Relative resistance to nasally induced tolerance in non-obese diabetic mice but not other I-A(g7)-expressing mouse strains.
I-A(g7) is a unique class II MHC molecule that is clearly associated with autoimmune diabetes in non-obese diabetic (NOD) mice. To determine if I-A(g7) is defective in its ability to deliver tolerogenic signals in vivo, H-2(g7) mice were nasally pretreated with antigen, prior to immunization, to induce antigen-specific regulation. Nasally pretreated NOR (H-2(g7)) and (NON).NOD (H-2(g7)) congenic mice showed responses similar to those of NON (H-2(nb1)), BALB/c (H-2(d)) and B10.PL (H-2(u)) mice-a reduced recall response and a deviated T(h) cytokine profile. However, we found that NOD (H-2(g7)) mice are comparatively resistant to immunological tolerance induced by nasal pretreatment, such that at the usually effective dose no significant reduction was seen in the proliferative recall responses to nominal antigen after immunization. (NOD x BALB/c)F(1) (H-2(g7/d)) and (NOD x NOR)F(1) (H-2(g7)) mice were similarly resistant to nasal-induced tolerance, although significantly higher nasal doses of antigen were able to overcome the resistance in NOD and F(1) mice. Interestingly, activated NOD T cells were resistant to cell death induced by re-stimulation with plate-bound anti-CD3. These results demonstrate that activated T cells in NOD mice are defective in their ability to respond to regulatory signals delivered in vivo or in vitro. Furthermore, NOD T cells have an increased resistance to tolerance induced by I-A(g7)-dependent (antigen) or I-A(g7)-independent (anti-CD3) mechanisms. Thus, while I-A(g7) may contribute to insulin-dependent diabetes mellitus by selecting a particular repertoire of self-reactive T cell clones, additional defects in the peripheral T cells themselves are required to allow the expansion of diabetogenic clones and the development of autoimmune disease.
Quinn
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La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, San Diego, CA 92121, USA.
Melo
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Ethell
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Sercarz
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D000281:Administration, Intranasal; D000818:Animals; D002999:Clone Cells; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens; D006412:Hematopoietic Stem Cells / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D016688:Mice, Inbred NOD; D009113:Muramidase / Q000008:administration & dosage; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*
D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D011948:Receptors, Antigen, T-Cell; C421864:hen egg lysozyme; D009113:Muramidase