The impact of nanoparticle ligand density on dendritic-cell targeted vaccines.

Dendritic-cell (DC) targeted antigen delivery systems hold promise for enhancing vaccine efficacy and delivery of therapeutics. However, it is not known how the number and density of targeting ligands on such systems may affect DC function and subsequent T cell response. We modified the surface of biodegradable nanoparticles loaded with antigen with different densities of the mAb to the DC lectin DEC-205 receptor and assessed changes in the cytokine response of DCs and T cells. DEC-205 targeted nanoparticles unexpectedly induced a differential cytokine response that depended on the density of ligands on the surface. Strikingly, nanoparticle surface density of DEC-205 mAb increased the amount of anti-inflammatory, IL-10, produced by DCs and T cells. Boosting mice with DEC-205 targeted OVA-nanoparticles after immunization with an antigen in CFA induced a similar pattern of IL-10 response. The correlation between DC production of IL-10 as a function of the density of anti-DEC-205 is shown to be due to cross-linking of the DEC-205 receptor. Cross-linking also increased DC expression of the scavenger receptor CD36, and blockade of CD36 largely abrogated the IL-10 response. Our studies highlight the importance of target ligand density in the design of vaccine delivery systems.

[1]  Praveen Elamanchili,et al.  Biodegradable Nanoparticle Mediated Antigen Delivery to Human Cord Blood Derived Dendritic Cells for Induction of Primary T Cell Responses , 2003, Journal of drug targeting.

[2]  M. Ritter,et al.  CD205 (DEC-205): A recognition receptor for apoptotic and necrotic self , 2009, Molecular immunology.

[3]  K. Moore,et al.  Scavenger Receptors Class A-I/II and CD36 Are the Principal Receptors Responsible for the Uptake of Modified Low Density Lipoprotein Leading to Lipid Loading in Macrophages* , 2002, The Journal of Biological Chemistry.

[4]  M. Akashi,et al.  Targeting of Antigen to Dendritic Cells with Poly(γ-Glutamic Acid) Nanoparticles Induces Antigen-Specific Humoral and Cellular Immunity1 , 2007, The Journal of Immunology.

[5]  M. Carrington,et al.  DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes , 2007, Proceedings of the National Academy of Sciences.

[6]  Si-Shen Feng,et al.  Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. , 2005, Biomaterials.

[7]  Tana,et al.  pH-Sensitive fusogenic polymer-modified liposomes as a carrier of antigenic proteins for activation of cellular immunity. , 2010, Biomaterials.

[8]  M. Ozkan,et al.  Delivery of a peptide via poly(D,L-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell-stimulatory capacity. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[9]  K. Moore,et al.  A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid* , 2002, The Journal of Biological Chemistry.

[10]  Richard A Flavell,et al.  Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. , 2009, Vaccine.

[11]  T. Fahmy,et al.  A comprehensive platform for ex vivo T-cell expansion based on biodegradable polymeric artificial antigen-presenting cells. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  R. Steinman,et al.  Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor , 1992, The Journal of experimental medicine.

[13]  R. Steinman,et al.  Intensified and protective CD4+ T cell immunity in mice with anti–dendritic cell HIV gag fusion antibody vaccine , 2006, The Journal of experimental medicine.

[14]  R. Steinman,et al.  Dendritic cells: translating innate to adaptive immunity. , 2006, Current topics in microbiology and immunology.

[15]  R. Steinman,et al.  The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells. , 2008, The Journal of clinical investigation.

[16]  Sai T Reddy,et al.  Targeting dendritic cells with biomaterials: developing the next generation of vaccines. , 2006, Trends in immunology.

[17]  P. Allavena,et al.  Cross-Linking of the Mannose Receptor on Monocyte-Derived Dendritic Cells Activates an Anti-Inflammatory Immunosuppressive Program 1 , 2003, The Journal of Immunology.

[18]  R. Steinman,et al.  Cutting Edge: Langerin/CD207 Receptor on Dendritic Cells Mediates Efficient Antigen Presentation on MHC I and II Products In Vivo1 , 2008, The Journal of Immunology.

[19]  Joseph Schlessinger,et al.  Signal transduction by receptors with tyrosine kinase activity , 1990, Cell.

[20]  R. Steinman,et al.  Taking dendritic cells into medicine , 2007, Nature.

[21]  V. Apostolopoulos,et al.  Delivery of DNA vaccines: an overview on the use of biodegradable polymeric and magnetic nanoparticles. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[22]  A. Alshamsan,et al.  Co-delivery of cancer-associated antigen and Toll-like receptor 4 ligand in PLGA nanoparticles induces potent CD8+ T cell-mediated anti-tumor immunity. , 2008, Vaccine.

[23]  J. Tschopp,et al.  Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome , 2009, Proceedings of the National Academy of Sciences.

[24]  R. Steinman,et al.  The Dendritic Cell Receptor for Endocytosis, Dec-205, Can Recycle and Enhance Antigen Presentation via Major Histocompatibility Complex Class II–Positive Lysosomal Compartments , 2000, The Journal of cell biology.

[25]  Todd G. Smith,et al.  CD36 and malaria: friends or foes? , 2003, Trends in parasitology.

[26]  Jason K. Pontrello,et al.  Activating B cell signaling with defined multivalent ligands. , 2007, ACS chemical biology.

[27]  L. Quintanilla‐Martinez,et al.  Polylactide-Coglycolide Microspheres CoEncapsulating Recombinant Tandem Prion Protein with CpG-Oligonucleotide Break Self-Tolerance to Prion Protein in Wild-Type Mice and Induce CD4 and CD8 T Cell Responses1 , 2007, The Journal of Immunology.

[28]  P. Fong,et al.  PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. , 2009, Nanomedicine : nanotechnology, biology, and medicine.

[29]  Jason E Gestwicki,et al.  Influencing receptor-ligand binding mechanisms with multivalent ligand architecture. , 2002, Journal of the American Chemical Society.

[30]  H. Merkle,et al.  Hydrophilic poly(DL-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[31]  P. Guermonprez,et al.  Selection of an Antibody Library Identifies a Pathway to Induce Immunity by Targeting CD36 on Steady-State CD8α+ Dendritic Cells1 , 2008, The Journal of Immunology.

[32]  J L Pedraz,et al.  Size dependent immune response after subcutaneous, oral and intranasal administration of BSA loaded nanospheres. , 2002, Vaccine.

[33]  M. Braunstein,et al.  Poly (Lactide-co-Glycolide) Microspheres in Respirable Sizes Enhance an In Vitro T Cell Response to Recombinant Mycobacterium tuberculosis Antigen 85B , 2007, Pharmaceutical Research.

[34]  K. S. Jones.  Biomaterials as vaccine adjuvants , 2008, Biotechnology progress.

[35]  Xiaojing Ma,et al.  Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. , 2007, Immunity.

[36]  S. Vyas,et al.  Strong systemic and mucosal immune responses to surface-modified PLGA microspheres containing recombinant hepatitis B antigen administered intranasally. , 2006, Vaccine.

[37]  D. Prabakaran,et al.  Development of a single‐dose stabilized poly(d,l‐lactic‐co‐glycolic acid) microspheres‐based vaccine against hepatitis B , 2004, The Journal of pharmacy and pharmacology.

[38]  C. C. Harness,et al.  Surface modification of biodegradable polyesters with fatty acid conjugates for improved drug targeting. , 2005, Biomaterials.

[39]  Roy L. Silverstein,et al.  CD36 and atherosclerosis , 2000, Current opinion in lipidology.

[40]  Indu Bala,et al.  PLGA nanoparticles in drug delivery: the state of the art. , 2004, Critical reviews in therapeutic drug carrier systems.

[41]  B. Frisch,et al.  Influence of ligand valency on the targeting of immature human dendritic cells by mannosylated liposomes. , 2008, Bioconjugate chemistry.

[42]  T. Nagai,et al.  Pharmaceutical and immunological evaluation of a single-dose hepatitis B vaccine using PLGA microspheres. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[43]  N. Shastri,et al.  In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[45]  E. Fikrig,et al.  TLR9-Targeted Biodegradable Nanoparticles as Immunization Vectors Protect against West Nile Encephalitis , 2010, The Journal of Immunology.

[46]  C. Figdor,et al.  Targeting antigens to dendritic cells in vivo. , 2006, Immunobiology.

[47]  I. Mellman,et al.  Design opportunities for actively targeted nanoparticle vaccines. , 2008, Nanomedicine.

[48]  H. Junginger,et al.  Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[49]  Kapil Khatri,et al.  M-cell targeted biodegradable PLGA nanoparticles for oral immunization against hepatitis B , 2007, Journal of drug targeting.

[50]  R. Steinman,et al.  Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses. , 2008, Blood.

[51]  K. Moore,et al.  A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. , 2002, The Journal of biological chemistry.

[52]  Adam Byron,et al.  Proteomic Analysis of Integrin-Associated Complexes Identifies RCC2 as a Dual Regulator of Rac1 and Arf6 , 2009, Science Signaling.

[53]  S. Hamdy,et al.  “Pathogen-Mimicking” Nanoparticles for Vaccine Delivery to Dendritic Cells , 2007, Journal of immunotherapy.

[54]  R. Silverstein,et al.  CD36, a Scavenger Receptor Involved in Immunity, Metabolism, Angiogenesis, and Behavior , 2009, Science Signaling.

[55]  G. Borchard,et al.  Stimulation of human macrophages (THP-1) using Toll-like receptor-2 (TLR-2) agonist decorated nanocarriers , 2009, Journal of drug targeting.

[56]  R. Steinman,et al.  In Vivo Targeting of Antigens to Maturing Dendritic Cells via the DEC-205 Receptor Improves T Cell Vaccination , 2004, The Journal of experimental medicine.

[57]  T. Sparwasser,et al.  Targeting glycan modified OVA to murine DC-SIGN transgenic dendritic cells enhances MHC class I and II presentation. , 2009, Molecular immunology.