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.
Highlights
Intradermal (ID) delivery of vaccines has been shown to induce protective immunity against many diseases, including hepatitis B [1,2], rabies [3], tuberculosis [4], measles [5], polio [6] and influenza [7,8]
On excision and subsequent culture of human skin, Langerhans cells (LCs) will inevitably begin to migrate from the epidermis due to physical and chemical changes in the tissue resulting in the propagation of migratory signals [15,31,36]
This non-antigen mediated depletion in LCs numbers in epidermal sheets is apparent in untreated human skin samples (Figure 2B) and as such represents the baseline against which LCs changes in skin samples in response to injected vaccine can be measured
Summary
Intradermal (ID) delivery of vaccines has been shown to induce protective immunity against many diseases, including hepatitis B [1,2], rabies [3], tuberculosis [4], measles [5], polio [6] and influenza [7,8]. ID vaccination aims to exploit the abundance of antigen presenting cells (APCs) found within the skin; that is dermal dendritic cells (DDCs) in the dermis and LCs in the epidermis. Both these cell types have the ability to uptake, process and present both self- and foreign antigens to naıve T-cells [9] following migration to the lymphatics, and have the potential to elicit an adaptive immune response [10]. LC activation and migration has been shown to depend on differing levels of cytokines and chemokines produced by the LCs themselves and the surrounding keratinocytes. The ultimate destination of actively migrating LCs is the paracortical regions of lymphatic nodes where presentation of peripherally acquired antigen to naıve T-cells occurs [13]
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