительности лечения и уменьшения формирования резистентных к лекарственной терапии микобактерий. В данной статье описаны возможности применения мезенхимных стволовых клеток в лечении ТБ у пациентов в том числе с широкой и множественной лекарственной устойчивостью, а также механизмы взаимодействия этих клеток с M. tuberculosis.
Tuberculosis, caused by the obligate intracellular microorganism Mycobacterium tuberculosis, is one of the oldest known infectious diseases in humans. Modern therapy of tuberculosis, consisting of several antibacterial drugs, is long-term, toxic and requires high compliance from the patient, therefore, the development of new therapeutic strategies that would minimize the duration of treatment and prevent the formation of drug-resistant forms of mycobacteria is relevant and important. Cellular therapy now holds the promise of potential complementary therapeutic options for the treatment of drug-resistant tuberculosis. In recent years, the possibilities of using mesenchymal stem cells in the treatment of tuberculosis of various localization have been widely studied. The use of such cells in conjunction with standard anti-tuberculosis therapy holds great promise for shortening the duration of treatment and reducing the formation of drug-resistant mycobacteria. This article describes the possibilities of using mesenchymal stem cells in the treatment of tuberculosis in patients, including those with extensive and multidrug resistance, as well as the mechanisms of interaction of mesenchymal stem cells with M. tuberculosis.
Keywords: mesenchymal stem cells, tuberculosis, multidrug resistance, broad drug resistance
1. Васильева И.А., Белиловский Е.М., Борисов С.Е., Стерликов С.А. Туберкулез с множественной лекарственной устойчивостью возбудителя в странах мира и в Российской Федерации. Туберкулез и болезни легких. 2017;95(11):5-17 [Vasil'eva IA, Belilovskii EM, Borisov SE, Sterlikov SA. Tuberkulez s mnozhestvennoi lekarstvennoi ustoichivost'iu vozbuditelia v stranakh mira i v Rossiiskoi Federatsii. Tuberkulez i bolezni legkih. 2017;95(11):5-17 (in Russian)].
DOI:10.21292/2075-1230-2017-95-11-5-17
2. Global Tuberculosis Report 2018. WHO/CDS/TB/2018.20. Geneva, World Health Organization, 2018; p. 95-6.
3. Иванова Д.А., Борисов С.Е., Родина О.В., и др. Безопасность режимов лечения больных туберкулезом с множественной лекарственной устойчивостью возбудителя согласно новым рекомендациям ВОЗ 2019 г. Туберкулез и болезни легких. 2020;98(1):5-15 [Ivanova DA, Borisov SE, Rodina OV, et al. Bezopasnost' rezhimov lecheniia bol'nykh tuberkulezom s mnozhestvennoi lekarstvennoi ustoichivost'iu vozbuditelia soglasno novym rekomendatsiiam VOZ 2019 g. Tuberkulez i bolezni legkikh. 2020;98(1):5-15 (in Russian)]. DOI:10.21292/2075-1230-2020-98-1-5-15
4. Бурмистрова И.А., Самойлова А.Г., Тюлькова Т.Е., и др. Лекарственная устойчивость M. tuberculosis (исторические аспекты, современный уровень знаний). Туберкулез и болезни легких. 2020;98(1):54-61 [Burmistrova IA, Samoilova AG, Tiul'kova TE, et al. Lekarstvennaia ustoichivost' M. tuberculosis (istoricheskie aspekty, sovremennyi uroven' znanii). Tuberkulez i bolezni legkikh. 2020;98(1):54-61 (in Russian)]. DOI:10.21292/2075-1230-2020-98-1-54-61
5. Кульчавеня Е.В. Служба внелегочного туберкулеза в Сибири и на Дальнем Востоке. Туберкулез и болезни легких. 2019;97(1):7-11 [Kul'chavenya EV. Sluzhba vnelegochnogo tuberkuleza v Sibiri i na Dal'nem Vostoke. Tuberkulez i bolezni legkikh. 2019;97(1):7-11 (in Russian)]. DOI:10.21292/2075-1230-2019-97-1-7-11
6. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723-32.
7. Mbuagbaw L, Guglielmetti L, Hewison C, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis. 2019;25(5):936-43. DOI:10.3201/eid2505.181823
8. Singh B, Cocker D, Ryan H, et al. Linezolid for drug-resistant tuberculosis. Cochrane Database Syst Rev. 2017;2017(11):CD012836. DOI:10.1002/14651858.CD012836
9. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. WHO/CDS/TB/2019.3. Geneva, World Health Organization, 2019.
10. Gomez JE, McKinney JD. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. 2004;84(1-2):29-44. DOI:10.1016/j.tube.2003.08.003
11. Levitte S, Adams KN, Berg RD, et al. Mycobacterial acid tolerance enables phagolysosomal survival and establishment of tuberculous infection in vivo. Cell Host Microbe. 2016;20(2):250-8. DOI:10.1016/j.chom.2016.07.007
12. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science. 1994;263(5147):678-81. DOI:10.1126/science.8303277
13. van der Wel N, Hava D, Houben D, et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell. 2007;129(7):1287-98. DOI:10.1016/j.cell.2007.05.059
14. Raghuvanshi S, Sharma P, Singh S, et al. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci. 2010;107(50):21653-8. DOI:10.1073/pnas.1007967107
15. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis drugs. New Engl J Med. 2001;344(17):1294-303. DOI:10.1056/NEJM200104263441706
16. Fatima S, Kamble SS, Dwivedi VP, et al. Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence. J Clin Invest. 2020;130(2):655-61. DOI:10.1172/JCI128043
17. Das B, Kashino SS, Pulu I, et al. CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013;5(170):170. DOI:10.1126/scitranslmed.3004912
18. Khan A, Mann L, Papanna R, et al. Mesenchymal stem cells internalize Mycobacterium tuberculosis through scavenger receptors and restrict bacterial growth through autophagy. Sci Rep. 2017;7(1):1-15. DOI:10.1038/s41598-017-15290-z
19. Tardif S, Ross C, Bergman P, et al. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J Gerontol A Biol Sci Med Sci. 2015;70(5):577-88. DOI:10.1093/gerona/glu101
20. Gutierrez MG, Master SS, Singh SB, et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119(6):753-66. DOI:10.1016/j.cell.2004.11.038
21. Parida SK, Madansein R, Singh N, et al. Cellular therapy in tuberculosis. Int J Infect Dis. 2015;32:32-8. DOI:10.1016/j.ijid.2015.01.016
22. Shah NS, Wright A, Bai GH, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis. 2007;13(3):380. DOI:10.3201/eid1303.061400
23. Wakamoto Y, Dhar N, Chait R, et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science. 2013;339(6115):91-5. DOI:10.1126/science.1229858
24. Cohen KA, Abeel T, McGuire AM, et al. Evolution of extensively drug-resistant tuberculosis over four decades revealed by whole genome sequencing of Mycobacterium tuberculosis from KwaZulu-Natal, South Africa. Int J Mycobacteriol. 2015;4:24-5. DOI:10.1016/j.ijmyco.2014.11.028
25. Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest. 2009;136(2):420-5. DOI:10.1378/chest.08-2427
26. Skrahin A, Ahmed RK, Ferrara G, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med. 2014;2(2):108-22. DOI:10.1016/S2213-2600(13)70234-0
27. Matthay MA, Goolaerts A, Howard JP, et al. Mesenchymal Stem Cells for Acute Lung Injury: Preclinical Evidence. Crit Care Med. 2010;38(10):569-73. DOI:10.1097/CCM.0b013e3181f1ff1d
28. Mei SH, McCarter SD, Deng Y, et al. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4(9):e269. DOI:10.1371/journal.pmed.0040269
29. Tropea KA, Leder E, Aslam M, et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302(9):829-37. DOI:10.1152/ajplung.00347.2011
30. Spees JL, Olson SD, Whitney MJ, et al. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci. 2006;103(5):1283-8. DOI:10.1073/pnas.0510511103
31. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759-65. DOI:10.1038/nm.2736
32. Sinclair K, Yerkovich ST, Chambers DC. Mesenchymal stem cells and the lung. Respirology. 2013;18(3):397-411. DOI:10.1111/resp.12050
33. Ерохин В.В., Васильева И.А., Коноплянников А.Г., и др. Системная трансплантация аутологичных мезенхимальных стволовых клеток костного мозга в лечении больных множественным лекарственно-устойчивым туберкулезом легких. Туберкулез и болезни легких. 2008;85(10):3-6 [Erohin VV, Vasil'eva IA, Konoplyannikov AG, et al. Sistemnaia transplantatsiia autologichnykh mezenkhimal'nykh stvolovykh kletok kostnogo mozga v lechenii bol'nykh mnozhestvennym lekarstvenno-ustoichivym tuberkulezom legkikh. Tuberkulez i bolezni legkikh. 2008;85(10):3-6 (in Russian)].
34. Danjuma L, Mok PL, Higuchi A, et al. Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity. Regen Ther. 2018;9:100-10. DOI:10.1016/j.reth.2018.09.001
35. Yudintceva NM, Bogolyubova IO, Muraviov AN, et al. Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis. J Tissue Eng Regen Med. 2018;12(3):1580-93. DOI:10.1002/term.2583
36. Орлова Н.В., Муравьев А.Н., Блюм Н.М., и др. Экспериментальная реконструкция мочевого пузыря кролика с использованием аллогенных клеток различного тканевого происхождения. Медицинский альянс. 2016;1:50-2 [Orlova NV, Murav'ev AN, Blium NM, et al. Eksperimental'naia rekonstruktsiia mochevogo puzyria krolika s ispol'zovaniem allogennykh kletok razlichnogo tkanevogo proiskhozhdeniia. Meditsinskii al'ians. 2016;1:50-2 (in Russian)].
37. Гусейнова Ф.М., Виноградова Т.И., Заболотных Н.В., и др. Влияние клеточной терапии мезенхимными клетками стромы костного мозга на процессы репарации при экспериментальном туберкулезном сальпингите. Медицинский альянс. 2017;3:35-43. [Guseinova FM, Vinogradova TI, Zabolotnykh NV, et al. Vliianie kletochnoi terapii mezenkhimnymi kletkami stromy kostnogo mozga na protsessy reparatsii pri eksperimental'nom tuberkuleznom sal'pingite. Meditsinskii al'ians. 2017;3:35-43 (in Russian)].
38. Ариэль Б.М., Гусейнова Ф.М., Виноградова Т.И., и др. Мезенхимные клетки стромы костного мозга при туберкулезе гениталий у кроликов (экспериментальное исследование с морфологическим контролем). Обзоры по клинической фармакологии и лекарственной терапии. 2017;15(2):47-55 [Ariel' BM, Guseinova FM, Vinogradova TI, et al. Mezenkhimnye kletki stromy kostnogo mozga pri tuberkuleze genitalii u krolikov (eksperimental'noe issledovanie s morfologicheskim kontrolem). Obzory po klinicheskoi farmakologii i lekarstvennoi terapii. 2017;15(2):47-55 (in Russian)].
________________________________________________
1. Vasil'eva IA, Belilovskii EM, Borisov SE, Sterlikov SA. Tuberkulez s mnozhestvennoi lekarstvennoi ustoichivost'iu vozbuditelia v stranakh mira i v Rossiiskoi Federatsii. Tuberkulez i bolezni legkih. 2017;95(11):5-17 (in Russian). DOI:10.21292/2075-1230-2017-95-11-5-17
2. Global Tuberculosis Report 2018. WHO/CDS/TB/2018.20. Geneva, World Health Organization, 2018; p. 95-6.
3. Ivanova DA, Borisov SE, Rodina OV, et al. Bezopasnost' rezhimov lecheniia bol'nykh tuberkulezom s mnozhestvennoi lekarstvennoi ustoichivost'iu vozbuditelia soglasno novym rekomendatsiiam VOZ 2019 g. Tuberkulez i bolezni legkikh. 2020;98(1):5-15 (in Russian). DOI:10.21292/2075-1230-2020-98-1-5-15
4. Burmistrova IA, Samoilova AG, Tiul'kova TE, et al. Lekarstvennaia ustoichivost' M. tuberculosis (istoricheskie aspekty, sovremennyi uroven' znanii). Tuberkulez i bolezni legkikh. 2020;98(1):54-61 (in Russian). DOI:10.21292/2075-1230-2020-98-1-54-61
5. Kul'chavenya EV. Sluzhba vnelegochnogo tuberkuleza v Sibiri i na Dal'nem Vostoke. Tuberkulez i bolezni legkikh. 2019;97(1):7-11 (in Russian). DOI:10.21292/2075-1230-2019-97-1-7-11
6. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723-32.
7. Mbuagbaw L, Guglielmetti L, Hewison C, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis. 2019;25(5):936-43. DOI:10.3201/eid2505.181823
8. Singh B, Cocker D, Ryan H, et al. Linezolid for drug-resistant tuberculosis. Cochrane Database Syst Rev. 2017;2017(11):CD012836. DOI:10.1002/14651858.CD012836
9. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. WHO/CDS/TB/2019.3. Geneva, World Health Organization, 2019.
10. Gomez JE, McKinney JD. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. 2004;84(1-2):29-44. DOI:10.1016/j.tube.2003.08.003
11. Levitte S, Adams KN, Berg RD, et al. Mycobacterial acid tolerance enables phagolysosomal survival and establishment of tuberculous infection in vivo. Cell Host Microbe. 2016;20(2):250-8. DOI:10.1016/j.chom.2016.07.007
12. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science. 1994;263(5147):678-81. DOI:10.1126/science.8303277
13. van der Wel N, Hava D, Houben D, et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell. 2007;129(7):1287-98. DOI:10.1016/j.cell.2007.05.059
14. Raghuvanshi S, Sharma P, Singh S, et al. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci. 2010;107(50):21653-8. DOI:10.1073/pnas.1007967107
15. Espinal MA, Laszlo A, Simonsen L, et al. Global trends in resistance to antituberculosis drugs. New Engl J Med. 2001;344(17):1294-303. DOI:10.1056/NEJM200104263441706
16. Fatima S, Kamble SS, Dwivedi VP, et al. Mycobacterium tuberculosis programs mesenchymal stem cells to establish dormancy and persistence. J Clin Invest. 2020;130(2):655-61. DOI:10.1172/JCI128043
17. Das B, Kashino SS, Pulu I, et al. CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013;5(170):170. DOI:10.1126/scitranslmed.3004912
18. Khan A, Mann L, Papanna R, et al. Mesenchymal stem cells internalize Mycobacterium tuberculosis through scavenger receptors and restrict bacterial growth through autophagy. Sci Rep. 2017;7(1):1-15. DOI:10.1038/s41598-017-15290-z
19. Tardif S, Ross C, Bergman P, et al. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J Gerontol A Biol Sci Med Sci. 2015;70(5):577-88. DOI:10.1093/gerona/glu101
20. Gutierrez MG, Master SS, Singh SB, et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119(6):753-66. DOI:10.1016/j.cell.2004.11.038
21. Parida SK, Madansein R, Singh N, et al. Cellular therapy in tuberculosis. Int J Infect Dis. 2015;32:32-8. DOI:10.1016/j.ijid.2015.01.016
22. Shah NS, Wright A, Bai GH, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis. 2007;13(3):380. DOI:10.3201/eid1303.061400
23. Wakamoto Y, Dhar N, Chait R, et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science. 2013;339(6115):91-5. DOI:10.1126/science.1229858
24. Cohen KA, Abeel T, McGuire AM, et al. Evolution of extensively drug-resistant tuberculosis over four decades revealed by whole genome sequencing of Mycobacterium tuberculosis from KwaZulu-Natal, South Africa. Int J Mycobacteriol. 2015;4:24-5. DOI:10.1016/j.ijmyco.2014.11.028
25. Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest. 2009;136(2):420-5. DOI:10.1378/chest.08-2427
26. Skrahin A, Ahmed RK, Ferrara G, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med. 2014;2(2):108-22. DOI:10.1016/S2213-2600(13)70234-0
27. Matthay MA, Goolaerts A, Howard JP, et al. Mesenchymal Stem Cells for Acute Lung Injury: Preclinical Evidence. Crit Care Med. 2010;38(10):569-73. DOI:10.1097/CCM.0b013e3181f1ff1d
28. Mei SH, McCarter SD, Deng Y, et al. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4(9):e269. DOI:10.1371/journal.pmed.0040269
29. Tropea KA, Leder E, Aslam M, et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302(9):829-37. DOI:10.1152/ajplung.00347.2011
30. Spees JL, Olson SD, Whitney MJ, et al. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci. 2006;103(5):1283-8. DOI:10.1073/pnas.0510511103
31. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759-65. DOI:10.1038/nm.2736
32. Sinclair K, Yerkovich ST, Chambers DC. Mesenchymal stem cells and the lung. Respirology. 2013;18(3):397-411. DOI:10.1111/resp.12050
33. Erohin VV, Vasil'eva IA, Konoplyannikov AG, et al. Sistemnaia transplantatsiia autologichnykh mezenkhimal'nykh stvolovykh kletok kostnogo mozga v lechenii bol'nykh mnozhestvennym lekarstvenno-ustoichivym tuberkulezom legkikh. Tuberkulez i bolezni legkikh. 2008;85(10):3-6 (in Russian).
34. Danjuma L, Mok PL, Higuchi A, et al. Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity. Regen Ther. 2018;9:100-10. DOI:10.1016/j.reth.2018.09.001
35. Yudintceva NM, Bogolyubova IO, Muraviov AN, et al. Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis. J Tissue Eng Regen Med. 2018;12(3):1580-93. DOI:10.1002/term.2583
36. Orlova NV, Murav'ev AN, Blium NM, et al. Eksperimental'naia rekonstruktsiia mochevogo puzyria krolika s ispol'zovaniem allogennykh kletok razlichnogo tkanevogo proiskhozhdeniia. Meditsinskii al'ians. 2016;1:50-2 (in Russian).
37. Guseinova FM, Vinogradova TI, Zabolotnykh NV, et al. Vliianie kletochnoi terapii mezenkhimnymi kletkami stromy kostnogo mozga na protsessy reparatsii pri eksperimental'nom tuberkuleznom sal'pingite. Meditsinskii al'ians. 2017;3:35-43 (in Russian).
38. Ariel' BM, Guseinova FM, Vinogradova TI, et al. Mezenkhimnye kletki stromy kostnogo mozga pri tuberkuleze genitalii u krolikov (eksperimental'noe issledovanie s morfologicheskim kontrolem). Obzory po klinicheskoi farmakologii i lekarstvennoi terapii. 2017;15(2):47-55 (in Russian).
1 ФГБОУ ВО «Санкт-Петербургский государственный университет», Санкт-Петербург, Россия;
2 ФГБУ «Санкт-Петербургский научно-исследовательский институт фтизиопульмонологии» Минздрава России, Санкт-Петербург, Россия;
3 ЧОУ ВО «Санкт-Петербургский медико-социальный институт», Санкт-Петербург, Россия;
4 СПб ГБУЗ «Городская Покровская больница», Санкт-Петербург, Россия;
5 ФГБУН «Институт цитологии» Российской академии наук, Санкт-Петербург, Россия
*gorelova_a@yahoo.com
________________________________________________
Anna N. Remezova1, Anna A. Gorelova*1,2, Alexander N. Muraviev2,3, Tatjana I. Vinogradova2, Andrey I. Gorelov1,4, Alexander I. Gorbunov2, Nadezhda V. Orlova2, Natalya M. Yudintseva5, Yulia A. Nashchekina5, Magomedsadyk G. Sheykhov2, Petr K. Yablonsky1,2
1 Saint Petersburg State University, Saint Petersburg, Russia;
2 Saint Petersburg Research Institute of Phtisiopulmonology, Saint Petersburg, Russia;
3 Saint Petersburg Medico-Social Institute, Saint Petersburg, Russia;
4 Pokrovskaya Municipal Hospital, Saint Petersburg, Russia;
5 Institute of Cytology, Saint Petersburg, Russia
*gorelova_a@yahoo.com