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* Centenary Institute of Cancer Medicine and Cell Biology,
Discipline of Medicine, and
Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases, University of Sydney, Camperdown, Australia; and
Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA 52240
Modulating the host-immune response by the use of recombinant vaccines is a potential strategy to improve protection against microbial pathogens. In this study, we sought to determine whether secretion of murine GM-CSF by the bacillus Calmette-Guérin (BCG) vaccine influenced protective immunity against Mycobacterium tuberculosis. BCG-derived GM-CSF stimulated the in vitro generation of functional APCs from murine bone marrow precursors, as demonstrated by the infection-induced secretion of IL-12 by differentiated APCs, and the ability of these cells to present Ag to mycobacterium-specific T cells. Mice vaccinated with BCG-secreting murine GM-CSF (BCG:GM-CSF) showed increased numbers of CD11c+MHCII+ and CD11c–CD11b+F480+ cells compared with those vaccinated with control BCG, and this effect was most apparent in the draining lymph nodes at 7 and 14 days postvaccination. Vaccination with BCG:GM-CSF also resulted in enhanced expression of costimulatory molecules on migratory dendritic cells in the draining lymph nodes. The increased APC number was associated with an increase in the frequency of anti-mycobacterial IFN-
-secreting T cells generated after BCG:GM-CSF vaccination compared with vaccination with control BCG, and this effect was sustained up to 17 wk in the spleens of immunized mice. Vaccination with BCG:GM-CSF resulted in an 
10-fold increase in protection against disseminated M. tuberculosis infection compared with control BCG. This study demonstrates the potential of BCG-secreting immunostimulatory molecules as vaccines to protect against tuberculosis and suggests BCG:GM-CSF merits further appraisal as a candidate to control M. tuberculosis infection in humans.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Health and Medical Research Council of Australia. J.A.T was supported by a National Health and Medical Research Council Career Development Award, A.A.R was supported by an Australian Postgraduate Award, and T.M.W. was the recipient of the University of Sydney Faculty of Medicine Postgraduate Scholarship.
2 Address correspondence and reprint requests to Dr. James A. Triccas, Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, NSW 2006, Australia. E-mail address: jamiet{at}infdis.usyd.edu.au
3 Abbreviations used in this paper: DC, dendritic cell; DLN, draining lymph nodes; NDLN, nonDLN; BCG, bacillus Calmette-Guérin; ADC, albumin-dextrose-catalase; BCG:GM-CSF, BCG-secreting murine GM-CSF; BCG:Ct, control BCG strain.
This article has been cited by other articles:
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  A. A. Ryan, J. K. Nambiar, T. M. Wozniak, B. Roediger, E. Shklovskaya, W. J. Britton, B. Fazekas de St. Groth, and J. A. Triccas Antigen Load Governs the Differential Priming of CD8 T Cells in Response to the Bacille Calmette Guerin Vaccine or Mycobacterium tuberculosis Infection J. Immunol., June 1, 2009; 182(11): 7172 - 7177. [Abstract] [Full Text] [PDF]
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