Analysis of immune response induction mechanisms implicating the dose-sparing effect of transcutaneous immunization using a self-dissolving microneedle patch.

Transcutaneous immunization (TCI) is an effective vaccination method that is easier and less painful than the conventional injectable vaccination method. We previously developed self-dissolving microneedle patches (sdMN) and demonstrated that this TCI method has a high vaccination efficacy in mice and humans. To elucidate the mechanism of immune response induction, which is the basis for the efficacy and safety of TCI with sdMN, we examined the local reaction of the skin where sdMN was applied and the kinetics and differentiation status of immune cells in the draining lymph nodes (DLNs). We found that gene expression of the proinflammatory cytokine Il1b and the downstream transcription factor Irf7 was markedly upregulated in skin tissues after sdMN application. Moreover, activation of Langerhans cells and CD207- dermal dendritic cells, which are subsets of antigen-presenting cells (APCs) in the skin, and their migration to the DLNs were promoted. Furthermore, the activated APC subsets promoted CD4+ T cell and B cell differentiation and the formation of germinal centers, which are the sites of high-affinity antibody production. These phenomena associated with sdMN application may contribute to the efficient production of antigen-specific antibodies after TCI using sdMN. These findings provide essential information regarding immune response induction mechanisms for the development and improvement of TCI preparations.

Characteristics of immune induction by transcutaneous vaccination using dissolving microneedle patches in mice.

Transcutaneous immunization (TCI) is an appealing vaccination method. Compared with conventional injectable immunization, TCI is easier and less painful. We previously developed a dissolving microneedle (MN) patch and demonstrated that TCI using MN patches demonstrates high vaccination efficacy without adverse events in humans. In this study, we investigated the immune induction mechanism of TCI using our MN patch, focusing on inflammatory responses in the skin and on the dynamics, activation, and differentiation of various immunocompetent cells in draining lymph nodes (dLNs). We demonstrate that inflammatory cytokines such as IL-6 and TNF-α increased in the skin at an early stage after MN patch application, inducing the infiltration of macrophages and neutrophils and promoting the activation and migration of skin-resident antigen-presenting cells (Langerhans and Langerin- dermal dendritic cells) to dLNs. Moreover, the activated antigen-presenting cells reaching the dLNs enhanced the differentiation of T (Teff, Tem, and Tcm) and B (plasma and memory) cells. This may contribute to the efficient antigen-specific antibody production induced by TCI using MN patches. We believe that our findings reveal a part of the immune induction mechanism by TCI and provide useful information for the development and improvement of TCI formulations based on the immune induction mechanism.