Alpha-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection.
BACKGROUND
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).


OBJECTIVE
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.


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.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Isabel
I
Sada-Ovalle
Markus
M
Sköld
Tian
T
Tian
Gurdyal S
GS
Besra
Samuel M
SM
Behar
D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D000995:Antitubercular Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005699:Galactosylceramides / Q000627:therapeutic use*; D056747:Immunomodulation; D007538:Isoniazid / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology
D055610:Antigens, CD1d; D000995:Antitubercular Agents; D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D007538:Isoniazid