Supplemental_Figures_072420.pdf (203.02 kB)
Download filePersistent IL-2R signaling by IL-2/CD25 fusion protein controls diabetes in NOD mice by multiple mechanisms
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posted on 2020-08-25, 16:46 authored by Ada AdminAda 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. MalekLow-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.