Changes in Human Langerhans Cells Following Intradermal Injection of Influenza Virus-Like Particle Vaccines

Abstract

There is a significant gap in our fundamental understanding of early morphological and migratory changes in human Langerhans cells (LCs) in response to vaccine stimulation. As the vast majority of LCs studies are conducted in small animal models, substantial interspecies variation in skin architecture and immunity must be considered when extrapolating the results to humans. This study aims to determine whether excised human skin, maintained viable in organ culture, provides a useful human model for measuring and understanding early immune response to intradermally delivered vaccine candidates. Excised human breast skin was maintained viable in air-liquid-interface organ culture. This model was used for the first time to show morphological changes in human LCs stimulated with influenza virus-like particle (VLP) vaccines delivered via intradermal injection. Immunohistochemistry of epidermal sheets and skin sections showed that LCs in VLP treated skin lost their typical dendritic morphology. The cells were more dispersed throughout the epidermis, often in close proximity to the basement membrane, and appeared vertically elongated. Our data provides for increased understanding of the complex morphological, spatial and temporal changes that occur to permit LC migration through the densely packed keratinocytes of the epidermis following exposure to vaccine. Significantly, the data not only supports previous animal data but also provides new and essential evidence of host response to this vaccination strategy in the real human skin environment.

Intradermal Immunization Triggers Epidermal Langerhans Cell Mobilization Required for CD8 T-Cell Immune Responses

“…A report by Pearton et al (2010) also demonstrates morphological changes of LCs in human skin explants after the dermal injection of virus-like particles. We have, however, noted differences in the kinetics of LC modifications between the two studies.…”

“…Quantitative parameters for LCs morphology and density in skin tissues have been chosen according to the literature ( (Pearton et al, 2010, skin LCs, or (Gervaz et al, 1995). …”

Macrophage- and Neutrophil-Derived TNF-α Instructs Skin Langerhans Cells To Prime Antiviral Immune Responses

“…injection of R848 or poly(I:C) induces the activation/maturation of LCs and their migration out of the skin in vivo. Studies in mice and with human skin have shown that LC activation was triggered by exposure to allergens (33), virus-like particles (34) or imiquimod (35). However, human LCs do not produce TLR7 or TLR8 mRNA (27) and do not respond directly to TLR7/8-Ls (26).…”

Immunogenicity of intramuscular MF59-adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: A literature review

“…21,22 These DCs favor rapid capture and movement of antigen via lymphatic vessels to lymph nodes, thus facilitating lymph node T and B cells activation/expansion and induction of antigen-specific humoral and cellular immunity. 21,23,24 Antigens can also drain into the lymph nodes with no involvement of peripheral tissue DCs and be captured by lymph node resident DCs from skin migratory DCs, with subsequent priming of na€ ıve T cells. 25 Clearly, the immune response induced by intradermal antigen delivery is generated by a mechanism which markedly differs from that of the intramuscular route.…”