UV Exposure Boosts Transcutaneous Immunization and Improves Tumor Immunity: Cytotoxic T-Cell Priming through the Skin

Stein, Pamela; Rechtsteiner, Gerd; Warger, Tobias; Bopp, Tobias; Fuhr, Thorsten; Prüfer, Steve; Probst, Hans Christian; Stassen, Michael; Langguth, Peter; Schild, Hansjörg; Radsak, Markus P.

doi:10.1038/jid.2010.254

Cited by 25 publications

(37 citation statements)

References 31 publications

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“…Surprisingly, DT treatment had no significant impact on EPI when using CT as adjuvant (Fig. 3A), suggesting that neither LC or CD103 + DC are required for the epicutaneous adjuvant effects of CT, in contrast with previous studies using different EPI approaches (26,27). We therefore sought to extend our analysis to other DC subsets.…”

Section: Epicutaneous Vaccination Using Cpg and Cholera Toxin As Adjumentioning

confidence: 56%

“…Also, in contrast to earlier reports (7-9, 26, 27), we observed minimal adjuvanticity of the TLR7 agonist imiquimod. These discrepancies may, at least in part, relate to the minimal skin pretreatment we used, because several previous studies employed extensive tape stripping (6,8,26,27) and Animals were immunized using sequential administration of free-OVA peptide, followed by either normal (column 3) or enzymatically inactive CT (CTmut) (column 4). Alternatively, mice were immunized by a single application of OVA peptide-tagged CT (column 5) or CTmut (column 6).…”

Section: Discussionmentioning

confidence: 99%

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Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination

Olvera-Gómez

Hamilton

Xiao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The ability to induce humoral and cellular immunity via antigen delivery through the unbroken skin (epicutaneous immunization, EPI) has immediate relevance for vaccine development. However, it is unclear which adjuvants induce protective memory CD8 T-cell responses by this route, and the molecular and cellular requirements for priming through intact skin are not defined. We report that cholera toxin (CT) is superior to other adjuvants in its ability to prime memory CD8 T cells that control bacterial and viral challenges. Epicutaneous immunization with CT does not require engagement of classic toll-like receptor (TLR) and inflammasome pathways and, surprisingly, is independent of skin langerin-expressing cells (including Langerhans cells). However, CT adjuvanticity required type-I IFN sensitivity, participation of a Batf3-dependent dendritic cell (DC) population and engagement of CT with suitable gangliosides. Chemoenzymatic generation of CT-antigen fusion proteins led to efficient priming of the CD8 T-cell responses, paving the way for development of this immunization strategy as a therapeutic option. M ost current vaccination methods involve intramuscular or intradermal injection of antigen with suitable adjuvants. However, this approach produces biohazardous needle waste, requires trained personnel for its implementation, and evokes needle phobia, a significant complication that reduces compliance (1). Transdermal or epicutaneous immunization (EPI) strategies aim to avoid these concerns through application of antigen and adjuvants to the unbroken skin. This approach yields both antibody and T-cell responses, including priming of CD8 T cells (2-5). However, little is known about the capacity of EPI to prime memory CD8 T cells capable of protection against pathogen challenge, nor do we understand how adjuvants operate when applied to the intact skin.Several adjuvants can induce CD8 T-cell priming through EPI. These include toll-like receptor (TLR) agonists such as imiquimod and CpG (6-9), but also the ADP ribosylating bacterial exotoxins such as cholera toxin (CT) and the closely related Escherichia coli heat-labile enterotoxin (LT) (10-12). Application of such toxins to the skin is safe and effective in priming humoral and cellular responses in both mice and humans (4, 10, 13-15). However, previous studies failed to define which adjuvants afford optimal priming of CD8 T-cell responses and durable protective memory. Furthermore, whereas TLR pathways are well characterized, the basis for adjuvanticity of bacterial exotoxins remains mysterious.Here we compared multiple adjuvants for epicutaneous priming and found that CT was superior in effective induction of CD8 T-cell responses, resulting in protective immunity against pathogen challenge. We find that CT-mediated adjuvanticity occurs in the absence of typical TLR and inflammasome signaling pathways and that langerin-expressing cells (including Langerhans cells) are dispensable for EPI using CT. The adjuvant properties of CT were, however, dependent on host sensi...

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Section: Epicutaneous Vaccination Using Cpg and Cholera Toxin As Adjumentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination

Olvera-Gómez

Hamilton

Xiao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…As a commercial product it is already in use as an immunomodulator for the treatment of human papillomavirus (HPV) infections [100]. Although imiquimod can be administered cutaneously alone it showed a superior activation of the immune system when combined with anti-CD40 ligands or UV light [96,99].…”

Section: Adjuvants For Cutaneous Vaccinationmentioning

confidence: 99%

“…Moreover, poly I:C additionally provides a Th1/Th2-balanced humoral immunity [97]. Imiquimod has until now mainly been studied with the focus on tumor immunity [96,99]. As a commercial product it is already in use as an immunomodulator for the treatment of human papillomavirus (HPV) infections [100].…”

Section: Adjuvants For Cutaneous Vaccinationmentioning

confidence: 99%

Recent insights into cutaneous immunization: How to vaccinate via the skin

Engelke

Winter

Hook

et al. 2015

Vaccine

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“…This is a priority issue conceded by the WHO based on the medical and socioeconomic consequences of needle injuries [3], [4]. From an immunological point of view the skin is an attractive target for shaping immune responses: the delivery of antigens is controlled and specifically targeted to skin resident APC [5] in direct conjunction with an adjuvant eliciting potent adaptive immune responses as pioneered by Glenn and coworkers [6]. While parenteral (subcutaneous or intramuscular) vaccine delivery systems are not as well controlled in terms of drug release and targeting of specific immune organs, the drug dosage and targeting to the skin in transcutaneous approaches can be more easily and specifically achieved, e. g. by specific modifications of the vaccine as recently demonstrated for a nanoparticle-formulated DNA vaccine [7].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Imiquimod-Based Transcutaneous Immunization Using a Nano-Dispersed Emulsion Gel Formulation

et al. 2014

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BackgroundTranscutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. However, the feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity.Methodology/Principal FindingsTo overcome these obstacles, we developed an imiquimod-containing emulsion gel (IMI-Gel) and characterized it in comparison to Aldara for rheological properties and in vitro mouse skin permeation in a Franz diffusion cell system. Imiquimod was readily released from Aldara, while IMI-Gel showed markedly decreased drug release. Nevertheless, comparing vaccination potency of Aldara or IMI-Gel-based TCI in C57BL/6 mice against the model cytotoxic T-lymphocyte epitope SIINFEKL, we found that IMI-Gel was equally effective in terms of the frequency of peptide-specific T-cells and in vivo cytolytic activity. Importantly, transcutaneous delivery of IMI-Gel for vaccination was clearly superior to the subcutaneous or oral route of administration. Finally, IMI-Gel based TCI was at least equally effective compared to Aldara-based TCI in rejection of established SIINFEKL-expressing E.G7 tumors in a therapeutic setup indicated by enhanced tumor rejection and survival.Conclusion/SignificanceIn summary, we developed a novel imiquimod formulation with feasible pharmaceutical properties and immunological efficacy that fosters the rational design of a next generation transcutaneous vaccination platform suitable for the treatment of cancer or persistent virus infections.

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UV Exposure Boosts Transcutaneous Immunization and Improves Tumor Immunity: Cytotoxic T-Cell Priming through the Skin

Cited by 25 publications

References 31 publications

Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination

Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination

Recent insights into cutaneous immunization: How to vaccinate via the skin

Efficacy of Imiquimod-Based Transcutaneous Immunization Using a Nano-Dispersed Emulsion Gel Formulation

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