Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses

Slides:

Advertisements

Similar presentations

Fig. 1. TLR4 expression is much greater on macrophages than on DCs

Advertisements

Immunomodulatory effects of aqueous birch pollen extracts and phytoprostanes on primary immune responses in vivo Jan Gutermuth, MD, Mayte Bewersdorff,

Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses

Cheng-Ming Sun, Edith Deriaud, Claude Leclerc, Richard Lo-Man Immunity

Flow cytometry imaging identifies rare TH2 cells expressing thymic stromal lymphopoietin receptor in a “proallergic” milieu Amanda J. Reefer, MS, Kathryn.

Vitamin D supplementation during pregnancy: Effect on the neonatal immune system in a randomized controlled trial Eve Hornsby, PhD, Paul E. Pfeffer,

In situ Delivery of Tumor Antigen– and Adjuvant-Loaded Liposomes Boosts Antigen- Specific T-Cell Responses by Human Dermal Dendritic Cells Martine A.

IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte- derived dendritic cell differentiation through histone hypoacetylation

IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation Regina K. Rowe, MD, PhD, David M. Pyle, MD,

Frank Kirstein, PhD, Natalie E

Ramses Ilarraza, PhD, Yingqi Wu, Christopher D

Volume 40, Issue 6, Pages (June 2014)

Abnormal CD161+ immune cells and retinoic acid receptor–related orphan receptor γt– mediate enhanced IL-17F expression in the setting of genetic hypertension

Targeting Toll-like receptors on dendritic cells modifies the TH2 response to peanut allergens in vitro Pierre Pochard, PhD, Brian Vickery, MD, M. Cecilia.

Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1–dependent.

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease Kirandeep.

Type 3 innate lymphoid cells induce proliferation of CD94+ natural killer cells Shuo Li, PhD, Hideaki Morita, MD, PhD, Beate Rückert, Sci Tec, Tadech.

Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand Junyan Han, PhD, Azzeddine.

Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL- 23 receptor signaling and IL-17A production in patients with severe.

Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells Jean-Pierre Allam, MD, Wen-Ming Peng, MSc, Torsten Appel,

Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1–dependent.

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses Melissa Y. Tjota, BA, Cara L. Hrusch, PhD, Kelly.

Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells.

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease Kirandeep.

Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia Asuka Honjo, MD, Nobuhiro Nakano, PhD, Susumu.

Human dendritic cell subset 4 (DC4) correlates to a subset of CD14dim/−CD16++ monocytes Federica Calzetti, BS, Nicola Tamassia, PhD, Alessandra Micheletti,

Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation

Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells Sofi Johansson, MSc, Göran Wennergren, MD, PhD, Nils Åberg,

Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to.

Jovana Maric, MSc, Avinash Ravindran, MSc, Luca Mazzurana, MSc, Åsa K

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells Cathryn A. Weston, PhD, Batika M.J. Rana,

Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1 Stephan M. Caucheteux, John P.

David M. Pyle, BS, Victoria S. Yang, MD, Rebecca S

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype Nicolas Gaudenzio, PhD, Camille Laurent, MD, Salvatore Valitutti,

Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells Zbigniew Zasłona, PhD, Katsuhide.

B-1a and B-1b Cells Exhibit Distinct Developmental Requirements and Have Unique Functional Roles in Innate and Adaptive Immunity to S. pneumoniae Karen.

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth.

Jethe O. F. Nunes, PhD, Juliana de Souza Apostolico, MSc, David A. G

Defective B-cell memory in patients with Down syndrome

Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor Kathryn E. Hulse, PhD, Amanda J. Reefer,

Karin E. de Visser, Lidiya V. Korets, Lisa M. Coussens Cancer Cell

Chronic cat allergen exposure induces a TH2 cell–dependent IgG4 response related to low sensitization Amedee Renand, PhD, Luis D. Archila, MSc, John.

Role of hyaluronan and hyaluronan-binding proteins in human asthma

Volume 13, Issue 12, Pages (December 2015)

Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells Zbigniew Zasłona, PhD, Katsuhide.

Role of B cells in TH cell responses in a mouse model of asthma

Volume 29, Issue 6, Pages (December 2008)

Jill A. Poole, MD, Neil E. Alexis, PhD, Conrad Parks, BS, Amy K

Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie.

Lung dendritic cells are stimulated by ultrafine particles and play a key role in particle adjuvant activity Colin de Haar, PhD, Mirjam Kool, BSc, Ine.

The relative contribution of IL-4 and IL-13 to human IgE synthesis induced by activated CD4+ or CD8+ T cells Juha Punnonen, MD, PhD, Hans Yssel, PhD,

Yilin Qi, MSc, Darwin J. Operario, PhD, Christopher M

Volume 33, Issue 4, Pages (October 2010)

Staphylococcal enterotoxin A–activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation Wei-ping Zeng,

Xin-Zi Tang, PhD, James B. Jung, BS, Christopher D.C. Allen, PhD

Antigen-specific and nonspecific determinants of cytokine production during topical sensitization of mice to chemical allergens Artin Moussavi, PhDa,

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells Véronique Schulten, PhD, Victoria Tripple, BSc, Grégory Seumois,

Inhibition of human allergic T-cell responses by IL-10–treated dendritic cells: Differences from hydrocortisone-treated dendritic cells Iris Bellinghausen,

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Ozone activates pulmonary dendritic cells and promotes allergic sensitization through a Toll-like receptor 4–dependent mechanism John W. Hollingsworth,

Ovalbumin-specific IgE modulates ovalbumin-specific T-cell response after repetitive oral antigen administration Nemuko Omata, MD, Yusei Ohshima, MD,

Julie Negri, BA, S. Brandon Early, BA, John W

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis Jennifer K. Mulligan, PhD, Whitney Nagel,

Human newborn B cells mount an interferon-α/β receptor-dependent humoral response to respiratory syncytial virus Jop Jans, MD, Matthew Pettengill, PhD,

Ramses Ilarraza, PhD, Yingqi Wu, Christopher D

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Presentation transcript:

Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses David J. Dowling, PhD, Evan A. Scott, PhD, Annette Scheid, MD, Ilana Bergelson, BSc, Sweta Joshi, PhD, Carlo Pietrasanta, MD, Spencer Brightman, BA, Guzman Sanchez-Schmitz, MSc, PhD, Simon D. Van Haren, PhD, Jana Ninković, PhD, Dina Kats, BSc, Cristiana Guiducci, PhD, Alexandre de Titta, PhD, Daniel K. Bonner, PhD, Sachiko Hirosue, PhD, Melody A. Swartz, PhD, Jeffrey A. Hubbell, PhD, Ofer Levy, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 5, Pages 1339-1350 (November 2017) DOI: 10.1016/j.jaci.2016.12.985 Copyright © 2017 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 1 Polymersomes preferentially associate with DCs in vivo. A, Cryogenic transmission electron microscopy revealed the self-assembly of approximately 50-nm filomicelles (F; left, PEG45-bl-PPS44), approximately 120-nm vesicular polymersomes (PS; middle, PEG17-bl-PPS30), or approximately 30-nm spherical micelles (M; right, PEG44-bl-PPS29). B, Flow cytometric analysis of single-cell suspensions from mouse lymph nodes and spleens was conducted 24 hours after subcutaneous injection of fluorescent nanocarriers into the footpad (n = 5-8). A heat map demonstrates percentages of key phagocyte populations that associated with PEG-bl-PPS filomicelles (F), vesicular polymersomes (PS), and spherical micelles (M). Amine-functionalized PEG17-bl-PPS30 block copolymers were conjugated to fluorescent Dy647-N-hydroxysuccinimide and assembled in the presence of block copolymers engineered to generate filamentous, vesicular, or spherical morphologies. See also Fig E1. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Synthesis, loading, and characterization of CL075-PS. A, Left, Size exclusion chromatography with Sepharose CL-6B resin and a PBS mobile phase indicated there was no free CL075 present after purification of the CL075-loaded polymersomes. The green line indicates a strong peak for the polymersomes, which elute very early, without a second peak for CL075 (dashed blue line). Data are plotted against blank unloaded polymersomes, demonstrating the location of the polymer (purple line). Right, CL075 dissolved readily in the solvent dimethylformamide, as did the PEG-PPS block copolymer used to assemble polymersomes. CL075-PS was lyophilized so that both the polymer and adjuvant were completely dissolved in the dimethylformamide. Both free (dashed blue line) and loaded CL075 (green line) eluted at approximately 14.48 minutes. B, Graphic depiction of the CL075-PS nanoparticles. See also Figs E2-E4. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 3 The TLR8 agonist CL075 retains robust TNF-inducing activity toward human newborn and adult MoDCs when encapsulated in polymersome nanoparticles. Human newborn (A) and adult (B) MoDCs were cultured in 10% (vol/vol) autologous plasma and stimulated for 24 hours with fixed concentrations of monophosphoryl lipid A (MPLA) or LPS (100 ng/mL) or increasing concentrations of free CL075 (dashed blue line), CL075-PS (green line), or CL075:Gag-PS (red line; mean ± SEM, n = 8-14). For analyses of individual treatments (eg, control RPMI vs 10 μmol/L CL075), the unpaired Mann-Whitney test was applied at each concentration, and statistical significance was denoted as follows: *P < .05, **P < .01, and ***P < .001. For comparisons between newborn and adult TLR4 agonist–treated conditions (ie, newborn LPS vs adult LPS), significance was denoted as follows: +P < .05 and ++P < .01. See also Fig E6. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 4 CL075-PS induces a robust MoDC activation profile similar to that of BCG and distinct from that of alum-adjuvanted subunit vaccines. A and B, Newborn (Fig 4, A) and adult (Fig 4, B) MoDCs were cultured in 10% (vol/vol) autologous plasma and stimulated for 24 hours with fixed concentrations of monophosphoryl lipid A (MPLA; 100 ng/mL), CL075, CL075-PS (both 0.1, 1, 5, and 10 μmol/L), alum (5, 50, and 500 μg/mL), BCG, PCV13, or HBV (each at 1:1000, 1:100, and 1:10 vol/vol). Surface expression of costimulatory molecules and HLA was determined by using flow cytometry and analyzed as fold change in mean fluorescent intensity (MFI) versus vehicle control (mean ± SEM, n = 5-8). C, Neither polymersomes (PS), CL075, nor CL075-PS induced cell death. Undetectable LDH levels are indicated by a circle with a diagonal line through it. D, PGE2 production, as measured by means of ELISA, benchmarked to adjuvants and licensed pediatric vaccines (mean ± SEM, n = 6). See also Figs E7 and E8 and Table E1. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 5 TLR8 agonist–encapsulating polymersomes match or exceed BCG's cytokine-inducing activity, dramatically enhancing human neonatal and adult MoDC IL-12p70 production. Newborn (A and C) and adult (B and D) MoDCs were cultured in 10% (vol/vol) autologous plasma and stimulated for 24 hours with increasing concentrations of CL075:Gag-PS (red; 1, 5, and 10 μmol/L), BCG (blue), PCV13 (purple), HBV (green; each at 1:1000, 1:100, and 1:10 vol/vol), or alum (5, 50, 500 and μg/mL; orange). Concentration-dependent cytokine production induction was measured in supernatants by using the multiplex assay. Data represent fold change over vehicle control (black; mean ± SEM, n = 6). For analyses of individual treatments (eg, control 10 μmol/L CL075:Gag-PS vs BCG 1:10 [vol/vol]), the unpaired Mann-Whitney test was applied at each concentration, and statistical significance was denoted as follows: **P < .01. For comparisons between overall groups (eg, CL075:Gag-PS vs BCG), significance was denoted as follows: ++P < .01. See also Figs E9 and E10. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig 6 CL075:Ag85Bp25-PS and BCG induce comparable Ag85B-specific CD4+ effector T cells in the spleens of neonatal huTLR8Tg mice. A, Experimental design: 7-day-old huTLR8Tg and matched littermate WT mice were immunized subcutaneously and killed 14 days later before harvesting spleens and staining splenocytes with a control versus Ag85B280–294 MHCII tetramer and for surface marker expression. B, Representative flow cytometric plots showing Tet+ T cells as CD44+ Neg Tet+ or CD44+ Ag85B Tet+ cells gated on live CD4+ splenic lymphocytes of BCG- or CL075-Ag85Bp25-PS–vaccinated mice 2 weeks after immunization. C and D, Similar to BCG, CL075-Ag85Bp25-PS induced a significant increase in CD44+ Ag85B Tet+ cells compared with CD44+ Neg Tet+ cells. Results represent means ± SEMs (n = 14-15), with significance relative to unspecific control tetramer. E, Neonatal humanized TLR8 mice have greater numbers of splenic Ag85B-specific CD4+ T cells versus their WT littermates. The unpaired Mann-Whitney test was applied, and statistical significance was denoted as follows: **P < .01 and ***P < .001. NS, Not significant. Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E10 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E11 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E12 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions

Fig E13 Journal of Allergy and Clinical Immunology 2017 140, 1339-1350DOI: (10.1016/j.jaci.2016.12.985) Copyright © 2017 The Authors Terms and Conditions