Transcutaneous immunization with a novel imiquimod nanoemulsion induces superior T cell responses and virus protection. Issue 3 (September 2017)

• Record Type: Journal Article
• Authors: Lopez, Pamela Aranda; Denny, Mark; Hartmann, Ann-Kathrin; Alflen, Astrid; Probst, Hans Christian; von Stebut, Esther; Tenzer, Stefan; Schild, Hansjörg; Stassen, Michael; Langguth, Peter; Radsak, Markus P.
• Is Part Of: Journal of dermatological science. Volume 87:Issue 3(2017:Sep.)
• Page Start: 252
• Page End: 259
• Publication Date: 2017-09
• Subjects: APC antigen presenting cell -- CCR CC chemokine receptor -- CTL cytotoxic T lymphocyte -- HLPC high performance liquid chromatography -- IFN interferon -- IL-1R interleukin 1 receptor -- IMI-Sol imiquimod solid nanoemulsions -- LCMV lymphocytic choriomeningitis virus -- MyD88 myeloid differentiation factor 88 -- OVA chicken ovalbumin -- SALT skin associated lymphatic tissue -- TCI transcutaneous immunization -- TLR toll-like receptor; Transcutaneous immunization -- Imiquimod -- Nanoemulsions -- T cell epitopes -- Lymphocytic choriomeningitis virus; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2017.06.012
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Transcutaneous immunization with the imiquimod formulation IMI-Sol induces superior responses in CD8 and CD 4 positive T-cells. T-cell activation upon transcutaneous immunization with IMI-Sol is MyD88/TLR7 and CCR7 dependent, but IL-1R independent. Transcutaneous immunization with IMI-Sol mediates enhanced protection in a LCMV infection model. Abstract: Background: Transcutaneous immunization (TCI) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. TCI using a cytotoxic T lymphocyte (CTL) epitope and the Toll-like receptor 7 (TLR7) agonist imiquimod mounts strong CTL responses by activation and maturation of skin-derived dendritic cells (DCs) and their migration to lymph nodes. However, TCI based on the commercial formulation Aldara only induces transient CTL responses that needs further improvement for the induction of durable therapeutic immune responses. Objective: Therefore we aimed to develop a novel imiquimod solid nanoemulsion (IMI-Sol) for TCI with superior vaccination properties suited to induce high quality T cell responses for enhanced protection against infections. Methods: TCI was performed by applying a MHC class I or II restricted epitope along with IMI-Sol or Aldara (each containing 5% Imiquimod) on the shaved dorsum of C57BL/6, IL-1R, Myd88, Tlr7 or Ccr7 deficient mice. T cell responses as well as DC migration upon TCI were subsequently analyzed by flow cytometry. To determine in vivo efficacy of TCI induced immune responses, CTL responses and frequency of peptide specific T cells were evaluated on day 8 or 35 post vaccination and protection in a lymphocytic choriomeningitis virus (LCMV) infection model was assessed. Results: TCI with the imiquimod formulation IMI-Sol displayed equal skin penetration of imiquimod compared to Aldara, but elicited superior CD8 + as well as CD4 + T cell responses. The induction of T-cell responses induced by IMI-Sol TCI was dependent on the TLR7/MyD88 pathway and independent of IL-1R. IMI-Sol TCI activated skin-derived DCs in skin-draining lymph nodes more efficiently compared to Aldara leading to enhanced protection in a LCMV infection model. Conclusion: Our data demonstrate that IMI-Sol TCI can overcome current limitations of previous imiquimod based TCI approaches opening new perspectives for transcutaneous vaccination strategies and allowing the use of this enhanced cutaneous drug-delivery system to be tailored for the improved prevention and treatment of infectious diseases and cancers.