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Anti-IL-6 Receptor Antibody Causes Less Promotion of Tuberculosis Infection than Anti-TNF-α Antibody in Mice

By Masaji Okada, Yoko Kita, Noriko Kanamaru, Satomi Hashimoto, Yasushi Uchiyama, Masahiko Mihara, Yoshikazu Inoue, Yoshiyuki Ohsugi, Tadamitsu Kishimoto and Mitsunori Sakatani


Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade

Topics: Research Article
Publisher: Hindawi Publishing Corporation
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Provided by: PubMed Central

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  1. (2004). A .Z g a n i a c z ,M .S a n t o s u o s s o ,J .W a n ge ta l .
  2. (1999). a i n i ,E .W .S tC l a i r ,F .B r e e d v e l de ta l . ,“ I n fl i x i m a b (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial,”
  3. (1997). a n dS .H .E .K a u f m a n n ,“ L e t h a lt u b e r c u l o s i si ni n t e r l e u k i n -6-deficient mutant mice,”
  4. An essential role for interferon γ in resistance to Mycobacterium tuberculosis infection,”
  5. (2002). Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman’s disease like symptoms emerged
  6. (2004). Anti-interleukin 6 receptor antibody inhibits murine AA-amyloidosis,”
  7. (1992). Anti-tumor necrosis factor ameliorates joint disease in murine collageninduced arthritis,”
  8. (2000). B a t h o n ,R .W .M a r t i n ,R .M .F l e i s c h m a n ne ta l . ,“ A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis,” New England
  9. (2001). CD4+ T cells are required for the development of cytotoxic CD8 T cells during Mycobacterium tuberculosis infection,”
  10. (2006). Cutting edge: IFNγ regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection,”
  11. (2001). e a n e ,S .G e r s h o n ,R .P .W i s ee ta l . ,“ T u b e r c u l o s i sa s s o c i a t e d with infliximab,a tumor necrosis factor α-neutralizingagent,” New England
  12. (2008). Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial,”
  13. (2006). Estes, “Bovine natural killer cells acquire cytotoxic/effector activity following activationwithIL-12/15andreduce Mycobacterium bovisBCG in infected macrophages,”Journal of Leukocyte Biology,
  14. (2009). Experience with Mycobacterium tuberculosis infection reported in the tocilizumab worldwide RA safety database,” Annals of the Rheumatic Diseases,vol. 68, supplement 3, article 557,
  15. (1989). h e e h a n ,N .H .R u d d l e ,a n dR .D .S c h r e i b e r , “Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors,”
  16. (1997). High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: synergistic action of TNF and IFN-γ in the differentiation of protective granulomas,”European
  17. (1990). I.E.A.FleschandS.H.E.Kaufmann,“Stimulationofantibacterial macrophage activities by B-cell stimulatory factor 2
  18. (1988). IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells,”
  19. (2003). Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis,”
  20. (2001). Immunology of tuberculosis,”
  21. (1994). Impaired immune and acute-phase responses in interleukin-6-deficient mice,”
  22. (1996). Impaired neutrophil response and CD4 T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans,”
  23. (2006). Impaired protection against Mycobacterium bovis bacillus Calmette-Gu´ erin infection in IL-15-deficient mice,”
  24. Induction of high-dose tolerance to the rat anti-mouse IL6 receptor antibody
  25. Induction of protective cellular immunity against Mycobacterium tuberculosis by recombinant attenuated self-destructing Listeria monocytogenes strains harboring eukaryotic expression plasmids for antigen 85 complex and
  26. (2001). Interleukin-6 regulates the phenotype of the immune response to a tuberculosis subunit vaccine,” Immunology,v o l .
  27. (2000). L i p s k y ,D .M .F .M .v a nd e rH e i j d e ,E .W .S t .C l a i re ta l . , “Infliximab and methotrexate in the treatment of rheumatoid arthritis,”
  28. (1995). L.A.Lucian,R.Slatteryet al.,“Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia,”
  29. (1998). M.Mihara,N.Takagi,Y.Takeda,andY.Ohsugi,“IL-6receptor blockage inhibits the onset of autoimmune kidney disease
  30. (2006). NK cellderived IFN-γ differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis,”
  31. (2005). Novel recombinant BCG and DNA-vaccination against tuberculosis in a cynomolgus monkey model,”
  32. (2003). Reactivation of latent tuberculosis infection in TNF-deficient mice,”
  33. (1994). Role of interleukin-6 in the induction of protective T cells during mycobacterial infections
  34. (1993). Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6,”
  35. (2003). Synergistic effe c to nt h ea t t e n u a t i o no fc o l l a g e ni n d u c e da r t h r i t i si n tumor necrosis factor receptor I (TNFRI) and interleukin 6 double knockout mice,”
  36. (1997). T e s s i e r ,P .H .N a c c a c h e ,I .C l a r k - L e w i s ,R .P .G l a d u e
  37. (1989). The inducing role of tumor necrosis factor in the development of bactericidal granulomas during
  38. (1996). The Philippine cynomolgus monkey (Macaca fasicularis)p r o v i d e san e w nonhuman primate model of tuberculosis that resembles human disease,”
  39. (2008). The recombinant humanized anti-IL-6 receptor antibody tocilizumab, an innovative drug for the treatment of rheumatoid arthritis,”
  40. (2003). Treatment ofrheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter activesurveillance report,”
  41. (1995). Tumor necrosis factor-α is required in the protective immuneresponse against Mycobacterium tuberculosis
  42. (2005). Why does tumor necrosis factor targeted therapy reactivate tuberculosis?”