Abstract
Although most cases of tuberculosis (TB) can be cured with antibiotics, relapse is common if patients do not continue chemotherapy for at least 6 months. Thus, improved therapeutic strategies are urgently needed. We previously found that the combined DNA vaccine encoding the Mycobacterium tuberculosis proteins Ag85B, MPT-64 and MPT-83 protected mice from TB following H37Rv challenge and considered whether this combined DNA vaccine has a therapeutic effect. In the present work, we demonstrate that boosting the efficiency of the immune system with the combined DNA vaccine may be a valuable adjunct to shorten the duration of antibacterial chemotherapy. Mice treated with the combined DNA vaccine along with isoniazid and pyrazinamide showed significantly higher interferon-γ responses to a mixture of the three specific antigens (P<0.001), which were accompanied by a significant reduction in colony-forming unit in H37Rv-infected animals 3–5 months after treatment (P<0.001). These results suggest that the combined DNA vaccine along with conventional TB chemotherapy has strong potential for TB immunotherapy and may provide new alternatives to control the disease.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Flynn JL, Chan J . Immunology of tuberculosis. Annu Rev Immunol 2001; 19: 93–129.
Rook GA, Seah G, Ustianowski A . M. tuberculosis: immunology and vaccination. Eur Respir J 2001; 17: 537–557.
Young D, Dye C . The development and impact of tuberculosis vaccines. Cell 2006; 124: 683–687.
Young DB, Duncan K . Prospects for new interventions in the treatment and prevention of mycobacterial disease. Annu Rev Microbiol 1995; 49: 641–673.
Bishai WR, Graham NM, Harrington S, Pope DS, Hooper N, Astemborski J et al. Molecular and geographic patterns of tuberculosis transmission after 15 years of directly observed therapy. JAMA 1998; 280: 1679–1684.
Barnes PF, Cave MD . Molecular epidemiology of tuberculosis. N Engl J Med 2003; 349: 1149–1156.
Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM . Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993; 178: 2243–2247.
Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR . An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993; 178: 2249–2254.
Lai WC, Pakes SP, Ren K, Lu YS, Bennett M . Therapeutic effect of DNA immunization of genetically susceptible mice infected with virulent Mycoplasma pulmonis. J Immunol 1997; 158: 2513–2516.
Lowrie DB, Tascon RE, Bonato VL, Lima VM, Faccioli LH, Stavropoulos E et al. Therapy of tuberculosis in mice by DNA vaccination. Nature 1999; 400: 269–271.
Bonato VL, Goncalves ED, Soares EG, Santos Junior RR, Sartori A, Coelho-Castelo AA et al. Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8+ cells, interferon-gamma recovery and reduction of lung injury. Immunology 2004; 113: 130–138.
Ha SJ, Jeon BY, Kim SC, Kim DJ, Song MK, Sung YC et al. Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis. Gene Therapy 2003; 10: 1592–1599.
Ha SJ, Jeon BY, Youn JI, Kim SC, Cho SN, Sung YC . Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis. Gene Therapy 2005; 12: 634–638.
Silva CL, Bonato VL, Coelho-Castelo AA, De Souza AO, Santos SA, Lima KM et al. Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice. Gene Therapy 2005; 12: 281–287.
Zhu D, Jiang S, Luo X . Therapeutic effects of Ag85B and MPT64 DNA vaccines in a murine model of Mycobacterium tuberculosis infection. Vaccine 2005; 23: 4619–4624.
Krieg AM . Immune effects and mechanisms of action of CpG motifs. Vaccine 2000; 19: 618–622.
Orme IM, Cooper AM . Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 1999; 20: 307–312.
Huygen K, Content J, Denis O, Montgomery DL, Yawman AM, Deck RR et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat Med 1996; 2: 893–898.
Kamath AT, Feng CG, Macdonald M, Briscoe H, Britton WJ . Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis. Infect Immun 1999; 67: 1702–1707.
Bandera A, Gori A, Catozzi L, Degli Esposti A, Marchetti G, Molteni C et al. Molecular epidemiology study of exogenous reinfection in an area with a low incidence of tuberculosis. J Clin Microbiol 2001; 39: 2213–2218.
van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341: 1174–1179.
Krieg AM, Love-Homan L, Yi AK, Harty JT . CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol 1998; 161: 2428–2434.
Cai H, Tian X, Hu XD, Li SX, Yu DH, Zhu YX . Combined DNA vaccines formulated either in DDA or in saline protect cattle from Mycobacterium bovis infection. Vaccine 2005; 23: 3887–3895.
Cai H, Tian X, Hu XD, Zhuang YH, Zhu YX . Combined DNA vaccines formulated in DDA enhance protective immunity against tuberculosis. DNA Cell Biol 2004; 23: 450–456.
Taylor JL, Turner OC, Basaraba RJ, Belisle JT, Huygen K, Orme IM . Pulmonary necrosis resulting from DNA vaccination against tuberculosis. Infect Immun 2003; 71: 2192–2198.
Skeiky YA, Ovendale PJ, Jen S, Alderson MR, Dillon DC, Smith S et al. T cell expression cloning of a Mycobacterium tuberculosis gene encoding a protective antigen associated with the early control of infection. J Immunol 2000; 165: 7140–7149.
Seder RA . The role of IL12 in the regulation of Th1 and Th2 differentiation. Res Immunol 1995; 146: 473–476.
MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF . Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci USA 1997; 94: 5243–5248.
Cai H, Hu XD, Yu DH, Li SX, Tian X, Zhu YX . Combined DNA vaccine encapsulated in microspheres enhanced protection efficacy against Mycobacterium tuberculosis infection of mice. Vaccine 2005; 23: 4167–4174.
Acknowledgements
This work was supported by Grant 2002AA206411 from the National 863 High Technology Program, the Chinese Ministry of Science and Technology.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yu, DH., Hu, XD. & Cai, H. Efficient tuberculosis treatment in mice using chemotherapy and immunotherapy with the combined DNA vaccine encoding Ag85B, MPT-64 and MPT-83. Gene Ther 15, 652–659 (2008). https://doi.org/10.1038/gt.2008.13
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2008.13
Keywords
This article is cited by
-
Immunogenicity and therapeutic effects of a Mycobacterium tuberculosis rv2190c DNA vaccine in mice
BMC Immunology (2017)
-
Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial
Scientific Reports (2017)
-
Tuberculosis vaccine research in China
Emerging Microbes & Infections (2012)
-
MPT 64 Antigen detection for Rapid confirmation of M.tuberculosis isolates
BMC Research Notes (2011)
-
Immunotherapeutic role of Ag85B as an adjunct to antituberculous chemotherapy
Journal of Immune Based Therapies and Vaccines (2011)