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Functionalized cationic carbon nanotubes are able to form a stable complex with CpG ODN based on charge interaction and to increase the immunostimulatory activity of CpG motifs.

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Outer membrane protein A (OmpA) is a class of bacterial cell wall protein that is immunogenic without adjuvant. As specific immune responses are initiated in the lymph nodes (LN), we analyzed the effect of the OmpA from Klebsiella pneumoniae (KpOmpA) on chemokine/ chemokine receptor expression by APC and on cell migration to the LN. Upon contact with KpOmpA, human immature DC and macrophages acquire CCR7 expression and responsiveness to CCL21. In parallel, CCR1 and CCR5 expression is down-regulated and CXCL8, CCL2, CCL3 and CCL5 production is up-regulated. Mice injected subcutaneously with KpOmpA present a transient inflammatory reaction at the site of injection accompanied by an enlargement of the draining LN with a higher proportion of DC and macrophages. Lastly, when exposed to KpOmpA prior injection, DC but not macrophages migrate to the draining LN. In conclusion, KpOmpA confers a migratory phenotype to DC and triggers their migration to the regional LN. This property contributes to explain how innate cells initiate adaptive immune response upon recognition of conserved bacterial components and also why OmpA is immunogenic in the absence of adjuvant.

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 ...

Purpose: E75, a peptide derived from the Her2/neu protein, is the most clinically advanced vaccine approach against breast cancer. In this study, we aimed to optimize the E75 vaccine using a delivery vector targeting dendritic cells, the B-subunit of Shiga toxin (STxB), and to assess the role of various parameters (Her2/neu expression, combination with trastuzumab) in the efficacy of this cancer vaccine in a relevant preclinical model.Experimental Design: We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8 þ T cells, and the impact of the vaccine on murine HLA-A2 tumors expressing low or high levels of Her2/neu. Results: STxB-E75 synergized with granulocyte macrophage colony-stimulating factors and CpG and proved to be more efficient than the free E75 peptide in the induction of multifunctional and high-avidity E75-specific anti-CD8 þ T cells resulting in a potent tumor protection in HLA-A2 transgenic mice. High expression of HER2/neu inhibited the expression of HLA-class I molecules, leading to a poor recognition of human or murine tumors by E75-specific cytotoxic CD8 þ T cells. In line with these results, STxB-E75 preferentially inhibited the growth of HLA-A2 tumors expressing low levels of Her2/neu. Coadministration of anti-Her2/neu mAb potentiated this effect.Conclusions: STxB-E75 vaccine is a potent candidate to be tested in patients with low Her2/neu-expressing tumors. It could also be indicated in patients expressing high levels of Her2/neu and low intratumoral T-cell infiltration to boost the recruitment of T cells-a key parameter in the efficacy of anti-Her2/neu mAb therapy.

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