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 a utoimmune diabetes in nonobese 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 indu ce 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(n b1)), BALB/c (H-2(d)) and B10.PL (H-2(u)) mice a reduced recall response an d a deviated Th cytokine profile. However, we found that NOD (H-2(g7)) mice are comparatively resistant to immunological tolerance induced by nasal pr etreatment, such that at the usually effective dose no significant reductio n was seen in the proliferative recall responses to nominal antigen after i mmunization. (NOD x BALB/c)F-1 (H-2(g7/d)) and (NOD x NOR)F-1 (H-2(g7)) mic e were similarly resistant to nasal-induced tolerance, although significant ly higher nasal doses of antigen were able to overcome the resistance in NO D 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 d emonstrate that activated T cells in NOD mice are defective in their abilit y to respond to regulatory signals delivered in vivo or in vitro. Furthermo re, 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, w hile I-Ag7 may contribute to insulin-dependent diabetes mellitus by selecti ng a particular repertoire of self-reactive T cell clones, additional defec ts in the peripheral T cells themselves are required to allow the expansion of diabetogenic clones and the development of autoimmune disease.