Pathogenetic role of tumor necrosis factor (TNF-α) for the development of peritoneal tuberculosis in an experiment

Currently tuberculosis is considered as a group of diseases united by one etiological factor. The pathogenesis of certain localizations of tuberculous inflammation, in particular peritoneum tuberculosis, hasn’t been sufficiently studied. The role of cytokine mechanisms in the development of the disease and the elaboration of non-sterile immunity requires further experimental studies, in particular the creation of a reproducible model on laboratory animals.

The aim: to study the effect of TNF-α on the development of tuberculosis of the serous coat of the abdominal cavity, as well as to evaluate the possibility of modeling tuberculous peritonitis in laboratory animals using infliximab.

Materials and methods. The studies were conducted on 18 male rabbits, which were simulated peritoneal tuberculosis by intra-abdominal administration of a suspension of Mycobacterium tuberculosis. 10 rabbits of the experimental group were intravenously injected with an infliximab solution and an iron (III) hydroxide sucrose complex intraperitoneally a day before infection.

Results. In the control group of animals, tuberculosis either didn’t develop, or in a third of cases it affected only the pulmonary parenchyma, while proliferative processes prevailed. On the contrary, in animals with inactivated TNF-α, in 100 % of observations, tuberculous peritonitis was detected with associated lung damage and the predominance of alterative caseous processes.

Conclusion. The created model of tuberculous peritonitis shows the leading role of TNF-α in the activation of macrophages, as well as in attracting cells to the site of infection. This is the primary signal necessary for the formation and stability of granulomas since the neutralization of this cytokine leads to a loss of control over the infection and the destruction of the granuloma with the development of destructive tuberculosis in the serous coat of the abdominal cavity. 

1. Jagger A, Reiter-Karam S, Hamada Y, Getahun H. National policies on the management of latent tuberculosis infection: review of 98 countries. Bull World Health Organ. 2018; 96(3): 173-184F. doi: 10.2471/BLT.17.199414

2. O’Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. The immune response in tuberculosis. Annu Rev Immunol. 2013; 31: 475-527. doi: 10.1146/annurev-immunol-032712-095939

3. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol. 2001; 19: 93-129. doi: 10.1146/annurev.immunol.19.1.93

4. Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009; 136(1): 37-49. doi: 10.1016/j.cell.2008.11.014

5. Lin PL, Plessner HL, Voitenok NN, Flynn JL. Tumor necrosis factor and tuberculosis. J Investig Dermatol Symp Proc. 2007; 12(1): 22-25. doi: 10.1038/sj.jidsymp.5650027

6. Keane J, Remold HG, Kornfeld H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol. 2000; 164(4): 2016-2020. doi: 10.4049/jimmunol.164.4.2016

7. Mezouar S, Diarra I, Roudier J, Desnues B, Mege JL. Tumor necrosis factor-alpha antagonist interferes with the formation of granulomatous multinucleated giant cells: New insights into Mycobacterium tuberculosis infection. Front Immunol. 2019; 10: 1947. doi: 10.3389/fimmu.2019.01947

8. Zhang Z, Fan W, Yang G, Xu Z, Wang J, Cheng Q, et al. Risk of tuberculosis in patients treated with TNF-α antagonists: A systematic review and meta-analysis of randomized controlled trials. BMJ Open. 2017; 7(3): e012567. doi: 10.1136/bmjopen-2016-012567

9. Voronina EV, Lobanova NV, Yakhin IR, Romanova NA, Seregin YuA. The role of tumor necrosis factor-alpha in the immunopathogenesis of diseases of various etiologies and its significance in the development of anti-cytokine therapy with monoclonal antibodies. Medical Immunology (Russia). 2018; 20(6): 797-806. (In Russ.). doi: 10.1183/09031936.00028510

10. Murdaca G, Spanò F, Contatore M, Guastalla A, Penza E, Magnani O, et al. Infection risk associated with anti-TNF-α agents: A review. Expert Opin Drug Saf. 2015; 14(4): 571-582. doi: 10.1517/14740338.2015.1009036

11. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002; 301(2): 418-426. doi: 10.1124/jpet.301.2.418

12. Borisov SE, Lukina GV, Slogotskaya LV, Kochetkov YaA, Guntupova LD, Kulikovskaya NV. Tuberculosis infection screening and monitoring in rheumatic patients receiving gene engineering biological. Tuberculosis and Lung Diseases. 2011; 88(6): 42-50. (In Russ.).

13. Lügering A, Schmidt M, Lügering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspasedependent pathway. Gastroenterology. 2001; 121(5): 1145-1157. doi: 10.1053/gast.2001.28702

14. Wang Q, Wen Z, Cao Q. Risk of tuberculosis during infliximab therapy for inflammatory bowel disease, rheumatoid arthritis, and spondyloarthropathy: A meta-analysis. Exp Ther Med. 2016; 12(3): 1693-1704. doi: 10.3892/etm.2016.3548

15. Botha T, Ryffel B. Reactivation of latent tuberculosis infection in TNF-deficient mice. J Immunol. 2003; 171(6): 3110-3118. doi: 10.4049/jimmunol.171.6.3110

16. Lin PL, Myers A, Smith L, Bigbee C, Bigbee M, Fuhrman C, et al. Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum. 2010; 62(2): 340-350. doi: 10.1002/art.27271

17. Capuano SV 3rd, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, et al. Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M.tuberculosis infection. Infect Immun. 2003; 71(10): 5831-5844. doi: 10.1128/IAI.71.10.5831-5844.2003

18. Tsenova L, O’Brien P, Holloway J, Peixoto B, Soteropoulos P, Fallows D, et al. Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis. J Interferon Cytokine Res. 2014; 34(9): 716-726. doi: 10.1089/jir.2013.0123

19. Vaid U, Kane GC. Tuberculous peritonitis. Microbiol Spectr. 2017; 5(1). doi: 10.1128/microbiolspec.TNMI7-0006-2016

20. Srivastava U, Almusa O, Tung KW, Heller MT. Tuberculous peritonitis. Radiol Case Rep. 2015; 9(3): 971. doi: 10.2484/rcr.v9i3.971

21. GOST 33216-2014. Rules for working with laboratory rodents and rabbits. Moscow, Standartinform; 2016. (In Russ.).

22. Shekunova EV, Kovaleva MA, Makarova MN, Makarov VG. Dose selection in preclinical studies: Cross-species dose conversion. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2020; 10(1): 19-28. (in Russ.). doi: 10.30895/1991-2919-2020-10-1-19-28

23. Nairz M, Theurl I, Swirski FK, Weiss G. “Pumping iron” – how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflugers Arch. 2017; 469(3-4): 397-418. doi: 10.1007/s00424-017-1944-8

24. Naymanov AKh, Gulyukin AM, Tolstenko NG, Vangeli EP, Kalmykov VM Diaskintest for the diagnosis of bovine tuberculosis. Tuberculosis and Lung Diseases. 2020; 98(12): 53-56. (In Russ.). doi: 10.21292/2075-1230-2020-98-12-53-56

25. Shepelkova GS, Evstifeev VV, Apt AS. Study of molecular mechanisms of the pathogenesis of tuberculosis in experimental models. Tuberculosis and Lung Diseases. 2012; 89(7): 3-11. (In Russ.).

26. Fonseca KL, Rodrigues PNS, Olsson IAS, Saraiva M. Experimental study of tuberculosis: From animal models to complex cell systems and organoids. PLoS Pathog. 2017; 13(8): e1006421. doi: 10.1371/journal.ppat.1006421

27. Naymanov AKh, Kalmykov VM, Kalmykova MS. Reproduction of tuberculosis in laboratory animals (bioassay). Veterinary, Zootechnics and Biotechnology. 2018; 5: 24-30. (In Russ.).

28. Gao J, Guo M, Teng L, Bao R, Xian Q, Wang X, et al. Guinea pig infected with Mycobacterium tuberculosis via oral consumption, J Appl Anim Res. 2018; 46(1): 1323-1328. doi: 10.1080/09712119.2018.1505622

29. Rybakova AV, Makarova MN, Makarov VG. Using rabbits in pre-clinical trials. International Bulletin of Veterinary Medicine. 2016; 4: 102-106. (In Russ.).

30. Lurie MB. The fate of human and bovine tubercle bacilli in various organs of the rabbit. J Exp Med. 1928; 48(2): 155-182. doi: 10.1084/jem.48.2.155

31. Dorman SE, Hatem CL, Tyagi S, Aird K, Lopez-Molina J, Pitt ML, et al. Susceptibility to tuberculosis: clues from studies with inbred and outbred New Zealand White rabbits. Infect Immun. 2004; 72(3): 1700-1705. doi: 10.1128/IAI.72.3.1700-1705

32. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345(15): 1098-1104. doi: 10.1056/NEJMoa011110

33. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol. 2002; 168(9): 4620-4627. doi: 10.4049/jimmunol.168.9.4620

34. Park HJ, Choi BY, Sohn M, Han NY, Kim I, Oh JM. Effects of tumor necrosis factor-alpha inhibitors on the incidence of tuberculosis. Korean J Clin Pharm. 2018; 28: 333-341. doi: 10.24304/kjcp.2018.28.4.333

35. Sartaeva GSh, Isaeva AG, Rahysheva AA. A special role of the tumor necrosis factor-alpha in the antitubercular response. Bulletin of the Kazakh National Medical University. 2018; 4: 69-73. (In Russ.).

36. Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity. 2008; 29(2): 283-294. doi: 10.1016/j.immuni.2008.06.011