Journal Article

α-Galactosylceramide as a Therapeutic Agent for Pulmonary Mycobacterium tuberculosis Infection

Sada-Ovalle, Isabel, Tian, Tian, Sköld, Markus, Besra, Gurdyal S., Behar, Samuel M.

2010

Overview

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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Aerosols / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Antigens, CD1d - immunology / Antitubercular Agents - therapeutic use / Biological and medical sciences / Drug Therapy, Combination / Female / Galactosylceramides - therapeutic use / H. Tuberculosis and Mycobacterial Disease / Immunomodulation / Infections / Intensive care medicine / Isoniazid - therapeutic use / Medical sciences / Mice / Mice, Inbred C3H / Mice, Inbred C57BL / Mycobacterium tuberculosis - drug effects / Mycobacterium tuberculosis - immunology / Natural Killer T-Cells - immunology / Pneumology / Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases / Treatment Outcome / Tuberculosis / Tuberculosis, Pulmonary - drug therapy / Tuberculosis, Pulmonary - immunology / Tuberculosis, Pulmonary - microbiology