Nadine Nagy1, Gernot Kaber2, Michael J Kratochvil2,3, Hedwich F Kuipers2, Shannon M Ruppert2, Koshika Yadava2, Jason Yang2, Sarah C Heilshorn3, S Alice Long4, Alberto Pugliese5, Paul L Bollyky2. 1. Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. nnagy@stanford.edu. 2. Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. 3. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. 4. Benaroya Research Institute, Seattle, WA, USA. 5. Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
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. Graphical 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. Graphical abstract.
Authors: Michelle Rosenzwajg; Guillaume Churlaud; Roberto Mallone; Adrien Six; Nicolas Dérian; Wahiba Chaara; Roberta Lorenzon; S Alice Long; Jane H Buckner; Georgia Afonso; Hang-Phuong Pham; Agnès Hartemann; Aixin Yu; Alberto Pugliese; Thomas R Malek; David Klatzmann Journal: J Autoimmun Date: 2015-01-26 Impact factor: 7.094
Authors: Paul L Bollyky; Ben A Falk; S Alice Long; Anton Preisinger; Kathy R Braun; Rebecca P Wu; Stephen P Evanko; Jane H Buckner; Thomas N Wight; Gerald T Nepom Journal: J Immunol Date: 2009-07-27 Impact factor: 5.422