Potential risk of oral insulin with adjuvant for the prevention of Type I diabetes: a protocol effective in NOD mice may exacerbate disease in BB rats.
The impact of oral treatment with insulin on disease development was studied in diabetes prone BB rats. Because of the positive outcome of a prior study in non obese diabetic (NOD) mice, BB rats received insulin in combination with a bacterial adjuvant. Porcine insulin was given orally twice weekly from 35-100 days of age, the E. coli preparation OM-89 was fed on alternate days. Other groups received vehicle, the bacterial adjuvant, or insulin alone. Both insulin containing oral dosing regimens induced a transient non significant delay in diabetes onset. Insulin alone, however did not decrease the final diabetes incidence. Oral dosing with insulin plus adjuvant caused exacerbation of disease development as judged from the decreased survival rate in comparison with the insulin treated group (p < 0.05). Intra-islet infiltration also increased (p < 0.005) compared with the insulin or vehicle treated groups. The effect correlated with enhanced interferon gamma (IFNgamma) and decreased interleukin 10 (IL-10) gene expression in the gut suggesting a shift towards proinflammatory T helper 1 (Th1) reactivity (p < 0.01). Although treatment with adjuvant alone also increased the degree of insulitis, an enhanced incidence of diabetes and a shift in cytokine expression was only seen in the group receiving insulin plus adjuvant. Taken together, the data suggest that treatment with a bacterial adjuvant and oral insulin may alter the gut immunoregulatory state such that disease promoting rather than protective immune responses are induced.
Bellmann
K
K
Institute of Diabetes Research at the University of Düsseldorf, Germany.
Kolb
H
H
Rastegar
S
S
Jee
P
P
Scott
F W
FW
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000375:Aging; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control*; D004926:Escherichia coli / Q000276:immunology*; D018928:Immunity, Mucosal; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016133:Polymerase Chain Reaction; D051381:Rats; D011913:Rats, Inbred BB; D012307:Risk Factors; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D007328:Insulin; C050501:OM 89; D016753:Interleukin-10; D007371:Interferon-gamma