@article{ed6140f0daa34bb394a1c89a26e290d3,
title = "Persistent il-2 receptor signaling by il-2/cd25 fusion protein controls diabetes in nod mice by multiple mechanisms",
abstract = "Low-dose interleukin-2 (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 pharmaco-dynamics when compared with recombinant IL-2 to enhance this type of immunotherapy. In this study, 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 to increase their activation and migration into lymphoid tissues and the pancreas. Lower incidence of diabetes is associated with increased se-rum 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 remain-ing 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/ effector T cell ratio that limits diabetes by expansion of activated Tregs that readily migrate into lymphoid tissues and the pancreas while inhibiting autoantibodies.",
author = "Ward, {Natasha C.} and Lui, {Jen Bon} and Rosmely Hernandez and Liping Yu and Mary Struthers and Jenny Xie and Savio, {Alicia Santos} and Dwyer, {Connor J.} and Sunnie Hsiung and Aixin Yu and Malek, {Thomas R.}",
note = "Funding Information: Acknowledgments. The authors thank the following individuals at the University of Miami: Michael Dee for technical assistance; Patricia Guevara, Shannon Saigh, and Jay Enten from the Flow Cytometry Core of the Sylvester Comprehensive Cancer Center (supported by National Institutes of Health grant P30CA240139) and Oliver Umland from the Flow Cytometry Core Center of the Diabetes Research Institute for help with FACS analyses; Kevin Johnson for help with preparation of slides for histology; and Carmen Fotino for help with islet imaging. The authors also thank the following individuals at Bristol-Myers Squibb: James Young and Priyanka Madia for helpful discussions and Nathan Cheadle, Leads Discovery & Optimization, for help with the mouse cytokine data. Funding. This research was supported by funding to T.R.M. from the National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK093866) and a sponsored research agreement from Bristol-Myers Squibb. Duality of Interest. The University of Miami, R.H., and T.R.M. have a patent pending (Wo2016022671A1) on mIL-2/CD25 fusion proteins and their use (PCT/ US20/13152; R.H., T.R.M.) that has been licensed exclusively to Bristol-Myers Squibb, and this research in part has been supported by a collaboration and sponsored research and licensing agreement with Bristol-Myers Squibb. M.S. and J.X. are employees of Bristol-Myers Squibb. No other potential conflicts of interest relevant to this article were reported. Author Contributions. N.C.W., J.B.L., M.S., J.X., and T.R.M. were responsible for conception and design of the study. N.C.W., J.B.L., R.H., L.Y., C.J.D., S.H., and A.Y. performed experiments. A.S.S. prepared and validated the fusion protein. N.C.W., J.B.L., R.H., M.S., A.Y., and T.R.M. analyzed and interpreted data. N.C.W. and T.R.M. wrote the manuscript. All authors edited and approved the manuscript. T.R.M. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented at the “Promise of Interleukin-2 Therapy” sponsored by the International Union of Immunological Sciences, Paris, France, 13–16 November 2019. Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",
year = "2020",
month = nov,
doi = "10.2337/db20-0186",
language = "English (US)",
volume = "69",
pages = "2400--2413",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",
}