Intervention in autoimmune diabetes by targeting the gut immune system.
BB rats and nonobese diabetic (NOD) mice spontaneously develop autoimmune insulin dependent diabetes and serve as models for human type I diabetes. During progression of the disease the cytokine pattern elaborated by islet infiltrating immune cells shifts from a Th2 or Th0 toward Th1 type. Only the latter is associated with "destructive" insulitis. We discuss here attempts to modulate disease progression by targeting the gut immune system with bacterial immunostimulants. Oral dosing of diabetes prone BB rats with lipopolysaccharide (LPS) or the Escherichia coli extract OM-89 lead to a Th2-shift of pancreatic mRNA expression. In vitro studies showed that repeated exposure toward LPS or OM-89 lead to downregulation of proinflammatory macrophage responses. In the NOD mouse, repeated oral dosing of OM-89 caused a Th2 shift in the gut cytokine gene expression, probably because of desensitization of macrophages and other antigen presenting cells. Concomitantly, diabetes prevention by oral insulin was improved. In conclusion, oral dosing with bacterial immunostimulants dampens Th1 type immune reactivities of the gut immune system and thereby promotes oral tolerance mechanisms. Downregulation of proinflammatory immune reactivities by repeated exposure to bacterial stimulants requires intact desensitization mechanisms in macrophages or other antigen presenting cells.
Bellmann
K
K
Diabetes Research Institute at the University of Düsseldorf, Germany.
Kolb
H
H
Hartmann
B
B
Rothe
H
H
Rowsell
P
P
Rastegar
S
S
Burghardt
K
K
Scott
F W
FW
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy*; D004064:Digestive System / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007515:Islets of Langerhans / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D051381:Rats; D011913:Rats, Inbred BB; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; C050501:OM 89