α-Galactosylceramide as a Therapeutic Agent for PulmonaryMycobacterium tuberculosisInfection
- 15 September 2010
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 182 (6), 841-847
- https://doi.org/10.1164/rccm.200912-1921oc
Abstract
Rationale: Invariant natural killer T (iNKT) cells are a unique subset of T cells that recognize lipid antigens presented by CD1d molecules. Recent studies have shown that iNKT cells can protect mice against Mycobacterium tuberculosis (Mtb) infection. We sought to determine whether pharmacological activation of iNKT cells by α-galactosylceramide (α-GalCer) could be used to treat tuberculosis (TB). Objectives: We hypothesized that α-GalCer, either alone or in combination with isoniazid, could be used to treat pulmonary TB. Methods: The ability of α-GalCer–activated iNKT cells to suppress Mtb replication was evaluated using an in vitro coculture system. To test its potency in vivo, mice infected with virulent Mtb were treated with α-GalCer alone or in combination with isoniazid. Measurements and Main Results: Quantitative colony-forming unit counts were compared for both experimental systems. Our results show that α-GalCer plus isoniazid controls bacterial growth better than α-GalCer or INH alone, and single or multiple α-GalCer administrations prolong the survival of the mice infected via the aerosol route. Conclusions: Our results demonstrate that α-GalCer administration can improve the outcome of Mtb infection, even when transmitted by the aerosol route. However, a combination of isoniazid and α-GalCer treatment has a synergistic effect on infection control. We conclude that more efficient treatment of TB will be achieved through a combination of classic chemotherapy and modulation of the host immune response.Keywords
This publication has 54 references indexed in Scilit:
- Immunomodulation with Recombinant Interferon-γ1b in Pulmonary TuberculosisPLOS ONE, 2009
- Incorporation of NKT Cell-Activating Glycolipids Enhances Immunogenicity and Vaccine Efficacy of Mycobacterium bovis Bacillus Calmette-GuérinThe Journal of Immunology, 2009
- Human NKT cells promote monocyte differentiation into suppressive myeloid antigen-presenting cellsJournal of Leukocyte Biology, 2009
- Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunityProceedings of the National Academy of Sciences of the United States of America, 2009
- Innate Invariant NKT Cells Recognize Mycobacterium tuberculosis–Infected Macrophages, Produce Interferon-γ, and Kill Intracellular BacteriaPLoS Pathogens, 2008
- α-Galactosylceramide enhances the protective and therapeutic effects of tumor cell based vaccines for ovarian tumorsVaccine, 2008
- Activation of Invariant NKT Cells Exacerbates Experimental Visceral LeishmaniasisPLoS Pathogens, 2008
- Clinical applications of natural killer T cell–based immunotherapy for cancerCancer Science, 2008
- Mechanism of CD1d-restricted natural killer T cell activation during microbial infectionNature Immunology, 2003
- CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lungNature Medicine, 2002