Oral administration of the immunodominant B-chain of insulin reduces diabetes in a co-transfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines.
Oral administration of antigen leads to systemic immune unresponsiveness. Low dose oral tolerance generates regulatory cells which, when triggered in an antigen-specific manner, suppress inflammatory responses. We have previously shown that oral administration of an organ-specific antigen, porcine insulin, protects against diabetes development in the NOD mouse. In the present study we extend these observations to the B-chain of insulin, a 30-amino-acid peptide which has now been shown by others to contain the immunogenic epitope. Oral administration of the B-chain slowed diabetes development in a co-transfer model in which cells from B-chain-fed animals were co-transferred with diabetogenic cells (P=0.02). Further exposure to antigen via feeding of the co-transfer recipient animals not only slowed diabetes development but prevented diabetes in some animals (P=0.01). In vitro proliferation of popliteal lymph node cells from fed and immunized animals was suppressed in an antigen-specific manner when cells were restimulated with the fed antigen. When those cells were cultured and restimulated in vitro with the B-chain of insulin, we also observed a decrease in IFN-gamma expression and an increase in IL-4, TGF-beta and IL-10 expression. These results demonstrate that an orally protective epitope resides in the B-chain of insulin and that refeeding following adoptive transfer enhances protection. Finally, the orally administered antigen is associated with a decrease in Th1 responses and an increase in Th2 responses to the insulin B-chain.
Polanski
M
M
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Melican
N S
NS
Zhang
J
J
Weiner
H L
HL
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D016207:Cytokines / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000737:chemistry; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010047:Ovalbumin / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D016056:Immunodominant Epitopes; D007328:Insulin; D010047:Ovalbumin