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Target Cell Expression of Suppressor of Cytokine Signaling-1 Prevents Diabetes in the NOD Mouse

¹ Department of Immunology, The Scripps Research Institute, La Jolla, California
² Department of Medical Cell Biology, Biomedicum, Uppsala University, Uppsala, Sweden

Although lymphocyte infiltration and islet destruction are hallmarks of diabetes, the mechanisms of ß-cell destruction are not fully understood. One issue that remains unresolved is whether cytokines play a direct role in ß-cell death. We investigated whether ß-cell cytokine signaling contributes to autoimmune type 1 diabetes. We demonstrated that NOD mice harboring ß-cells expressing the suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling, have a markedly reduced incidence of diabetes. Similar to their non-transgenic (Tg) littermates, SOCS-1-Tg mice develop insulitis and their splenocytes transfer disease to NODscid recipients. Disease protection correlates with suppression of cytokine-induced STAT-1 phosphorylation in SOCS-1–expressing ß-cells and with a reduced sensitivity of these cells to destruction by diabetogenic cells in vivo. Interestingly, lymphocytes recruited to the pancreas of SOCS-1-Tg mice transferred diabetes to NODscid recipients with a reduced efficiency, suggesting that the pancreatic environment in SOCS-1-Tg mice does not support the maintenance of functionally differentiated T-cells. These results suggest that cytokines contribute to the development of type 1 diabetes by acting directly on the target ß-cell. Importantly, given that the SOCS-1–expressing mouse maintain normal blood glucose levels throughout life, this study also showed that SOCS-1 expression by ß-cells can represent a promising strategy to prevent type 1 diabetes.

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