Pulmonary Interleukin-23 Gene Delivery Increases Local T-Cell Immunity and Controls Growth of Mycobacterium tuberculosis in the Lungs
| Autor: | Steve Nelson, Carol M. Mason, Elizabeth Porretta, Euan A. Lockhart, Anthony R. Odden, Alistair J. Ramsay, Kyle I. Happel, Elizabeth Keoshkerian |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
T-Lymphocytes
Immunology Genetic Vectors Antitubercular Agents Gene delivery Lymphocyte Activation Microbiology Interleukin-23 Adenoviridae Mycobacterium tuberculosis Interferon-gamma Mice Immunity Interleukin 23 medicine Animals Interferon gamma IL-2 receptor Lung Tuberculosis Pulmonary biology Interleukins Interleukin-17 Gene Transfer Techniques Genetic Therapy biology.organism_classification Mice Inbred C57BL Infectious Diseases medicine.anatomical_structure Microbial Immunity and Vaccines Interleukin-23 Subunit p19 Parasitology Interleukin 17 medicine.drug |
| Popis: | 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-γ) 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-γ 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. |
| Databáze: | OpenAIRE |
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