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Infection and Immunity, September 2005, p. 5782-5788, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5782-5788.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pulmonary Interleukin-23 Gene Delivery Increases Local T-Cell Immunity and Controls Growth of Mycobacterium tuberculosis in the Lungs

Kyle I. Happel,^1,* Euan A. Lockhart,^2,, Carol M. Mason,¹ Elizabeth Porretta,¹ Elizabeth Keoshkerian,² Anthony R. Odden,¹ Steve Nelson,¹ and Alistair J. Ramsay²

Section of Pulmonary/Critical Care Medicine,¹ Gene Therapy Program, Louisiana State University Health Sciences Center, New Orleans, Louisiana²

Received 18 January 2005/ Returned for modification 2 March 2005/ Accepted 20 May 2005

Interleukin-23 (IL-23) is a heterodimeric cytokine that shares IL-12 p40 but contains a unique p19 subunit similar to IL-12 p35. Previous studies indicate a greater importance for intact IL-12/23 p40 expression than IL-12 p35 for immunity against Mycobacterium tuberculosis, suggesting a role for IL-23 in host defense. The effects of IL-23 on the outcome of pulmonary infection with M. tuberculosis have not been described. Here, we show that local delivery of replication-defective adenovirus vectors encoding IL-23 (AdIL-23) greatly stimulated expression of both gamma interferon (IFN-) and IL-17 in lung tissues of otherwise normal mice. When given 72 h prior to infection with M. tuberculosis, AdIL-23 significantly reduced the bacterial burden at 14, 21, and 28 days. Markedly lower levels of lung inflammation were observed at 28 days than in control mice pretreated with control adenovirus (AdNull) or vehicle controls. AdIL-23 pretreatment resulted in increased numbers of CD4⁺ CD25⁺ activated T cells in lungs and draining lymph nodes compared to control groups and more CD4⁺ T cells bearing surface memory markers in lung lymph nodes. IL-23 gene delivery also significantly enhanced host anti-mycobacterial T-cell responses, as shown by elevated levels of IFN- and IL-17 secreted in vitro following restimulation with M. tuberculosis purified protein derivative. Overall, our data show that transient IL-23 gene delivery in the lung is well tolerated, and they provide the initial demonstration that this factor controls mycobacterial growth while augmenting early pulmonary T-cell immunity.

Editor: J. D. Clements

K.I.H. and E.A.L. contributed equally to this work.

Present address: University of Pittsburgh School of Medicine, Dept. of Molecular Genetics & Biochemistry, Pittsburgh, PA.

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