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Persistent IL-2R signaling by IL-2/CD25 fusion protein controls diabetes in NOD mice by multiple mechanisms

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posted on 25.08.2020 by Ada Admin, Natasha C. Ward, Jen Bon Lui, Rosmely Hernandez, Liping Yu, Mary Struthers, Jenny Xie, Alicia Santos Savio, Connor J. Dwyer, Sunnie Hsiung, Aixin Yu, Thomas R. Malek
Low-dose IL-2 represents a new therapeutic approach to regulate immune homeostasis to promote immune tolerance in patients with autoimmune diseases, including type 1 diabetes. We have developed a new IL-2-based biologic, an IL-2/CD25 fusion protein, with greatly improved pharmacokinetics and pharmacodynamics when compared to recombinant IL-2 to enhance this type of immunotherapy. Here we show that low-dose mouse IL-2/CD25 (mIL-2/CD25), but not an equivalent amount of IL-2, prevents the onset of diabetes in NOD mice and controls diabetes in hyperglycemic mice. mIL-2/CD25 acts not only to expand regulatory T cells (Tregs) but also by increasing their activation and migration into lymphoid tissues and the pancreas. Lower incidence of diabetes is associated with increased serum levels of IL-10, a cytokine readily produced by activated Tregs. These effects likely act in concert to lower islet inflammation while increasing Tregs in the remaining inflamed islets. mIL-2/CD25 treatment is also associated with lower anti-insulin autoantibody levels in part by inhibition of T follicular helper cells. Thus, long-acting mIL-2/CD25 represents an improved IL-2 analog that persistently elevates Tregs to maintain a favorable Treg:Teff cell ratio that limits diabetes by expansion of activated Tregs that readily migrate into lymphoid tissues and the pancreas while inhibiting autoantibodies.

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This research was support by funding to TRM from the NIH (RO1DK093866) and a sponsored research agreement from Bristol Myers Squibb.

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