Suppression of allergic airway disease using mycobacterial lipoglycans.
BACKGROUND
Administration of heat-killed mycobacteria can suppress allergic disease in mice and humans. The active components of mycobacteria mediating these effects remain unresolved.


OBJECTIVE
We sought to identify the active components of mycobacteria mediating suppression of allergic disease and to determine structural features important for function.


METHODS
Using a murine model of allergic airway disease, we tested the ability of the lipoglycan fractions of the mycobacterial cell wall to suppress airway eosinophilia. Lipoglycans isolated from different strains of mycobacteria and chemical modifications were used to explore structure-function relationships. Markers of allergic disease including bronchoalvealor lavage cytokines, spleen and lymph node T-cell cytokine production, and serum specific immunoglobulin (Ig) E/IgG1 were examined.


RESULTS
We identified the mycobacterial cell wall lipoglycans lipoarabinomannan and phosphatidylinositol mannan as components of mycobacteria capable of suppressing airway disease (>70% reduction in airway eosinophilia; P <.03). Structure-function analysis identified the acyl chains and mannose groups of the molecules as having a role in mediating this effect. Mechanistic studies provided no evidence for a T-helper cell (Th) 1-mediated suppression of an ongoing Th2 response. An increased capacity of T cells to secrete interleukin 10 in the spleen and lymph node of treated animals was identified, suggesting a potential T-cell-mediated suppression mechanism.


CONCLUSIONS
We have identified immunomodulatory component(s) of mycobacteria responsible for the protective effects observed in allergic disease; these findings will lead to the generation of synthetic compounds or agonists devoid of the unwanted characteristics of whole mycobacteria for evaluation in a human clinical setting.
Malaghan Institute of Medical Research, Wellington School of Medicine, New Zealand.
Ian
I
Sayers
Wayne
W
Severn
Connie B
CB
Scanga
Jenny
J
Hudson
Graham
G
Le Gros
Jacquie L
JL
Harper
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology; D010716:Phosphatidylinositols / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D018926:Anti-Allergic Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D010716:Phosphatidylinositols; C050016:lipoarabinomannan; C034154:phosphatidylinositol mannoside