Protein corona–mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses Limei Shen, PhD, Stefan Tenzer, PhD, Wiebke.

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Protein corona–mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses Limei Shen, PhD, Stefan Tenzer, PhD, Wiebke Storck, MSc, Dominika Hobernik, MSc, Verena Katherina Raker, PhD, Karl Fischer, PhD, Sandra Decker, PhD, Andrzej Dzionek, Susanne Krauthäuser, PhD, Mustafa Diken, PhD, Alexej Nikolaev, Joachim Maxeiner, MSc, Petra Schuster, Cinja Kappel, MSc, Admar Verschoor, PhD, Hansjörg Schild, PhD, Stephan Grabbe, MD, Matthias Bros, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 5, Pages 1558-1570 (November 2018) DOI: 10.1016/j.jaci.2017.08.049 Copyright © 2018 The Authors Terms and Conditions

Fig 1 DEX-NPs colocalize with CD19+ B cells. Cy5-labeled DEX-NPs (DEX-NP[−]) were administered intravenously into mice. After 4 hours, retrieved spleen sections were incubated with antibodies (green fluorescence) and DAPI (blue) to identify immature myeloid cells/neutrophils (GR-1+), macrophages (CD68+), DC (CD11c+), and FDCs (FDC+; arrows denote cells colocalizing with DEX-NP[−]; A) and B cells (CD19+; B). Results are representative of 4 experiments. Fig 1, A and B, left panel, ×20 magnification; Fig 1, B, right panel, ×40 magnification. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 2 Complement opsonization of DEX-NPs mediates B-cell binding. A and C-E, Frequencies of B cells (in vitro) binding differentially pretreated DEX-NP(−) derived from wild-type (WT; Fig 2, A and D) or knockout (Fig 2, E) mice after 4 hours of coincubation (n = 3). B, Internalization of DEX-NP(OVA-CpG) by B cells (in vitro) after 4 hours. Fig 2, D, Complement C3 abundance in the DEX-NP(−) protein corona (n = 3). Fig 2, A and C-E: *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 3 Serum-opsonized NPs bind B cells through CD21/CD35. A, Frequencies of B cells (in vitro) binding DEX-NP(−) in the presence of neutralizing anti-CD21/CD35 antibody (n = 3). B, DEX-NPs in spleens of mice pretreated with isotype control or anti-CD21/CD35 antibody assessed 4 hours after injection (3 mice per group, n = 2; magnification ×10). C, Quantification of NP-binding B cells (300 cells counted per experiment, n = 2). D, B cells (in vitro) binding starch-coated NPs (gated, n = 3). E-G, Frequencies of B cells binding starch-coated (Fig 3, E) and dextran-coated (Fig 3, F) NPs (n = 3) and carboxylated silica NPs (Fig 3, G; n = 4). Fig 3, A, C, and E-G: *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 4 Functionalized DEX-NPs activate B cells and DCs in vivo and evoke CD4+ T-cell proliferation. A-D, Frequencies of activated B cells (24 hours; Fig 4, A and B), DCs and macrophages (4 hours; Fig 4, C), and activated DCs (24 hours; Fig 4, D) after intravenous application of DEX-NP formulations (3 mice per group, compiled from n = 2 [total of 6 mice per group]). E and F, Proliferation of CD4+ OT-II T cells assessed 3 days after vaccination with DEX-NP(OVA) and soluble CpG (4 mice per group; representative of 3 experiments; Fig 4, E) and according quantification (n = 3; a total of 12 mice per group; Fig 4, F). Fig 4, B-D and F: *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 5 Functionalized DEX-NPs induce profound antibody production dependent on complement activity and binding to CD21/CD35. A, B, and D, OVA-specific IgG1, IgG2a, and IgE in sera of mice obtained 10 (Fig 5, B and D) or 14 (Fig 5, A) days after vaccination with OVA and soluble CpG or DEX-NP formulations or PBS alone (control group) and in the presence of anti-CD21/CD35 or isotype control antibody (Fig 5, D). C, Frequencies of splenic B cells that colocalized with DEX-NPs 4 hours after application. Fig 5, A and C, Five mice per group compiled from n = 2 (a total of 10 mice per group); Fig 5, B and D, 3 mice per group compiled from n = 3 (a total of 9 mice per group). Fig 5, A-D: *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 6 Vaccination of OVA-sensitized mice with OVA CpG−codelivering DEX-NPs prevents IgE induction and inhibits anaphylactic shock. A, Experimental design. i.v., Intravenous; s.c., subcutaneous. B, Alterations of body temperature after challenge (15 mice per group, compiled from n = 3). C and D, OVA-specific IgE (Fig 6, C) and IgG2a (Fig 6, D) in serum obtained before the first (day 14) and after the last (day 28) vaccination with indicated DEX-NP formulations or PBS alone (control group). E, IgG2a/IgG1 ratio. Fig 6, C-E, Five mice per group; 1 experiment representative of 5. Fig 6, B-E, *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig 7 Treatment of OVA-sensitized mice with OVA/CpG-codelivering DEX-NPs prevents asthma. A, Experimental design. i.p., Intraperitoneal; i.v., intravenous. B, Airway resistance measurements of mice vaccinated with the indicated DEX-NP formulations or PBS alone after challenge and administration of methacholine (6 mice per group, representative of n = 2). C, Eosinophil numbers in bronchoalveolar lavage fluid (BAL; 300 cells counted per sample; 7 samples per group; compiled from n = 2). D, Lung inflammation scores (40 sections scored per group; 10-12 mice per group; n = 2). E, OVA-specific antibodies in sera (10-12 mice per group; compiled from n = 2 [a total of 20-24 mice per group]). Fig 7, B-E: *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2018 142, 1558-1570DOI: (10.1016/j.jaci.2017.08.049) Copyright © 2018 The Authors Terms and Conditions