ST8Sia6 overexpression protects pancreatic β cells from spontaneous autoimmune diabetes in nonobese diabetic mice
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
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Research Article Autoimmunity Immunology

ST8Sia6 overexpression protects pancreatic β cells from spontaneous autoimmune diabetes in nonobese diabetic mice

Abstract

Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β cells, resulting in permanent loss of glucose homeostasis. Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect β cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in β cells of female nonobese diabetic mice (NOD βST) decreased the spontaneous incidence of diabetes by 90% and preserved β cell mass. NOD βST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. β Cell–autoreactive B and T cells were present in NOD βST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD βST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. These results demonstrate that ST8Sia6 protects β cells from immune-mediated attack and rejection, highlighting its therapeutic potential for autoimmune disorders.

Authors

Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro

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Figure 3

Protection from autoimmunity in βST mice is localized to the islet and peripheral in nature.

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Protection from autoimmunity in βST mice is localized to the islet and p...
(A) Representative H&E staining of salivary glands from female 300-day-old nondiabetic NOD βST mice or nondiabetic or diabetic littermate controls. Images are stitched composites (original magnification, ×5). (B) Number of foci of immune infiltrates and percentage area of immune foci in salivary glands of 7 nondiabetic NOD littermate, 5 diabetic NOD littermate, or 8 euglycemic NOD βST mice. Error bars represent SD, and 1-way ANOVA was used for comparisons. (C) ELISA quantification of serum anti-insulin antibodies from nondiabetic female NOD βST and littermate mice. Mice were stratified by age into the first half of the disease kinetics study (6 NOD βST and 14 littermates) or the latter half (15 NOD βST or 23 littermates). Serum from B6 mice (n = 4) was analyzed to determine threshold of detection. Error bars represent SD, and Mann-Whitney U test was used for indicated comparisons. (D) Diabetes-free incidence in 16-week-old female euglycemic mice challenged intraperitoneally with anti–PD-L1 (8 NOD βST and 16 littermates) or anti–PD-1 (8 NOD βST and 11 littermates). Log-rank Mantel-Cox test was performed to analyze statistical differences between indicated groups. (E) Representative immunofluorescence images of CD8 in pancreas from NOD βST and littermate mice after challenge with anti–PD-1 from D. Original magnification, ×2 (islets ). (F) Quantification of CD8+ T cell infiltration in islets from pancreas sections from D. n = 15 islets from 3 NOD littermate pancreas sections (14 islets from 1 mouse challenged with anti–PD-L1, 1 islet from 1 mouse challenged with anti–PD-1) or 16 islets from 4 NOD βST pancreas sections (6 islets from 2 mice challenged with anti–PD-L1, 9 islets from 2 mice challenged with anti–PD-1). Error bars represent SD. Mann-Whitney U test was used for indicated comparison. (G) Insulitis distribution in pancreas sections from F scored and analyzed as in Figure 1E.