The high accessibility of the skin and the presence of immunocompetent cells in the epidermis makes this surface an attractive route for needle-free administration of vaccines. However, the lining of the skin by the stratum corneum is a major obstacle to vaccine delivery. In this study we examined the effect of skin barrier disruption on the immune responses to the cross-reacting material CRM 197 , a nontoxic mutant of diphtheria toxin (DTx) that is considered as a vaccine candidate. Application of CRM 197 , together with cholera toxin (CT), onto the tape-stripped skin of mice elicited antibody responses that had anti-DTx neutralizing activity. Vaccine delivery onto mildly ablated skin or intact skin did not elicit any detectable anti-CRM 197 antibodies. Mice immunized with CRM 197 alone onto the tape-stripped skin mounted a vigorous antigen-specific proliferative response. In contrast, the induction of cellular immunity after CRM 197 deposition onto mildly ablated or intact skin was adjuvant dependent. Furthermore, epidermal cells were activated and underwent apoptosis that was more pronounced when the stratum corneum was removed by tape stripping. Overall, these findings highlight the potential for transcutaneous delivery of CRM 197 and establish a correlation between the degree of barrier disruption and levels of antigen-specific immune responses. Moreover, these results provide the first evidence that the development of a transcutaneous immunization strategy for diphtheria, based on simple and practical methods to disrupt the skin barrier, is feasible.The high accessibility of the skin and the presence of immunocompetent cells in the epidermis make this surface an attractive route for needle-free administration of vaccines (7,9,17). However, the lining of the skin by the stratum corneum is a major obstacle to vaccine delivery. Advances in drug delivery have created new opportunities to successfully breach the skin barrier using devices that work with one or both of the following two methods: change of the skin's physical environment and application of a driving force (18). A common characteristic of all of these methods is the disruption to a various degree (depending on the method) of the skin barrier. After this damage, the skin immune system senses dangerous signals, and Langerhans cells (LCs) and keratinocytes are activated to protect the body, repair the barrier and reestablish the epidermal homeostasis (16,23). Disruption of the skin barrier also increases the percutaneous penetration of antigens that access more easily the LCs that reside at the basal layer of the epidermis. LCs play a sentinel role in the epidermis and initiate immune responses by presenting antigens to T lymphocytes at the regional lymph nodes (4).Since the skin provides an attractive interface for simple, practical, and injection-free delivery of vaccines in the present study we sought to examine the immunogenicity of the crossreacting material CRM 197 , a nontoxic mutant of diphtheria toxin (DTx) after application onto the intact ...
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