Polymeric hepatitis C virus non-structural protein 5A nanocapsules induce intrahepatic antigen-specific immune responses.
Targeting antigen combined with adjuvants to hepatic antigen-presenting cells (APCs) is essential for the induction of intrahepatic T cellular immunity controlling and resolving viral infections of the liver. Intravenous injection of antigen-loaded nanoparticles is a promising approach for the delivery of antigens to liver APCs. Accordingly, polymeric nanocapsules (NCs) synthesized exclusively of hepatitis C virus non-structural protein 5A (NS5A) and the adjuvant monophosphoryl lipid A (MPLA) adsorbed to the nanocapsule surface were developed. Aim of the present study was the evaluation of the in vitro and in vivo behavior of MPLA-functionalized NS5A-NCs regarding the interaction with liver dendritic cells (DCs) and the potential to induce intrahepatic immune responses in a mouse model. Maturation of DCs was significantly increased by application of NS5A+MPLA-NCs compared to non-functionalized NS5A-NCs promoting a vigorous expression of CD40, CD80, CD86 and a strong secretion of the Th1-related cytokine IL-12. NS5A-NCs were preferentially deposited in DCs and Kupffer cells residing in the liver after intravenous administration. Immunization with NS5A-NCs induced intrahepatic antigen-specific CD4(+) T cellular immune responses determined by the secretion of IFNγ and IL-2. Furthermore, supplementation with MPLA induced significant levels of NS5A-specific antibodies. The application of polymeric nanocapsules synthesized exclusively out of antigen avoids the risk of unintended side effects caused by additional carrier substances. Functionalization with adjuvants like MPLA and the efficient targeting to liver-resident APCs inherits the potential for application of antigen nanocapsules in further vaccination approaches against pathogens affecting the liver.
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Michael
M
Fichter
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
Keti
K
Piradashvili
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Anette
A
Pietrzak-Nguyen
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Leah
L
Pretsch
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany; Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Gabor
G
Kuhn
III. Department of Internal Medicine, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Susanne
S
Strand
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany; Children's Hospital, Dr. Horst-Schmidt-Kliniken, Ludwig-Erhard-Str. 100, 65199, Wiesbaden, Germany.
Markus
M
Knuf
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Fred
F
Zepp
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
Frederik R
FR
Wurm
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany; Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Volker
V
Mailänder
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
Katharina
K
Landfester
Children's Hospital, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany. Electronic address: stephan.gehring@uni-mainz.de.
Stephan
S
Gehring
D000818:Animals; D016207:Cytokines / Q000276:immunology; D005260:Female; D006526:Hepatitis C / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007114:Immunization / Q000379:methods; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D011108:Polymers; D017361:Viral Nonstructural Proteins / Q000008:administration & dosage* / Q000276:immunology*; D012324:RNA-Dependent RNA Polymerase
D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008050:Lipid A; D053769:Nanocapsules; D011108:Polymers; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C048436:monophosphoryl lipid A
HCV NS5A; Immunization; MPLA; Nanocapsules; Vaccination