Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes.
The onset of type 1 diabetes in NOD mice is delayed by oral administration of a bacterial extract (OM-85) and can be completely prevented by its intraperitoneal administration. Optimal prevention is observed when starting treatment at 3 or 6 weeks of age, and some effect is still observed with treatment at 10 weeks of age. Using genetically deficient mice and cytokine-neutralizing monoclonal antibodies, we demonstrate here that the therapeutic effect does not involve T-helper type 2 cytokines (interleukin [IL]-4 and -10) but is tightly dependent on transforming growth factor (TGF)-beta. Natural killer T-cells also participate in the therapeutic effect because CD1d(-/-) NOD mice are partially resistant to the protective effect of OM-85. The question remains of the specificity of the protective effect of OM-85, which may include proinflammatory components. It will thus be important to further characterize the molecular components that afford protection from type 1 diabetes. Lipopolysaccharide is excluded, but other Toll-like receptor (TLR) agonists could be involved because OM-85 stimulated dendritic cells and induced TGF-beta production by splenocytes in a TLR-2-, TLR-4-, and MyD88-dependent fashion.
Alyanakian
Marie-Alexandra
MA
INSERM U580, Hôpital Necker-Enfants Malades, 161 Rue de Sèvres, 75015 Paris, France.
Grela
Françoise
F
Aumeunier
Aude
A
Chiavaroli
Carlo
C
Gouarin
Christine
C
Bardel
Emilie
E
Normier
Gérard
G
Chatenoud
Lucienne
L
Thieblemont
Nathalie
N
Bach
Jean-François
JF
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics; D001419:Bacteria; D002457:Cell Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D015847:Interleukin-4 / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D000095983:Bacterial Lysates
D048868:Adaptor Proteins, Signal Transducing; D018949:Antigens, CD1; D002457:Cell Extracts; D015847:Interleukin-4; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; C030259:Broncho-Vaxom; D000095983:Bacterial Lysates; C507780:Myd88 protein, mouse