Transgenic Expression of Mouse Proinsulin II Prevents Diabetes in Nonobese Diabetic Mice

Abstract

IDDM in humans and in nonobese diabetic (NOD) mice is a T-cell-dependent autoimmune disease in which the beta-cells of the pancreatic islets are destroyed. Several putative beta-cell autoantigens have been identified, but insulin and its precursor, proinsulin, are the only ones that are beta-cell specific. (Pro)insulin may be a key autoantigen in IDDM. To address the role of proinsulin in the development of IDDM, we generated NOD mice transgenic for the mouse proinsulin II gene driven off a major histocompatibility complex (MHC) class II promoter to direct expression of the transgene to MHC class II bearing cells, including those in the thymus, with the aim of deleting proinsulin-reactive T-cells. The mononuclear cell infiltration of the islets (insulitis) is almost completely absent, and diabetes is prevented in these transgenic NOD mice. The mononuclear cell infiltration of the salivary glands (sialitis) and immune responses to ovalbumin (OVA) are not altered, indicating that the protective effect of the transgene is specific for islet pathology and not due to general immunosuppression. We conclude that autoimmunity to proinsulin plays a pivotal role in the development of IDDM.

T cells in the pathogenesis of type 1 diabetes

“…NOD mice defective for the PI2 gene, the prevalent isoform in the thymus, display accelerated T1D, likely related to defective deletion of PI-reactive T cells [18]. Consistent with this hypothesis, NOD mice are protected from diabetes when a PI transgene is inserted that deletes the specific T cells in the thymus [19]. Conversely, NOD mice defective for the PI1 gene, the prevalent isoform in the islets but lacking expression in the thymus, are less susceptible to T1D.…”

Peripheral antigen-expressing cells in type 1 diabetes

“…1) [27,28]. Consistent with this hypothesis, NOD mice overexpressing Ins2 under the control of the major histocompatibility complex (MHC) class II promoter are protected from insulitis and diabetes [24]. Additional evidence supporting this hypothesis comes from studies showing that levels of insulin expression in the human thymus correlate with allelic variation and parent-of-origin effects at the IDDM2 susceptibility locus, which corresponds to a polymorphic mini-satellite upstream of the insulin gene [11,12].…”

“…Summarizes the key findings and hypothetical mechanisms underlying the effects of insulin expression and manipulation in the thymus and peripheral lymphoid tissue (PLT) in nonobese diabetic (NOD) mice, NOD Ins2 [22••,23••], and Ins1 [23••] knockouts, and in NOD mice overexpressing Ins2 in major histocompatibility complex class II positive cells[24]. APCs-antigen-presenting cells; DCs-dendritic cells; TECs-thymic epithelial cells.…”

The Beta Cell Immunopeptidome

“…It is hypothesized that lower thymic expression of proinsulin allows autoreactive T cells to escape thymic deletion and move to the periphery. This is supported by studies in the NOD mouse in which thymic overexpression of proinsulin protects from disease (French et al, 1997). Moreover, graded expression of proinsulin in the thymus of NOD mice shows a dose-dependent, inverse correlation with peripheral T cell responses to proinsulin (Chentoufi & Polychronakos, 2002).…”