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* Centre for Gene Therapeutics, M. G. DeGroote Institute for Infectious Disease Research, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;
Respiratory Division, Royal Victoria Hospital, Montreal, Quebec, Canada; and
Department of Pathology, University of Michigan, Ann Arbor, MI 48109
Protection by parenteral immunization with plasmid DNA vaccines against pulmonary tuberculosis (TB) is very modest. In this study, we have investigated the underlying mechanisms for the poor mucosal protective efficacy and the avenues and mechanisms to improve the efficacy of a single i.m. immunization with a monogenic plasmid DNA TB vaccine in a murine model. We show that i.m. DNA immunization fails to elicit accumulation of Ag-specific T cells in the airway lumen despite robust T cell responses in the spleen. Such systemically activated T cells cannot be rapidly mobilized into the airway lumen upon Mycobacterium tuberculosis exposure. However, airway deposition of low doses of soluble mycobacterial Ags in previously immunized mice effectively mobilizes the systemically activated T cells into the airway lumen. A fraction of such airway luminal T cells can persist in the airway lumen, undergo quick, robust expansion and activation and provide marked immune protection upon airway M. tuberculosis exposure. Airway mucosal deposition of soluble mycobacterial Ags was found to create a tissue microenvironment rich in proinflammatory molecules including chemokines and hence conducive to T cell recruitment. Thus, in vivo neutralization of MIP-1
or IFN-inducible protein-10 markedly inhibited the accumulation of Ag-specific T cells in the airway lumen. Our data suggest that immunoprotective efficacy on the mucosal surface by i.m. plasmid DNA immunization could be substantially improved by simple mucosal soluble Ag inoculation and restoration of mucosal luminal T cells. Our study holds implication for the future design of DNA vaccination strategies against intracellular infections.
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 study is supported by funds from the Canadian Institutes for Health Research.
2 Address correspondence and reprint requests to Dr. Zhou Xing, Room 4012-MDCL, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada. E-mail address: xingz{at}mcmaster.ca
3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; IP-10, IFN-inducible protein-10; RPA, RNase protection assay; BAL, bronchoalveolar lavage; ICCS, intracellular cytokine staining; LSD, least significant difference.
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  I. M. Belyakov and J. D. Ahlers What Role Does the Route of Immunization Play in the Generation of Protective Immunity against Mucosal Pathogens? J. Immunol., December 1, 2009; 183(11): 6883 - 6892. [Abstract] [Full Text] [PDF]
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