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Natasha C Ward, Aixin Yu, Alejandro Moro, Yuguang Ban, Xi Chen, Sunnie Hsiung, James Keegan, Jaren M Arbanas, Martine Loubeau, Anil Thankappan, Aaron P Yamniuk, Jonathan H Davis, Mary Struthers, Thomas R Malek, IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells, The Journal of Immunology, Volume 201, Issue 9, November 2018, Pages 2579–2592, https://doi.org/10.4049/jimmunol.1800907
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Abstract
Low-dose IL-2 represents an immunotherapy to selectively expand regulatory T cells (Tregs) to promote tolerance in patients with autoimmunity. In this article, we show that a fusion protein (FP) of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, has greater in vivo efficacy than rIL-2 at Treg expansion and control of autoimmunity. Biochemical and functional studies support a model in which IL-2 interacts with CD25 in the context of this FP in trans to form inactive head-to-tail dimers that slowly dissociate into an active monomer. In vitro, IL-2/CD25 has low sp. act. However, in vivo IL-2/CD25 is long lived to persistently and selectively stimulate Tregs. In female NOD mice, IL-2/CD25 administration increased Tregs within the pancreas and reduced the instance of spontaneous diabetes. Thus, IL-2/CD25 represents a distinct class of IL-2 FPs with the potential for clinical development for use in autoimmunity or other disorders of an overactive immune response.