Weekly injection of IL-2 using an injectable hydrogel reduces autoimmune diabetes incidence in NOD mice
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SHORT COMMUNICATION
Weekly injection of IL-2 using an injectable hydrogel reduces autoimmune diabetes incidence in NOD mice Nadine Nagy 1 & Gernot Kaber 1 & Michael J. Kratochvil 1,2 & Hedwich F. Kuipers 1 & Shannon M. Ruppert 1 & Koshika Yadava 1 & Jason Yang 1 & Sarah C. Heilshorn 2 & S. Alice Long 3 & Alberto Pugliese 4 & Paul L. Bollyky 1 Received: 15 May 2020 / Accepted: 25 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Aims/hypothesis IL-2 injections are a promising therapy for autoimmune type 1 diabetes but the short half-life of this cytokine in vivo limits effective tissue exposure and necessitates frequent injections. Here we have investigated whether an injectable hydrogel could be used to promote prolonged IL-2 release in vivo. Methods Capitalising on the IL-2-binding capabilities of heparin, an injectable hydrogel incorporating clinical-grade heparin, collagen and hyaluronan polymers was used to deliver IL-2. The IL-2-release kinetics and in vivo stability of this material were examined. The ability of soluble IL-2 vs hydrogel-mediated IL-2 injections to prevent autoimmune diabetes in the NOD mouse model of type 1 diabetes were compared. Results We observed in vitro that the hydrogel released IL-2 over a 12-day time frame and that injected hydrogel likewise persisted 12 days in vivo. Notably, heparin binding potentiates the activity of IL-2 and enhances IL-2- and TGFβ-mediated expansion of forkhead box P3-positive regulatory T cells (FOXP3+ Tregs). Finally, weekly administration of IL-2-containing hydrogel partially prevented autoimmune diabetes while injections of soluble IL-2 did not. Conclusions/interpretation Hydrogel delivery may reduce the number of injections required in IL-2 treatment protocols for autoimmune diabetes. Keywords Autoimmune . Controlled release . Diabetes . Heparin . Hyaluronan . Hydrogels . IL-2 . Treg
Abbreviations FOXP3 Forkhead box P3 HA Hyaluronan HI Heparin LN Lymph node Tconv Conventional T cell Treg FOXP3+ regulatory T cell
* Nadine Nagy [email protected] 1
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
2
Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
3
Benaroya Research Institute, Seattle, WA, USA
4
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
Introduction Type 1 diabetes is characterised by the progressive immune cell-mediated destruction of pancreatic beta cells and the failure of regulatory mechanisms that normally prevent this, including regulatory T cells (Tregs) [1]. One critical factor that governs Treg function is the cytokine IL-2 [2]. The potential role of low-dose IL-2 in type 1 diabetes is a subject of active exploration and a frontier in the treatment and prevention of autoimmunity [3]. Low-dose IL-2 affects two critical cell populations of the immune system: T cells and natural killer (NK) cells. However, IL-2 has a short
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