Dissertation

The initiation, progression to and protection from T1D in NOD mice

Song, Aihua

2002

Overview

Type I diabetes (T1D) in human and rodents is an autoimmune disease, selectively targeting pancreatic β cells in islets of Langerhans. Disease development is determined by polygenic and multiple environmental factors. In NOD mice, the disease initiates at 4–5 weeks of age with periinsulitis, and transforms into aggressively invasive insulitis by 8–10 weeks of age. In our colony, the first overtly diabetic animals are about 16 weeks old, but disease can take as much as 36 weeks in some animals. Prediabetes is thus a slow process, involving multiple immune cells and molecules, and its progression is determined by finely tuned balance and shifting bias among multiple players. It remains unknown what drives the loss of self-tolerance to islets, and what precipitates and/or halts prediabetes progression in NOD mice. Autoantigens are core elements in T cell mediated islet β cell damage, thus serving as excellent tools to study these issues. Conscious of the fact that expression of major autoantigens in T1D, including (pro)insulin, GAD65/67, ICA69, HSP and IA-2, is not islet restricted, we generated transgenic NOD mice expressing an ICA69-EGFP fusion protein under control of a β-actin promoter. Transgenics showed significant disease protection, associated with a dramatic absence of CD8+ T cells in the enhanced IFNγ-rich insulitis lesion. There was no infiltration of other ‘green’ tissues. Islet and heart transplantation as well as alloxan experiments demonstrated that transgene-specific T cells were primed and maintained only by islets. In this model, prediabetes appears to reflect strictly local events, initiated and maintained by islet-exclusive tissue factors. Autoantigen expression in the thymus is critical for the induction of tolerance and formation of T cell repertoire. We generated one tet07-ICA69 transgenic line with a promoter-independent ICA69 overexpression exclusively in thymus and spleen. These transgenic mice showed persistent tolerance to the dominant epitope of ICA69, Tep69, and disease protection. With adoptive transfer and thymus transplant experiments, it was clear that the transgene modified T cell repertoire was important for disease protection, and that re-selection of such a T cell pool in the thymus or by immunotherapy could arrest prediabetes progression even in models of late NOD prediabetes.

• Publisher: ProQuest Dissertations & Theses
• Subject: Immunology
• ISBN: 0612746771, 9780612746770