Beta cell expression of ST8Sia6 protects from autoimmune diabetes in the murine NOD model

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B631
Abstract ID: 5747

Presenting Author:
Justin Choe , student at Mayo Clin. Grad. Sch. of Biomed. Sci.

Abstract:

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of β-cells within the islets of the pancreas, resulting in permanent loss of glucose homeostasis. Since the discovery of insulin over a century ago, limited progress has been made toward a permanent cure, and diabetics remain reliant on lifelong external insulin dosing. In this study, β-cells in the non-obese diabetic (NOD) murine model of spontaneous T1D were engineered to express the sialyltransferase ST8Sia6 (βST mice). This enzyme generates sialic-acid modifications on cell surface glycans that can engage inhibitory receptors such as Siglec-E to dampen immune activation, employed here as a modality to abrogate the autoimmune process. While 60% of female NOD littermates developed diabetes, only 6% of NOD βST mice became diabetic over 300 days. Although immune infiltration of the islets still initiates in the NOD βST, histologic analysis demonstrated a lack of progression of insulitis over time compared to littermates. Transgenic expression of ST8Sia6 led to durable tolerance, as shutting off expression in βST mice after 20 weeks of age maintained protection from T1D. Within the islets of NOD βST mice, we found a dampened type 1 response alongside reduced IL12p35 expression from Siglec-E expressing dendritic cells. These results demonstrate that ST8Sia6 protects β-cells from immune attack and highlights its therapeutic potential for autoimmune disorders.