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

Author:

French Michelle B,Allison Janette1,Cram David S,Thomas Helen E,Dempsey-Collier Majella,Silva Anabel,Georgiou Harry M2,Kay Thomas W,Harrison Leonard C,Lew Andrew M

Affiliation:

1. Burnet Clinical Research Unit, Thymus Biology Unit Parkville, Victoria, Australia

2. Transplantation Unit, The Walter and Eliza Hall Institute of Medical Research Parkville, Victoria, Australia

Abstract

IDDM in humans and in nonobese diabetic (NOD) mice is a T-cell–dependent autoimmune disease in which the β-cells of the pancreatic islets are destroyed. Several putative β-cell autoantigens have been identified, but insulin and its precursor, proinsulin, are the only ones that are β-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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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