title: Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis.
abstract: Lipids and glycolipid molecules derived from Mycobacterium tuberculosis can be presented to T cells by CD1 cell-surface molecules in humans. These lipid-specific T cells are cytolytic, secrete pro-inflammatory cytokines and have bactericidal activity. Here, we describe studies in which lipids from M. tuberculosis were incorporated into liposomes with adjuvant and tested as vaccines in a guinea pig aerosol tuberculosis challenge model. Animals vaccinated with mycobacterial lipids showed reduced bacterial burdens in the lung and spleen at 4 weeks after infection. In addition, the lungs of lipid-vaccinated animals also had significantly less pathology, with granulomatous lesions being smaller and more lymphocytic. In contrast, animals receiving only vehicle control immunizations had granulomatous lesions that were larger and often contained caseous necrotic centers. Quantification of histopathology by morphometric analysis revealed that the overall percentage of lung occupied by diseased tissue was significantly smaller in lipid-vaccinated animals as compared to vehicle control animals. In addition, the mean area of individual granulomatous lesions was found to be significantly smaller in both lipid- and bacillus Calmette-Guerin-vaccinated guinea pigs. These data support an important role for lipid antigens in the immune response to M. tuberculosis infection, potentially through the generation of CD1-restricted T cells. Immunogenic lipids thus represent a novel class of antigens that might be included to enhance the protective effects of subunit vaccine formulations.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and Harvard Medical School, Smith 552, 1 Jimmy Fund Way, Boston, MA 02115, USA. cdascher@rics.bwh.harvard.edu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dascher
authors.forename: Kenji
authors.initials: K
authors.lastname: Hiromatsu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xiong
authors.forename: Caroline
authors.initials: C
authors.lastname: Morehouse
authors.forename: Gerald
authors.initials: G
authors.lastname: Watts
authors.forename: Gui
authors.initials: G
authors.lastname: Liu
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: LeClair
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000280:Administration, Inhalation; D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006017:Glycolipids / Q000032:analysis / Q000737:chemistry / Q000276:immunology; D006099:Granuloma / Q000276:immunology / Q000473:pathology; D006168:Guinea Pigs; D006651:Histocytochemistry; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000254:growth & development / Q000276:immunology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000276:immunology; D012503:Saponins / Q000008:administration & dosage / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D018949:Antigens, CD1; D006017:Glycolipids; D008055:Lipids; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D012503:Saponins; D014612:Vaccines; C048938:glucose mycolate; C015831:dimethyldioctadecylammonium; C078785:saponin QA-21V1