Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells

T Cells are Unresponsive to Transgenic MHC Class II Molecules Expressed on Pancreatic β Cells

“…Although we cannot see any islet infiltration, the T cells in IP-A k positive mice are not tolerant to the A k molecule [8]. This observation contrasts with the reports on transgenic mice expressing E or K b molecules on the b cells, where the T cells are tolerant to the allogeneic MHC [14,15]. These mice display a toxic, non-immunological diabetes state, presumably due to an overload of the cellular protein secretion pathways, and in fact present much higher E and K b levels on the b cells than A k on b cells in our mice [16].…”

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

“…This finding is consistent with a direct, nonimmune role for MHC class I molecules in the destructive process (20). p cells appear to be especially susceptible to MHC molecules expressed transgenically (1,23,34) because the expression of other transgenes in the p cell that encode several cell surface or nuclear proteins does not, in general, lead to diabetes (20). The mechanism of this deleterious effect of MHC overexpression on differentiated cell function and * Corresponding author.…”

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

“…Thus, IFNg and TNFa synergism seem to have a dual effect on the course of autoimmune diabetes mellitus: firstly, through the apoptosis of pancreatic beta cells; and secondly through the induction of MHC class II molecules. Previous reports have shown that transgenic expression of MHC class II molecules on pancreatic beta cells could not initiate autoimmunity [15,16]. However, the effect of constitutive transgenic expression of MHC class II molecules from birth can be different from that of their de novo expression.…”

“…More controversial is the immunological impact of such an induction of MHC class II molecules on nonlymphoid cells such as pancreatic beta cells. Ectopic expression of MHC class II molecules on pancreatic beta cells by transgenic technology did not lead to autoimmune diabetes mellitus, in contrast to the original suggestion that aberrant expression of MHC class II molecules on nonlymphoid cells would lead to selfantigen presentation by non-APC and autoimmune process [15,16]. It led instead to immunological tolerance or ignorance depending on the amount and type of antigens expressed [17].…”